NUTRITION and DIABETES Pathophysiology and Management
NUTRITION and DIABETES Pathophysiology and Management Edited by
EMMANUEL OPARA
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Foreword Diabetes mellitus is increasing in frequency worldwide; there is even talk of its reaching epidemic proportions. No one doubts that this has something to do with changes in diet and methods of food preparation — but exactly what and how is disputed, sometimes quite acrimoniously. The dispute is not new, however, and has been raging ever since Thomas Willis wrote in 1697, “diabetes was so rare among the ancients that many famous physicians made no mention of it and Galen knew only two sick of it. But in our age given to good fellowship and gushing down chiefly unalloyed wine, we meet with examples and instances enough, I may say daily, of this disease.” He clearly implicated changes in eating habits and lifestyle in what he perceived was an increasing incidence of what we would now call type 2 diabetes. So, what is new? Is it the ease of making a diagnosis and changing the diagnostic criteria, and our increasing awareness of it, ageing of the population, changes in lifestyle, especially as regards exercise and the availability of plentiful food, or, as seems increasingly likely, a combination of all of them? The increasing incidence of diabetes is not confined to any particular country or to either of the two common types of illness, which, though sharing a final common path, have such different origins. The rate of increase is faster in older people, with presumed type 2, than in children and adolescents with presumed type 1 diabetes, as was already apparent from epidemiological studies of the incidence of diabetes in New York as long as 80 years ago. The increase in diabetes is, at least in part, attributable to an even more rapid increase in the prevalence of obesity. Nevertheless there is a well-established increase in the incidence of type 1 diabetes along with that of many other autoimmune diseases and it is almost certainly associated with changes in the environment and eating habits, but not with obesity. The special role of nutrition in the management of diabetes was recognized long before the era of modern scientific medicine, but it is only within the past century that it has been firmly linked to pathogenesis. Differentiation of diabetes into two main and many subordinate types is comparatively recent, and, while suspected on clinical grounds, was only established, like so many advances in medical knowledge, by major changes in technology. Some of these, such as the use of respiratory quotients to unravel the complexities of metabolism in health and disease, have almost vanished undeservedly from the investigative armamentarium. Others, such as molecular genetics, have still to fulfill their potential. Meanwhile, diabetologists and nutritionists must depend upon advances made possible by the application of nutritional biochemistry, epidemiology, and laboratory medicine, most notably in the measurement of hormones and neurotransmitters by immunoassay, to improve their understanding and management of this increasingly important syndrome.
This book examines all aspects of the relationship between nutritional status and the pathogenesis, diagnosis, and treatment of patients with the various illnesses that manifest themselves as diabetes. It will be of especial value to medical practitioners and dieticians giving day-to-day care to the growing number of patients at both ends of the age spectrum, as well as to those in the middle. Epidemiologists and directors of public health policy will also find in it much to interest them, as will laboratory scientists concerned with unraveling the complex interactions between us and our food. The seminal discovery that diabetes, referred to by Willis as the pissing disease because of its most prominent symptom, was associated with an abnormality of sugar metabolism led many early investigators to direct their attention to carbohydrates in the diet to the exclusion of other constituents. This has gradually, but still not completely, changed with recognition that most types of diabetes are but one manifestation of a more general disturbance of metabolism in which fats, and, to a lesser extent, proteins, are equally or more profoundly affected. The rediscovery of the endocrine role of the gastrointestinal tract in determining the fate and disposal of ingested food has been complemented, in more recent times, by recognition of the role of the gut in regulating appetite through its ability to release neurotransmitters such as Ghrelin and peptide PPY. Together, these make the plea, constantly heard from the obese in the past, that their condition was “all due to my gland’s doctor” no longer dismissible as complete nonsense. Important as endocrine factors are in the pathogenesis of diabetes, it is impossible to deny the role of genetic, environmental, sociological, and even commercial factors in its genesis. The relevance of antenatal, and possibly prenatal, nutrition of the child’s mother in determining its metabolic fate and later development of obesity, hypertension, and other features of the metabolic syndrome was highlighted by the epidemiological studies of David Barker, who painstakingly scrutinized the obstetric records of large cohorts of patients and their appropriate controls in the United Kingdom (U.K.). His conclusions have subsequently been confirmed by Nick Hales in experiments on laboratory animals, and explain, at least in part, the observed worldwide increase in the metabolic syndrome and all its manifestations, including type 2 diabetes. Incrimination of specific items of diet — notably refined sugars, including highfructose corn syrups and saturated fats — especially when combined in what are disparagingly described as junk foods — and by more temperate commentators as energy-dense foods — is even more contentious today than it was more than half a century ago. So, too, is the importance of the glycemic index, which, though relevant to individual foods, rarely applies to mixed meals. The importance of dietary fiber in determining the bioavailability of absorbable carbohydrates in the diet is undeniable, but whether this is due to their chemical or physical characteristics, or a combination of both, is a moot point, as are generalizations drawn from selected geographical epidemiological studies. Difference in the glycemic index of foods depends as much upon their physical form — whole versus ground brown rice, for example — as upon their chemical composition and brings into question much of the value of what is often described as nutritional labeling. Methods of food preparation and storage that alter the nature
and amount of protein glycated prior to ingestion, though long recognized as important by food scientists, has received scant attention from diabetologists and nutritionists in the past. This may be expected to change with the demonstration that ingested, glycated proteins have a detrimental effect upon the body akin to that produced by glycation in vivo and which is held to be responsible for many of the adverse effects of chronic hyperglycemia. It is impossible to overemphasize the importance of micronutrients in the pathogenesis of disease. This has been recognized ever since the link between vitamin C deficiency and scurvy was first established more than two centuries ago. Nevertheless, despite many claims made for them, evidence that incriminates micronutrients in the pathogenesis of the common forms of diabetes and for their use in prevention and treatment is far from clear. None of them yet has a definite role. Meanwhile, other nonessential constituents of the diet, such as coffee and alcoholic drinks, that have attracted opprobrium or downright condemnation by those seeking to demonstrate a link between their habitual consumption and the pathogenesis of diabetes have undergone radical revision or reversal. Large-scale, prospective epidemiological studies have revealed, contrary to expectations, their possibly beneficial rather than detrimental effect when used appropriately within the diet. How much this is due to their antioxidant content and how much to their pharmacologically active constituents is unsettled, but illustrates the importance of establishing a firm data base before proffering nutritional advice, which has been all too rare in the past. There clearly is no simple, one-stop solution to the role of nutrition in general, and of food and drink in particular, in the pathogenesis of diabetes and obesity — as many politicians and their nutritionist gurus would have us believe. Science is the growth of knowledge based upon evidence, and readers will find within the pages that follow the evidence upon which to base answers to many of the questions posed by the rising incidence of diabetes and obesity in the modern world. They will, more importantly, also find pointers to gaps in our knowledge and areas of ignorance that have hitherto been glossed over, ignored, or just not considered, but which will, in all probability, yield to further investigation. Vincent Marks Emeritus Professor of Clinical Biochemistry University of Surrey Guildford, Surrey, U.K.
Preface Diabetes and obesity are two common disorders that have come to be appropriately recognized as enormous burdens both to the afflicted individuals, their countries, and the modern society in general. What is most striking is the relationship between obesity and impaired glucose regulation that predominantly results in overt diabetes. Consequently, as the incidence of obesity has risen in virtually every population, so has the prevalence of type 2 diabetes. Perhaps more alarming is the trend of increased incidence of obesity and type 2 diabetes among children. When one considers that both disorders are by nature chronic and tend to be associated with a host of complications, it becomes quite obvious how they can become the bane of today’s world. The purpose of Nutrition and Diabetes: Pathophysiology and Management is to provide a unique forum that highlights the link between the problems of obesity and diabetes, albeit various aspects of each disorder are separately discussed in different sections of the book. However, the interrelationships of the various areas of the disease processes become quite apparent in the many overlaps among the contents of many topics covered in this book. Enormous efforts have been made by the different contributors in each section of the book to first provide an overview of each topic, then discuss the mechanistic aspects of the given problem, and to finally link the pathophysiological processes to the treatment. The book is divided into three sections: Pathophysiology and Treatment of Obesity; Pathophysiology and Treatment of Diabetes; and The Role of Oxidative Stress in the Pathogenesis and Treatment of Diabetic Complications. Each section begins with an introduction. Nutrition and Diabetes: Pathophysiology and Management is intended to be a reference handbook for physicians, nutritionists, and other health-care workers who deal daily with the various problems associated with obesity and diabetes. Researchers who need to see the gaps that still need to be filled in our understanding of the disease processes, as well as strategies for drug development for effective management of the problems, will find the book to be of significant interest. The book should also be of significant interest to public-policy makers involved in formulating health policies, especially in developing countries. Finally, by reading this book, individual subjects afflicted with either obesity or diabetes or both would learn a lot about how to help themselves and about understanding the basis of the treatment provided by their health-care team. I would like to express my sincere gratitude to a lot of people who have helped in my career in different ways. First, I would like to thank all my former teachers, particularly Professor Vincent Marks and John E. Gerich, M.D., who inspired in me the love of metabolic and diabetes research at the University of Surrey and the Mayo Clinic, respectively. I am also greatly indebted to Vay Liang W. Go, M.D., presently of the University of California Los Angeles, for giving me the opportunity to work
with him at the National Institutes of Health, Bethesda, Maryland, and for his continued mentorship in my academic career. Secondly, I would like to express my gratitude to all my former students and fellows at Duke University, Durham, North Carolina, who have helped to shape my career by making seminal contributions to my research. Some of these former trainees of mine, such as Dr. Marc Garfinkel, director of islet transplantation at the University of Chicago, and Dr. William Kendall of the Duke University Medical Center, who are now among my best friends, deserve special mention. I am also particularly grateful to another one, Marcus Darrabie, currently a medical student at Duke, who helped with the illustrations used in my chapters in this book. Finally, I would like to acknowledge the great patience, personal sacrifice, and unqualified support of my wife, Clarice, and our four children, Ogechi, Chiedu, Chucky, and Ike. I am eternally grateful to them for giving me the luxury of extended periods of time away from home in my career and during the preparation of this book. I wish to dedicate this book to my parents, Eugene and Caroline (deceased), for their sacrifices in providing me a most rewarding education that prepared me for an academic career and for their love and support for what I do.
Editor Emmanuel C. Opara, Ph.D., is a research professor and co-director, Engineering Center for Diabetes Research and Education at the Pritzker Institute of Medical Engineering, Illinois Institute of Technology, Chicago, and a senior investigator at the University of Chicago Human Islet Transplant Program. He was previously a member of faculty of the Duke University School of Medicine in Durham, North Carolina (1988–03), a visiting fellow at the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health, Bethesda, Maryland (1986–88), and a World Health Organization (WHO) Fellow in endocrinology/metabolism at the Mayo Clinic, Rochester, Minnesota (1984–86). Dr. Opara’s main research focus is diabetes, and he has worked in many areas of diabetes research for more than 20 years. Currently, he is mainly working on developing a bioartificial pancreas using the approach of islet cell microencapsulation. He also studies the role of oxidative stress in the pathogenesis and progression of diabetes and digestive disease. His other research interests include the role of nutritional factors in the etiology and management of diabetes. He has about 200 publications of original articles, abstracts reviews, and book chapters on these subjects. Dr. Opara is a member of many professional organizations, including: American Diabetes Association, American Federation for Medical Research, American Pancreatic Association, American Gastroenterological Association, Society for Black Academic Surgeons, Transplantation Society, and International Pancreas and Islet Transplantation Association.
Contributors Tan Attila, M.D. Division of Gastroenterology & Hepatology Medical College of Wisconsin Milwaukee, Wisconsin Connie W. Bales, Ph.D., R.D. Center for Aging Duke University Medical Center Durham, North Carolina Jarol Boan, M.D., M.P.H. Associate Professor of Medicine Penn State College of Medicine Hershey Medical Center Hershey, Pennsylvania Ali Cinar, Ph.D. Department of Chemical Environmental Engineering Illinois Institute of Technology Chicago, Illinois Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Department of Medicine & General Clinical Research Center The University of Tennessee Health Science Center Memphis, Tennessee G. Lynis Dohm, Ph.D. Departments of Physiology, Internal Medicine, and Pediatrics East Carolina University Greenville, North Carolina
Fateh Entabi, M.D. Department of Surgery Massachusetts General Hospital Boston, MA Mark N. Feinglos, M.D., C.M. Division of Endocrinology, Metabolism, and Nutrition Department of Medicine Duke University Durham, North Carolina Michael Freemark, M.D. Division of Pediatric Endocrinology and Diabetes Duke University Medical Center Durham, North Carolina Leonid E. Fridlyand, Ph.D. Department of Medicine University of Chicago Chicago, Illinois Roger Harms, M.D. Department of Obstetrics & Gynecology Mayo Clinic Rochester, Minnesota Robert D. Hoeldtke, M.D., Ph.D. Department of Medicine West Virginia University School of Medicine Morgantown, West Virginia
Alexander J. Kaminsky, M.D. University of Michigan Department of Neurology Ann Arbor Veterans Administrative Medical Center Ann Arbor, Michigan William F. Kendall, Jr., M.D. Department of Surgery Duke University Medical Center Durham, North Carolina Timothy R. Koch, M.D. Washington Hospital Center Section of Gastroenterology Washington, D.C. William E. Kraus, M.D. Division of Cardiology Department of Medicine Duke University Medical Center Durham, North Carolina Lillian F. Lien, M.D. Division of Endocrinology, Metabolism, and Nutrition Department of Medicine Duke University Durham, North Carolina Jean Claude Mbanya, M.D., M. Phil., Ph.D. Endocrine and Diabetes Unit Development of Internal Medicine & Specialties Faculty of Medicine and Biomedical Sciences University of Yaoundé 1 Yaoundé, Cameroon Ross L. McMahon, M.D., F.R.C.S.C., FACS Weight Loss Surgery Center Duke University Medical Center Durham, North Carolina
Linda M. Morgan, Ph.D. School of Biomedical and Molecular Sciences University of Surrey Guildford, United Kingdom Emmanuel C. Opara, Ph.D. Pritzker Institute of Biomedical Science & Engineering Illinois Institute of Technology Chicago, Illinois Louis H. Philipson, M.D., Ph.D. Department of Medicine University of Chicago Chicago, Illinois Jama L. Purser, P.T., Ph.D. Center for Aging Duke University Medical Center Durham, North Carolina James W. Russell, M.D., M.S., F.R.C.P. Department of Neurology University of Michigan Ann Arbor Veterans Administrative Medical Center Ann Arbor, Michigan Cris A. Slentz, Ph.D. Division of Cardiology Department of Medicine Duke University Medical Center Durham, North Carolina Eugene Sobngwi, M.D., M. Phil., Ph.D. Department of Endocrinology and Diabetes and Clinical Investigation Centre Saint-Louis University Paris, France
John P. Thyfault, Ph.D. Department of Physiology Brody School of Medicine East Carolina University Greenville, North Carolina Michael T. Watkins, M.D. Harvard Medical School Massachusetts General Hospital Division of Vascular Surgery Boston, MA
Carlton J. Young, M.D. University of Alabama Birmingham, AL
Table of Contents SECTION I
Pathophysiology and Treatment of Obesity
Introduction................................................................................................................3 Chapter 1 Neuroendocrine Regulation of Food Intake..............................................................5 Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Chapter 2 The Enteroinsular Axis ............................................................................................27 Linda M. Morgan, Ph.D. Chapter 3 Achieving a Healthy Body Weight: Diet and Exercise Interventions for Type 2 Diabetes .................................................................................................43 Connie W. Bales, Ph.D., R.D., and Jama L. Purser, P.T., Ph.D. Chapter 4 Metabolic Syndrome: Recognition, Etiology, and Physical Fitness as a Component............................................................................................................57 William E. Kraus, M.D. and Cris A. Slentz, Ph.D. Chapter 5 Metabolic Alterations in Muscle Associated with Obesity ....................................79 John P. Thyfault, Ph.D. and G. Lynis Dohm, Ph.D. Chapter 6 Nonsurgical Management of Obesity......................................................................99 Jarol Boan, M.D., M.P.H. Chapter 7 Bariatric Surgery for Obesity ................................................................................111 Ross L. McMahon, M.D., F.R.C.S.C., FACS
Chapter 8 Postoperative Management of the Bariatric-Surgery Patient................................125 Jarol Boan, M.D., M.P.H.
SECTION II
Pathophysiology and Treatment of Diabetes
Introduction............................................................................................................137 Chapter 9 Epidemiology, Risks, and Health-Care Expenditures for Diabetes and Its Complications ...................................................................................................139 William F. Kendall, Jr., M.D. Chapter 10 Nutrient Interactions and Glucose Homeostasis ...................................................161 Emmanuel C. Opara, Ph.D. Chapter 11 Type 2 Diabetes in Childhood: Diagnosis, Pathogenesis, Prevention, and Treatment ........................................................................................................177 Michael Freemark, M.D. Chapter 12 Management of Obesity-Associated Type 2 Diabetes ..........................................205 Lillian F. Lien, M.D., and Mark N. Feinglos, M.D., C.M. Chapter 13 Management of Type 2 Diabetes in Underrepresented Minorities in the U.S. ..................................................................................................................227 Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P. Chapter 14 Management of Diabetes in Developing Countries..............................................249 Jean Claude Mbanya, M.D., M. Phil., Ph.D. and Eugene Sobngwi, M.D., M. Phil., Ph.D. Chapter 15 Diabetes in Pregnancy ...........................................................................................267 Roger Harms, M.D.
Chapter 16 Web-Based Simulations for Dynamic Variations in Blood-Glucose Concentration of Patients with Type 1 Diabetes ..................................................281 Ali Cinar, Ph.D.
SECTION III
The Role of Oxidative Stress in the Pathogenesis and Treatment of Diabetes and Its Complications
Introduction............................................................................................................301 Chapter 17 The Nutrient Paradox: Oxidative Stress in Pancreatic β-Cells ............................303 Leonid E. Fridlyand, Ph.D. and Louis H. Philipson, M.D., Ph.D. Chapter 18 Oxidative Stress in Type 1 Diabetes: A Clinical Perspective...............................319 Robert D. Hoeldtke, M.D., Ph.D. Chapter 19 Oxidative Stress and Glycemic Control in Type 2 Diabetes................................345 Emmanuel C. Opara, Ph.D. Chapter 20 Oxidative Stress and Vascular Complications of Diabetes Mellitus ....................361 Fateh Entabi, M.D. and Michael T. Watkins, M.D. Chapter 21 Oxidative Injury in Diabetic Neuropathy..............................................................381 James W. Russell, M.D., M.Sc. and Alexander J. Kaminsky, M.D. Chapter 22 Diabetic Nephropathy............................................................................................399 Carlton J. Young, M.D. Chapter 23 Pathophysiology and Management of Diabetic Gastropathy ...............................427 Tan Attila, M.D. and Timothy R. Koch, M.D. Index ......................................................................................................................449
Section I Pathophysiology and Treatment of Obesity
Introduction For more than two decades, there has been an exponential increase in the incidence of obesity around the world. This trend has been more apparent in the United States of America where the incidence of obesity in adults has more than doubled over that period. With this uncontrolled rise in obesity has been a concomitant increase in the diseases associated with obesity, such as type 2 diabetes, hypertension, and cardiovascular disease. It is perhaps more disturbing to note that over this same period, there has even been a higher increase in the prevalence of obesity in the American pediatric community. Not surprisingly, we have also seen an unprecedented increase in the number of diagnosed cases of type 2 diabetes in children and adolescents. It is therefore most timely to have different aspects of this problem addressed by reputable experts who routinely deal with it. Thus, this section is focused on the disease obesity, which is defined as an excess of body fat, which increases body weight beyond physical and skeletal requirements. It is well-established that a delicate balance between energy intake and expenditure is required to maintain a healthy body weight. Certainly, the amount of energy intake depends both on the quantity and quality of food consumed. On the other hand, energy expenditure is critically dependent upon the basal metabolic rate, the thermic effect of food, and mandatory and volitional physical activity. Although many factors affect food consumption, it is very clear that appetite and satiety, which are regulated by neuroendocrine factors, play a key role, as is efficiently reviewed in this section. The role of the factors released from the canal through which food is consumed and processed, prior to utilization by various tissues, is also important in regulating the fate of the nutrients. Obviously, obesity is the result of an imbalance between food intake and disposal, and it is a consequence of the failure of one or more factors involved in any of the two processes. Once a primary cause of the failure is recognized, it is required that appropriate steps first be taken to try and correct the problem. In most cases, returning an overweight individual to normal weight through reversal of the failed processes of maintaining a normal body weight does not achieve the desired objective by conventional treatment, and extraordinary measures, such as surgery, become unavoidable, as outlined in this section. Unfortunately, adoption of a drastic procedure to treat obesity, such as surgery, comes at price to the patient. There are also key issues required in routine management of such patients. These issues and the other chronic complications of obesity, such as the metabolic syndrome, insulin resistance, and type 2 diabetes, are also addressed in this section.
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1
Neuroendocrine Regulation of Food Intake Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P.
CONTENTS I. Introduction....................................................................................................6 II. Appetite and Satiety ......................................................................................6 III. Central Nervous System Localization of Feeding Control...........................7 A. Hypothalamus and Brain Stem .............................................................7 IV. Hypothalamic Neuropeptides That Stimulate Food Intake...........................7 A. Neuropeptide Y......................................................................................7 B. Agouti-Related Protein..........................................................................8 C. Hypocretins/Orexins..............................................................................8 V. Anorexigenic Neuropeptides .........................................................................9 A. Melanocortins ........................................................................................9 B. Cocaine- and Amphetamine-Regulated Transcript ...............................9 C. Serotonin..............................................................................................10 VI. Peripheral Signals in the Regulation of Food Intake..................................10 A. Adipocyte-Derived Signals .................................................................11 B. Adipocytokines....................................................................................11 C. Leptin...................................................................................................11 1. Mechanism of Leptin Action ........................................................12 2. Leptin and Insulin Action .............................................................12 3. Exogenous Leptin Therapy for Human Obesity...........................14 VII. Pancreatic Signals........................................................................................14 A. Insulin ..................................................................................................14 B. Pancreatic Polypeptide ........................................................................15 VIII. Gastrointestinal Peptides .............................................................................16 A. Ghrelin.................................................................................................16 B. Peptide YY ..........................................................................................17 C. Glucagon-Like Peptide-1 ....................................................................17 D. Cholecystokinin ...................................................................................18 IX. Conclusions..................................................................................................18 5
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Acknowledgments....................................................................................................19 References................................................................................................................19
I. INTRODUCTION Regulation of energy homeostasis is critical to the survival of any species. Therefore, intricate behavioral, metabolic, and neuroendocrine mechanisms have evolved to integrate energy intake and dissipation. A delicate balance between intake and expenditure of energy is required to maintain healthy weight. Perhaps for teleological reasons, the mechanisms that regulate energy homeostasis are biased in favor of net positive energy and are geared toward defense of weight loss rather than prevention of obesity. Hence, spontaneous weight loss in the absence of disease is rare and the experience of progressive weight gain in free-living humans is common. The adaptations that defend against weight loss eventually become maladaptive when obesity and its related metabolic and cardiovascular complications supervene, as in the present era (1, 2). At its core, obesity signifies chronic disequilibrium between food consumption and energy expenditure. Total energy expenditure (TEE) comprises basal or resting energy expenditure (REE), thermic effect of food (TEF), mandatory physical activities of daily living (ADL), and volitional physical activity or exercise (3). The contributions of TEF and ADL to TEE are rather modest, and the rate of voluntary physical activity is universally low among modern humans, leaving REE the energy-expenditure mode of choice for most people. The REE declines with age, which explains the tendency of positive energy balance and obesity in older persons. The TEE also is correlated positively with body surface area and is higher in obese than lean individuals. However, the REE compensation for obesity is ineffective in inducing weight loss or restoring normal weight. Therefore, REE, the major component of energy expenditure for most sedentary persons, is a practically nonmodifiable factor in energy homeostasis. This leaves restriction of food intake and volitional exercise as the main strategies for effective weight control.
II. APPETITE AND SATIETY The “afferent” limb of the energy homeostasis loop is food consumption. Food intake is driven by appetite and terminated by satiety. Hunger is the physiological response to appetite, whereas meal termination occurs in response to satiety signals. The exact mechanisms controlling the primal instincts of appetite and hunger are not understood precisely. It is known, however, that a host of behavioral, environmental, cognitive, and situational influences can modify responses to hunger. Thus, appetite triggers hunger, but the latter can be overridden or suppressed to enable delay of food intake to a more appropriate time. Similarly, several organic and psychiatric disorders are associated with perturbation of appetite. The present review focuses on the neurohormonal regulation of food intake, and attempts to integrate seminal experimental findings in rodents with current and future directions in human metabolic research and antiobesity drug development.
Neuroendocrine Regulation of Food Intake
7
III. CENTRAL NERVOUS SYSTEM LOCALIZATION OF FEEDING CONTROL A. HYPOTHALAMUS
AND
BRAIN STEM
The hypothalamus integrates diverse signals, including brain neurotransmitters, peripheral neurohumoral afferents, adipocyte-derived signals, gastrointestinal peptides, and other afferent inputs, to regulate energy homeostasis. The arcuate nucleus (ARC) at the base of the hypothalamus expresses receptors for hormones and neuropeptides that regulate feeding. The paraventricular nucleus (PVN) in the anterior hypothalamus, the major site of corticotropin releasing hormone (CRH) and Thyroid Releasing Hormone (TRH) secretion, receives rich projections from the ARC. Thus, the PVN integrates diverse paracrine and endocrine metabolic signals with classical neuroendocrine pathways mediated through the thyroid and hypothalamic-pituitary-adrenal axes. Following ingestion of a meal, vagal afferent projections to the brain stem provide satiety signals (4). Neuronal projections from the nucleus tractus solitarius to the PVN and lateral hypothalamus link the brain stem with the hypothalamus. These projections include GLP-1 and serotoninergic neurons. Studies in decerebrate rats, in which the brain stem and the forebrain are disconnected, show a critical role of the brain stem in control of meal size (5).
IV. HYPOTHALAMIC NEUROPEPTIDES THAT STIMULATE FOOD INTAKE The hypothalamic orexigenic signals include neuropeptide Y (NPY), agouti-related protein (AgRP), and the hypocretins/orexins.
A. NEUROPEPTIDE Y NPY, a 36-amino-acid, COOH-terminally amidated polypeptide first isolated from porcine brain, has structural analogy with peptide YY and pancreatic polypeptide (6). NPY rapidly stimulates food intake following intracerebroventricular (i.c.v.) injection in rodents. The appetite-stimulating effects of NPY lead to sustained hyperphagia and weight gain in mice receiving chronic i.c.v. administration. The specificity of NPY’s effect has been established in studies that employed coadministration NPY antagonists or its antibodies, both of which inhibited food intake in rats (7). The role of NPY as a central physiological trigger of meal initiation is suggested by studies showing a rapid increase in hypothalamic NPY expression in the PVN before meal times and persistence of NPY gene expression throughout the period of enforced hunger. The orexigenic action of NPY is mediated by interaction with Y1 and Y5 receptors (8). Interestingly, NPY expression in the arcuate nucleus is potently antagonized by the anorexigenic hormone leptin. Furthermore, activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Central administration of PYY3-36 (a Y2 receptor agonist secreted by intestinal endocrine L cells) into the
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Nutrition and Diabetes: Pathophysiology and Management
arcuate elicits a marked inhibition of food intake. Also, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (9). Thus, NPY antagonism appears to be a rather promising potential strategy for antiobesity drug development. The location of the median eminence outside the blood-brain barrier suggests that novel compounds that inhibit NPY gene expression, secretion, or interaction with Y1 and Y5 receptors could possibly be delivered to the hypothalamus when administered systemically.
B. AGOUTI-RELATED PROTEIN AgRP is expressed exclusively in the arcuate nucleus of the hypothalamus and colocalizes to the same neurons that secrete NPY (10). Several reports have confirmed the status of AgRP as a potent orexigenic factor: A single i.c.v. injection of AgRP increases food intake for several days in rodents (11). In contrast to the shortlived effect of NPY, chronic treatment with AgRP leads to sustained hyperphagia and obesity (12). The orexigenic effect of AgRP is mediated through antagonism of MC3 and MC4 receptors. Such antagonism effectively reverses the inhibition of food intake induced by alpha-MSH. The arcuate neurones that cosecrete NPY/AgRP are potently inhibited by leptin and insulin, and activated by ghrelin (8, 13).
C. HYPOCRETINS/OREXINS The hypothalamic peptides hypocretin-1 and hypocretin-2 were discovered in 1998 by subtractive polymerase chain reaction (14). In the same year, homologous hypothalamic peptides named orexins 1 and 2 were discovered by Sakurai et al. (15) and were shown to potently stimulate food intake in rats (15). The hypocretins/orexins stimulate food intake in rodents, an effect that is blocked by neutralizing antibodies to endogenous hypocretins (17). In addition to directly stimulating food intake, the hypocretins/orexins may also influence energy homeostasis in other ways. For example, hypocretin levels increase in response to exercise, neuroglycopenia, and enforced wakefulness (16). Hypocretin-secreting neurons localize exclusively to the lateral hypothalamus, the region of the brain long known to integrate appetite signals. Although intriguing as modulators of food intake, interest in the hypocretins/orexins shifted to their role in sleep regulation when the genes for hypocretins/orexins were found to be the loci for narcolepsy (18, 19). Documented mutations in the human hypocretin/orexin genes are rare among patients with sleep disorders, but nearly 90 percent of patients with narcolepsy-cataplexy have subnormal cerebrospinal fluid hypocretin levels (20). The latter finding is inconsistent with a primary orexigenic role of the hypocretins/orexins as the mechanism for the increased prevalence of obesity, insulin resistance, and type 2 diabetes among patients with narcolepsy (Nishino 2001b). These metabolic disorders are more likely the result of the physical hypoactivity associated with narcolepsy. It must be noted, however, that the hypocretin/orexin system functions centrally as the major integrator of excitatory impulses from monoaminergic (dopamine, norepinephrine, serotonin, histamine) and cholinergic fibers that maintain wakefulness and vigilance (21). Thus, besides a direct orexigenic effect, the
Neuroendocrine Regulation of Food Intake
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hypocretins/orexins could exert metabolic effects through modulation of central autonomic outflow. However, the hypocretins/orexins are less attractive candidates for drug development because their reported effects on food intake are less robust and consistent compared with the orexigenic effects of NPY.
V. ANOREXIGENIC NEUROPEPTIDES As a central integrator of energy homeostasis, the hypothalamus also is a source of neuropeptides that inhibit food intake or induce satiety. The hypothalamic anorexigenic agents include the melanocortins, cocaine- and amphetamine-regulated transcript (CART), and serotonin.
A. MELANOCORTINS The melanocortins are derived from site-specific, posttranslational cleavage of the precursor parent molecule proopiomelanocortin (POMC). Cleavage of POMC within the anterior pituitary gives rise to Adrenocorticotrophic hormone (ACTH), which acts through the MC2 receptor to stimulate adrenal steroidogenesis. Elsewhere in the brain, POMC is cleaved to another melanocortin, alpha-MSH, which is an agonist for the MC3 and MC4 receptors. Administration of alpha-MSH (i.c.v.) in rodents results in weight loss through inhibition of food intake and stimulation of energy expenditure (22). These actions are mediated through activation of two neuronal melanocortin receptor subtypes (MC3r and MC4r) and antagonized by an adjacent subset of hypothalamic neurons that express AgRP and NPY. The NPY/AgRP neurons that inhibit MC3r and MC4r are themselves inhibited by leptin and insulin. The integrated physiology of the interactions of these opposing neuropeptides is evident from their weight-related alterations. Following weight loss, the deceasing levels of insulin and leptin lead to activation of NPY/AgRP neurons and inhibition of POMC neurons (23). These counterregulatory changes induce accelerated food intake and accumulation of fat. Defects along the melanocortin signaling pathway, such as those seen in transgenic mice with targeted disruption of the MC4 receptor (knock-outs), result in hyperphagic and massive obesity (24). Recently, fairly widespread functional mutations of the human MC4 receptor have been demonstrated in patients with severe childhood obesity (25) and also linked to binge-eating disorder (26). It should be noted, however, that the majority of obese patients have no demonstrable mutations in MC4, yet such persons may possibly benefit from future therapies targeting activation of MC4 pathways. Indeed, intransal administration of a melanocortin fragment (MSH/ACTH 4-10) looks promising in that regard by inducing modest weight loss (27).
B. COCAINE-
AND
AMPHETAMINE-REGULATED TRANSCRIPT
Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the brain, especially in the hypothalamic nuclei and in the anterior pituitary. Within the arcuate nucleus, POMC colocalizes to neurons that also express CART. Injection of CART (1–100 pmol, i.c.v.) resulted in dose-dependent inhibition of food intake in
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rats. The effect was observed within 20 minutes and lasted approximately four hours. The decrease in food intake following treatment with CART was accompanied by inhibition of gastric emptying and reduction of oxygen consumption. The arcuate POMC/CART neurons act as downstream effectors of the anorexigenic action of leptin and are markedly stimulated by i.c.v. injection of leptin (28). Interactions between CART and the endogenous opioid, serotononergic (29), and cannabinoid (30) systems provide additional mechanisms for the anorexigenic effects of CART.
C. SEROTONIN The amino acid derivative 5-hydroxytryptamine (serotonin, 5-HT) has ubiquitous neurotransmitter functions on numerous central nervous system (CNS) targets (31). Receptors for 5-HT are widely expressed in regions, including the limbic system, Raphe nucleus, and the hypothalamus. Activation of 5-HT receptors (especially the 5-HT2C subtype) is associated with inhibition of food intake. A similar anorexigenic effect is observed following augmentation of serotonin abundance through inhibition of its reuptake. Studies in rodents have shown that deletion of the serotonin 5-HT2C gene results in marked hyperphagia (32). Unfortunately, clinical experience with selective serotonin reuptake inhibitors shows only modest and inconsistent effects on body weight, indicating that the serotoninergic pathway is overridden by more powerful orexigenic impulses under normal physiological conditions. The major central neuropeptides that impact food intake are summarized in Table 1.1.
VI. PERIPHERAL SIGNALS IN THE REGULATION OF FOOD INTAKE The peripheral hormones that regulate food intake include several gastrointestinal, pancreatic, and adipocyte-derived peptides (Table 1.2). Based on extensive studies in rodents and limited human data, these peptides can be classified as having orexigenic (e.g., ghrelin) or anorexigenic (e.g., insulin, peptide YY, glucagon-like polypeptide, cholecystokinin, leptin) effects.
TABLE 1.1 Selected Central Neuropeptides that Modulate of Food Intake Orexigenic
Anorexigenic
Neuropeptide Y Agouti-related protein Orexins a Orexin b
alpha-Melanocyte stimulating hormone Corticotropin-releasing hormone Cocaine-amphetamine regulated transcript Serotonin
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TABLE 1.2 Selected Peripheral Modulators of Food Intake Signal
Main Targets
Anorexigenic Leptin Hypothalamus Peptide YY Hypothalamus Pancreatic polypeptide Hypothalamus Insulin Hypothalamus Cholecystokinin Brain stem/Vagus GLP-1 Local GI/diverse
Ghrelin
Orexigenic Hypothalamus
A. ADIPOCYTE-DERIVED SIGNALS There is a mature and growing literature on the roles of several adipocyte products (including nonesterified fatty acids, adipocytokines, and leptin) in the regulation of metabolic fuel economy, energy balance, glucoregulation, food intake, and body weight. Products such as nonesterified fatty acids have long been proposed as mediators of obesity-associated insulin resistance and glucose dysregulation (33–35), as discussed elsewhere in this book.
B. ADIPOCYTOKINES The adipocytokine TNF-alpha (also known as cachectin, for its association with cachexia or wasting) is a mediator of insulin resistance and is secreted in higher amounts by adipocytes from obese subjects (36–41). Other circulating and adiposederived proinflammatory cytokines also have been implicated in the pathogenesis of obesity-associated insulin resistance and diabetes (42, 43). On the other hand, adiponectin is secreted in abundant amounts by fat cells from insulin-sensitive persons and is deficient in persons with obesity or insulin resistance (44, 45). Thus, numerous adipose tissue products serve as markers, signals, or modulators of energy balance, fuel economy, intermediary metabolism, glucoregulation, and other metabolic events that intersect with food intake and body-weight homeostatsis. Of these numerous adipose tissue products, leptin is perhaps the best characterized in terms of its role in the regulation of food intake and related mechanisms.
C. LEPTIN The positional cloning of the mouse (ob) gene and its human homologue (46) represents a major milestone in obesity research. Two separate mutations of the ob gene result in either a premature stop codon or complete absence of ob mRNA in the ob/ob mouse (46). The resultant absence of a normal ob gene product leads to
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overfeeding, massive obesity, delayed sexual maturation, and immune defects in ob/ob mice. The human ob or lep gene is transcribed and translated into a secreted protein mainly in white adipose tissue, but activity can also be reported in brown adipose tissue and gastric epithelium (47). Circulating leptin levels are increased by feeding, decreased during fasting or following weight loss, and are altered by a variety of hormonal and physiological factors (48, 49). A pedigree with severe childhood obesity associated with deletion of a guanine nucleotide in codon 133 of the human lep gene was the first human example of congenital leptin deficiency to be identified (50). A missense lep mutation in codon 105 has also been identified in a Turkish pedigree (51). Three individuals (two female, one male) homozygous for this mutation have the phenotype of hypoleptinemia, marked hyperphagia, massive obesity, and hypothalamic hypogonadism. Excluding these rare reports, common forms of human obesity do not appear to be caused by discernible lep mutations (52). Treatment with recombinant leptin results in a marked reduction in food intake and profound weight loss in ob/ob mice (53, 54). Leptin therapy also is remarkably effective in correcting obesity in humans with congenital leptin deficiency (55–57). 1. Mechanism of Leptin Action Leptin exerts its effects through interaction with cognate cell membrane receptors (lep-r) (58). One full-length (isoform-b) and several alternatively spliced forms (a, c, d, e, f) of lep-r have been identified in brain and peripheral tissues (59, 60). Lepr is a member of the class 1 cytokine receptor family (61). This receptor family mediates gene transcription via activation of the jak-stat pathway (42). The long isoform lep-r (b), expressed in the hypothalamus, mediates the central effects of leptin; the shorter isoforms are truncated in the cytoplasmic domain, but can bind leptin and probably mediate in some of its peripheral action (62). Leptin-receptor activation results in decreased expression of NPY, thereby inhibiting the powerful orexigenic effects of NPY (63). Leptin’s action to suppress food intake is mediated through an elaborate neuronal circuitory that involves suppression of orexigenic signals (NPY, AgRP, MCH, hypocretins 1 and 2/orexins a and b) and activation of anorexigenic (alpha-MSH, MC4, CRH, CART) neuronal pathways (23). Mutations in the lep-r gene result in obesity and leptin resistance in rodents (64, 65) and humans (66). Adipose tissue lep mRNA (67, 68) and circulating leptin (69) levels are elevated in obese subjects, suggesting that obese persons are not responding optimally to the weight-regulating effects of leptin. The basis of this leptin resistance is unclear, but may be related to impaired blood-to-brain leptin delivery (70) or defects in leptin-receptor signaling, probably mediated by altered expression of the suppressor of the cytokine signaling (socs)-3 gene in leptin-responsive cells (71). 2. Leptin and Insulin Action Replacement doses of recombinant leptin, administered systemically, normalized plasma glucose and insulin levels in hyperglycemic, hyperinsulinemic ob/ob mice
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(54) and leptin-deficient subjects with diabetes and insulin resistance (57). Low doses of leptin administered either i.v. or i.c.v. increased glucose utilization and decreased hepatic glycogen storage in wild-type mice (72). Furthermore, leptin therapy selectively depletes visceral fat stores and stimulates insulin sensitivity in rats (73). These findings indicate that leptin is a naturally occurring insulin sensitizer. Indeed, addition of leptin to cultured human hepatocytes stimulates signaling along the phosphatidyl inositol 3’ kinase pathway, one of the mediators of insulin action (74). Reversal of lipotoxicity may be another mechanism for the insulin-sensitizing effects of leptin (75). There is a marked variability in plasma leptin levels (even among persons of comparable adiposity), at least part of which may relate to differences in insulin sensitivity (48, 76). Basal (fasting) plasma leptin levels are similar in patients with diabetes compared with body mass index (BMI)- and gender-matched nondiabetic subjects (77, 78), but dynamic leptin response to secretagogues is attenuated in patients with diabetes (78, 79) or morbid obesity (80). We have postulated that increased leptin secretory response to food (as well as insulin and glucocorticoids) represents a counterregulatory attempt (48, 49, 81) to limit hyperphagia and weight gain (Figure 1.1). This adaptation may be of physiological relevance, because fasting abolishes the plasma leptin response to glucocorticoids (82, 83). Theoretically, a defect in leptin secretion could permit hyperphagia, promote weight gain, and aggravate insulin resistance. If impaired leptin secretion is confirmed as a general feature of diabetes, such diabetic dysleptinemia would provide a rationale for evaluation of leptin therapy. Indeed, patients with lipodystrophic diabetes and leptin deficiency respond remarkably well (+) NPY(–)
Hypothalamus
(+) (–) FEEDING (Insulin (–) resistance) Gcs (–) (lipolysis)
(+) (–) MEDIATORS
(+) (–) LEPTIN
(Glucose, insulin, PP, etc.)
Adipocyte
FIGURE 1.1 Glucocorticoid-leptin interactions. Glucocorticoids stimulate hypothalamic neuropeptide Y (NPY) expression, which stimulates food intake. Leptin inhibits NPY expression and induces satiety. Local gastrointestinal signals from putative postprandial mediators, such as glucose, insulin, pancreatic polypeptide (PP), Peptide YY (PYY), or other gastrointestinal humors (broken lines) may play a role in satiety, besides the suppressive action of leptin on NPY. Glucocorticoids also stimulate leptin synthesis and secretion, which could counteract the orexigenic effect of NPY. (+, stimulation; –, inhibition). (From Dagogo-Jack, S, Diabet. Rev., 7:23–38, 1999, with permission.)
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to leptin replacement, and often achieve independence from insulin and oral hypoglycemic agents (84). Leptin also potently reduced hepatic steatosis in these patients (84). 3. Exogenous Leptin Therapy for Human Obesity Administration of low physiological doses of recombinant methionyl-human-leptin (0.01-0.04 mg/kg) produced dramatic results in morbidly obese leptin-deficient patients (55–57). Following daily subcutaneous injection of recombinant leptin, significant weight loss was reported within two weeks. The weight loss was maintained at a rate of approximately 1–2 kg per month, without evidence of tachyphylaxis, throughout the period of treatment. Daily food consumption (and food-seeking behavior) decreased within one week of initiation of leptin replacement, and 95 percent of the total weight loss was accounted for by selective body-fat depletion. Basal energy expenditure decreased (due to weight loss), but dynamic energy expenditure increased during leptin treatment, the latter being due to increased physical activity (55). Thus, the major mechanisms of weight-loss following leptin replacement are sustained reduction in caloric intake and stimulation of physical activity. The stimulatory effect of recombinant leptin on physical activity was first noted in ob/ob mice (53, 54) and is probably mediated by activation of the sympathetic nervous system (85). Similar but less dramatic benefits on weight reduction were observed following leptin augmentation in a cohort of 54 lean and 73 obese men and women with normal leptin genotype (as indicated by baseline serum leptin levels > 10 ng/ml) (86). The subjects were randomized to daily self-injection with placebo or different doses (0.01, 0.03, 0.10, or 0.30 mg/kg) of recombinant methionyl human leptin. The mean weight changes at 24 weeks ranged from –0.7 ±5.4 kg for the 0.01 mg/kg dose to –7.1 ± 8.5 kg for the 0.3 mg/kg dose. As in patients with congenital leptin deficiency, loss of fat mass accounted for most of the weight loss following leptin treatment. However, there was a marked heterogeneity in the responses to recombinant leptin among subjects with normal leptin gene. Thus, leptin-deficient patients are exquisitely more sensitive to leptin therapy than patients with common obesity. Nonetheless, augmentation of circulating leptin levels induces variable but significant weight loss in leptin-replete obese subjects. This suggests that leptin resistance may be overcome by exogenous supplementation, similar to the experience with insulin therapy in type 2 diabetes. The currently known metabolic and behavioral effects of leptin are summarized in Table 1.3.
VII. PANCREATIC SIGNALS A. INSULIN Insulin was the first peripheral signal shown to regulate food intake through interaction with central-hypothalamic neurons (87). Protagonists of popular diets have claimed in the lay press that limitation of insulin secretion is the mechanism for hunger control in subjects fed low-carbohydrate, ketotic diets. Yet, the scientific
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TABLE 1.3 Behavioral and Metabolic Effects of Leptin Behavioral Inhibition of food intake (55–57) Stimulation of physical activity (53–55) Body composition Induction of fat-mass loss (55–57) Preservation of lean-muscle mass (55–57) Preservation of bone mass (55–57) Glucoregulation Improvement in insulin sensitivity (54, 57, 72, 84) Improvement in glucose tolerance (54, 57, 84) Visceral Reversal of hepatic steatosis (73, 84)
evidence strongly disputes that claim. Insulin fulfills the role (shared by leptin) of serving as a marker of adipose tissue mass and is secreted in direct proportion to fat mass. Insulin secretion also serves as an acute response to caloric influx: Increased secretion begins within minutes of initiation of feeding, is maintained for the duration of food intake, and returns to basal secretory rate in the postabsorptive period. If insulin were an appetite stimulant (like ghrelin), its secretion would have preceded, not followed, ingestion of food. The timing and pattern of postprandial insulin secretion suggest a role in the regulation of satiety and meal termination. Indeed, direct administration of insulin to the central nervous system suppresses food intake in rodents (88). Since circulating insulin reaches the central nervous system via receptor-mediated transport across the blood-brain barrier, it is possible that peak insulin levels attained during feeding trigger central mechanisms that mediate satiety. Postprandial insulin secretion also is a potent signal for leptin secretion (48). Thus, in addition to a direct effect, insulin could exert anorectic effects via a leptin-mediated mechanism. Paradoxically, diabetic patients treated with exogenous insulin or medications that increase insulin secretion or sensitivity tend to gain weight. Although several mechanisms explain the weight gain during intensive diabetes therapy, additional putative mechanisms include “central” insulin resistance and diabetic dysleptinemia (78–80).
B. PANCREATIC POLYPEPTIDE Pancreatic polypeptide (PP) is secreted by specialized endocrine cells located within the pancreatic islets of Langerhans. Plasma levels of PP increase after meals in proportion to meal size, as well as during insulin-induced hypoglycemia. The increased plasma PP level during insulin-induced hypoglycemia is a marker of cholinergic or parasympathetic activation and may have little bearing on the
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metabolic role of PP under normal physiological conditions. Postprandial PP levels probably add to the physiological satiety-signaling cascade that limits hyperphagia and helps maintain interprandial intervals. In this regard, systemic administration of PP has been shown to reduce food intake in rodents (89). Furthermore, administration of PP in patients with chronic pancreatitis has been shown to improve glucose tolerance (90). Thus, circulating PP levels, though not a major determinant of caloric balance, may be part of the afferent signals that transmit metabolic information to higher centers. However, little mechanistic information is available for the possible anorexigenic action of PP. The related peptides PP, PYY, and NPY bind to G-proteincoupled transmembrane receptors Y1–Y5 that have different affinities for each of the ligands: PP binds to Y4 and Y5 receptor subtypes expressed in the hypothalamus and other tissues (7, 8, 91). Thus, it is possible that circulating PP levels exert their effects through interaction with central receptors in a manner that antagonizes the orexigenic effects of NPY.
VIII. GASTROINTESTINAL PEPTIDES A. GHRELIN The polypeptide ghrelin was initially described and characterized as the endogenous ligand for the growth hormone secretagogue receptor in 1999 (92). The ghrelin molecule contains 28 amino acids and an acyl radical, the latter being essential for biological effect. Ghrelin is synthesized and secreted principally by the oxyntic cells of the stomach, reaches the anterior pituitary via the circulation, and stimulates growth-hormone secretion by the somatotrophs. The nutritional effects of ghrelin became evident when it was shown that central (i.c.v.) administration potently increased food intake in rodents (93). A similar effect on food intake was observed following peripheral (i.v.) injection of ghrelin in rats (93). In humans, intravenous administration of ghrelin stimulates food intake by ~30 percent (94). Interestingly, ghrelin is the only metabotrophic peptide thus far identified that stimulates food intake directly when administered peripherally. Physiological studies have indicated that ghrelin serves as a peripheral signal for hunger and meal initiation: Blood levels increase during fasting, peak sharply just before feeding, and fall rapidly following food intake (95). Prolonged administration of ghrelin in rodents leads to chronic hyperphagia and weight gain, and obese persons typically have high plasma leptin and low ghrelin levels (96). There is a diurnal rhythm in ghrelin secretion, with peak levels in the morning and the nadir at night (95). The mechanism of action of ghrelin involves stimulation of hypothalamic neurons (97) and inhibition of gastric vagal afferent signals (98). Based on the foregoing, it is plausible that ghrelin or its analogues could be candidates for future therapy for primary anorexia as well as the anorexia and cachexia often seen in patients with HIV/AIDS, systemic disorders, and malignant diseases. Conversely, ghrelin antagonism is an attractive idea for drug development for obesity and hyperphagic disorders.
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B. PEPTIDE YY The gut-derived peptideYY (PYY) is a member of a family of structurally related peptides that includes PP and NPY (7, 8, 91). PYY is synthesized by the mucosal endocrine L cells, which are located in the small intestine and large bowel. PYY336 is the major isoform secreted into the circulation (98). Feeding is a major stimulus for the release of PYY, which then serves as an anorectic/satiety signal from the intestinal cells. The potent, anorectic effect of PYY3-36 has been demonstrated in rodent studies involving direct administration of PYY3-36 into the arcuate nucleus. In human volunteers, peripheral administration of PYY3-36 inhibited food intake by 30 percent compared with placebo (99). PYY3-36 appears to exert its anorectic effect through coordinate inhibition of orexigenic NPY neurons and stimulation of POMC neurons in the arcuate nucleus. These molecular changes are observed following peripheral administration of PYY336 (99). High-affinity hypothalamic Y receptors are the target of PYY3-36 action. Activation of the Y2 receptor subtype on NPY neurons triggers inhibitory presynaptic signals. Consonant with this mechanism, Y2 receptor knock-out mice lose their responsiveness to the anorectic effect of PYY3-36 (99). Notably, the NPY neurons in the arcuate nucleus are the central integrating sites for numerous peripheral signals (including leptin, insulin, PYY3-36, and ghrelin) that regulate food intake. Initial experience indicates that PYY3-36 is well tolerated and effective in suppressing appetite over the short term in human studies (100). Clearly, PYY or its analogues hold immense promise as candidates for obesity-drug development.
C. GLUCAGON-LIKE PEPTIDE-1 Glucagon-like peptide-1 (GLP-1) is derived from the precursor molecule preproglucagon. Site-specific cleavage of prepro-glucagon in the pancreas results in glucagon, whereas in the intestinal endocrine L cells the result is GLP-1. Both GLP-1 and PYY are cosecreted by the intestinal L cells in response to the arrival of nutrients in the gut. Like PYY, GLP-1 also appears to serve as a gut-derived satiety signal. Administration of GLP-1 into the cerebral ventricles results in marked inhibition of feeding in rodents (101). GLP-1 often is described as an incretin because of its effect in boosting postprandial insulin secretion. Additional glucoregulatory actions of GLP-1 include suppression of glucagon secretion and prolongation of gastric emptying (102). GLP-1 can induce modest weight loss probably through inhibition of food intake, induction of satiety, and delay in gastric emptying (103). In clinical trials, subcutaneous injection of GLP-1 before each meal in patients with diabetes resulted in improvement in glycemic control without untoward effects (104). Exendin-4, a GLP-1 receptor agonist with longer biological action than GLP1, also is showing promise in clinical trials (105). Endogenous GLP-1 abundance can be augmented by inhibition of dipeptidyl peptidase-4 (DPP4), the enzyme involved in GLP-1 breakdown. Such a strategy using a novel DPP-4 inhibitor (NVP DPP728) has been reported to improve glycemic control in subjects with diabetes (106). Thus, GLP-1 appears to be an intestinal satiety factor with diverse metabolic effects favorable for control of hyperglycemia. Not surprisingly, there are current
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efforts that are focused on developing novel antidiabetic agents based on GLP-1 augmentation, as reviewed elsewhere in the book.
D. CHOLECYSTOKININ Cholecystokinin (CCK) is best known for its role in food digestion, namely stimulation of pancreatic-enzyme secretion and gallbladder contraction. However, CCK has been recognized as a potent satiety factor for more than three decades (107). Peripheral and central mechanisms appear to mediate the anorectic/satiety effects of CCK. Peripherally, activation of CCKA receptors on vagal nerve endings and pyloric sphincter reduces food intake (108). Centrally, interactions between CCK and leptin pathways elicit synergistic anorectic effects; an additional mechanism of action of CCK might also involve activation of brain stem neurons that regulate portion size (8, 109). The effect of peripheral administration of CCK usually is transient and more consistent with a modulatory effect on satiety/meal termination rather than primary inhibition of meal initiation (108, 110). To induce durable inhibition of food intake, high doses and prolonged administration of CCK have been tried, but success has been limited by rapid development of tolerance (111).
IX. CONCLUSIONS An elaborate network of central and peripheral neurohormonal signals has evolved to regulate feeding, one of the primal activities necessary for survival and selfpreservation. Despite decades of animal and human research, the full extent of the processes and humors involved in the regulation of food intake remains to be elucidated. Current understanding indicates that energy homeostasis in health is predicated upon a balance between orexigenic and anorexigenic factors, both centrally and peripherally. Virtually all of the peripheral signals (e.g., insulin, PYY, leptin, CCK) are triggered by food ingestion and attenuated by fasting or starvation, indicating a response system that is tailored at satiety and meal termination. Ghrelin, the only peripheral signal activated preprandially, may be unique in its role as a rare peripheral signal for hunger and meal initiation. The rarity of peripheral hormonal signals that trigger meal initiation may be a reflection of the incompleteness of current understanding. However, a more plausible explanation is that appetite and hunger are under predominantly central control, and are orchestrated by neuronal projections from various brain centers to the NPYexpression arcuate neurons. The central control of feeding is organized into an integrated neuroendocrine system that either stimulates or inhibits food intake. The orexigenic (e.g., NPY, AgRP) and anorexigenic (e.g., melanocortins) components of this system receive afferent neuroendocrine and metabolic signals from the periphery but may also be subject to local and paracrine influences, as well as inputs from higher brain centers. The coordinate regulation of these various opposing mechanisms leads to energy homeostasis that is physiologically skewed toward positive balance. An increased understanding of these mechanisms is a prerequisite for the discovery of drug interventions that can dependably modulate food intake and prevent or treat obesity.
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ACKNOWLEDGMENTS Dr. Dagogo-Jack is supported in part by NIH Clinical Research Center Grant MO1 RR00211.
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The Enteroinsular Axis Linda M. Morgan, Ph.D.
CONTENTS I. Introduction..................................................................................................27 II. The Enteroinsular Axis and Insulin Secretion ............................................28 A. GIP.......................................................................................................28 B. GLP 1 ..................................................................................................30 III. Extrapancreatic Effects of GIP and GLP 1.................................................31 A. GIP — The Obesity Hormone? ..........................................................31 B. GLP 1 — A Spectrum of Antidiabetic Actions..................................33 IV. The Enteroinsular Axis in Diabetes ............................................................33 V. Therapeutic Aspects of GIP and GLP 1 .....................................................34 A. Type 2 Diabetes Mellitus ....................................................................34 B. Obesity.................................................................................................37 VI. Conclusions..................................................................................................37 References................................................................................................................38
I. INTRODUCTION The concept that signals arising from the gut have the ability to affect endocrine responses and the disposal of carbohydrates has a long history that has classically centered around the modulation of insulin secretion. At the turn of the century, Moore tried to treat diabetics with injections of gut extracts, suggesting that “the duodenum does yield a chemical excitant for the internal secretion of the pancreas.” In the 1930s, Heller proposed a duodenal extract that reduced postprandial hyperglycemia, which he named duodenin, but interest in it waned because the active constituent could not be isolated. However, in the 1960s, a series of classical studies [1, 2] demonstrated that the insulin response to oral glucose was up to 50 percent greater than that observed after an IV glucose infusion providing similar glucose levels, and the search was on to isolate the gut factors responsible for this effect. The term enteroinsular axis [3] was coined to embrace all those factors that contributed to enhance insulin secretion after a meal, and the putative gut hormones were called incretins. Many of the gastrointestinal hormones show a large degree of structural homology and can be divided up into distinct families on the basis of similarities in their amino-acid sequences and biological activities. The secretin family forms one such group, and many of its members have the ability to stimulate
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insulin when administered in pharmacological amounts. However, only two hormones, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP 1), have the ability to act as physiological incretins. GIP was isolated from porcine intestine in 1969, and, initially characterized for its ability to inhibit gastric-acid secretion, was named gastric-inhibitory polypeptide. However, it was quickly found to be a potent insulin secretogogue [4, 5] and was renamed glucose-dependent insulinotropic polypeptide (retaining the acronym GIP) to reflect the biological role which was perceived to be the more relevant. GIP alone does not account for the entire incretin effect, as was demonstrated initially by the retention of an incretin effect following GIP immunoneutralization [6] and, subsequently, in studies with GIP receptor antagonists [7]. A second biologically active incretin, GLP 1, was later identified. GLP 1, the product of differential processing of the preproglucagon gene in the gut, is a powerful insulinotropic factor, more powerful, on a molar basis, than GIP [8]. The relative importance of these two hormones in the enteroinsular axis, particularly in diabetes, is a source of continuing debate, [9, 10] but together they account for most, if not the entire, incretin effect.
II. THE ENTEROINSULAR AXIS AND INSULIN SECRETION A. GIP GIP is a 42 amino-acid peptide secreted from specific endocrine cells, the K cells, which have the highest density in the upper part of the small intestine. In man, GIPrelease studies in response to glucose stimulation have confirmed the proximal small intestine to be the major, but not exclusive, site of endogenous GIP release, as small quantities of GIP are also released from the distal small intestine, by cells in which GIP and GLP 1 are colocalized [11]. In addition to carbohydrate, GIP secretion is also stimulated by fat and amino acids [12], though in practice, protein ingestion, per se, is not an important nutritional stimulus for GIP release, as protein is largely absorbed as dipeptides or tripeptides, which do not stimulate release of the hormone (Figure 2.1). Its secretion is dependent upon the absorption of nutrients rather than their mere presence in the gut lumen, and monosaccharide perfusion studies in rats have shown that it is only those sugars actively transported via the SGLT1 transporter that stimulate GIP secretion [13]. Studies in pigs fitted with mesenteric and hepatic portal cannulae have shown that the rate of GIP secretion is proportional to the rate of glucose absorption from the gut [14]. The magnitude of the GIP response increases with the glucose load ingested, thus the contribution of the enteroinsular axis to insulin secretion is proportionately greater when large carbohydrate loads are ingested, or when mixed meals of fat and carbohydrate are consumed. GIP is insulinotropic both in vitro, in isolated islets, or perfused pancreas, and in vivo in both animals and humans, provided that the prevailing circulating glucose concentration is above a threshold of approximately 6 mmol/l [15]. This glucose dependence of GIP provides a safeguard against inappropriate insulin secretion and hypoglycemia as a consequence of fat-stimulated GIP secretion. In addition to insulin secretion, GIP also enhances insulin-gene expression [16], the growth, differentiation, and
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Plasma GIP (pmol/l)
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FIGURE 2.1 Plasma GIP and GLP 1 in healthy human subjects following 375 Kcal meals of glucose (), protein () or fat (●). (Mean + SEM, n = 8). From Elliott, RM, et al., Glucagonlike peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol, 138, 159, 1993. Reproduced by permission.
proliferation of pancreatic B cells [17, 18], and acts as a Β cell mitogenic and antiapoptopic factor [19], thus acting as a true insulinotropic agent. An intact N-terminal is necessary to preserve GIP’s insulintropic activity, but studies with synthetic GIP/GLP 1 chimeric peptides have indicated that the entire GIP sequence is important for receptor recognition [20]. The truncated peptide GIP(3-42)amide has been shown to act as a receptor antagonist and contains a highaffinity receptor-binding region [21]. These factors are important, as both GIP and GLP 1 are rapidly and extensively degraded in vivo by the ubiquitous enzyme dipeptidyl peptidase IV (DPP-IV) to produce their respective N-terminally truncated metabolites [22], thus diminishing the biological activity of the two hormones (see also the following section). The receptor for GIP is distinct from that for GLP 1, but both belong to the superfamily of G-protein-coupled receptors and are functionally coupled to the adenylate cyclase system. Interaction of GIP with its receptor on the pancreatic B cells increases intracellular calcium concentrations and enhances exocytosis of insulin-containing granules. Activation of mitogen activated protein (MAP) kinase and P13 kinase/protein kinase B signaling pathways have been implicated, secondary to the rise in cyclic adenosine monophosphate (AMP) in this process [23, 24].
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B. GLP 1 GLP 1 shares many similarities with GIP in terms of its insulinotropic activity, and numerous studies have demonstrated its insulinotropic activity in vitro and in vivo [25]. It is a 30-amino-acid peptide secreted from the L-cells of the intestinal mucosa, which occur predominantly in the lower part of the small intestine and in the colon. In common with GIP, GLP 1 secretion is stimulated by carbohydrate and fat [26], but it is also stimulated by protein (2. 1). However, circulating levels of GLP 1(736)amide, the GLP 1 isoform that is bioactive, are severalfold lower than those of bioactive GIP. In contrast to GIP, GLP 1 secretion is not dependent upon nutrient absorption, and secretion can be elicited by the presence of nutrients in the gut lumen. Regulation of GLP 1 secretion by nutrients is complex and involves both direct and indirect mediators. While glucose and long-chain fatty acids in the lumen of the gut can exert direct stimulatory effects on the GLP 1 secretion, the physiological significance of this is questionable. GLP 1 secretion occurs very rapidly after nutrient ingestion, whereas the L-cells are located mainly in the distal part of the intestine, where, under normal conditions of feeding, lumenal glucose concentrations are far below the apparent limit of sensitivity of the L-cell. It therefore seems likely that the early GLP 1 response to ingested nutrients is mediated via a proximal-distal loop involving hormonal or neural signals generated from the upper small intestine [27]. Like GIP, GLP 1’s insulinotropic activity is strictly glucose-dependent, and it has no effect on glucose concentrations below ~ 4.5 mmol/l [28]. GLP 1 also has trophic effects on pancreatic B cells. It stimulates all stages of insulin biosynthesis, as well as insulin-gene transcription [29], stimulates B cell proliferation, and enhances the differentiation of new B cells [30]. GLP 1 has also been shown to mediate endocrine proliferation in aging glucose-intolerant rats, with a resulting improvement in glucose tolerance [31], raising the exciting possibility that it might be capable of stimulating the growth of new cells in type 2 diabetic patients. An intact N-terminal is also necessary to preserve GLP 1’s insulinotropic activity, and the N-terminally truncated peptide, the product of DPP-IV cleavage, acts as a receptor antagonist [32]. GLP 1 is particularly sensitive to degradation by DPP-IV. Whereas approximately half an infusion of exogenous GIP remains intact in vivo, as little as 10 percent to 20 percent exogenous GLP 1 survives in intact form following infusion of the peptide. This rapid degradation of GLP 1 (and to a lesser extent, GIP) represents a major difficulty associated with attempting to utilize these hormones as potential therapeutic agents in diabetes. The relative importance of GIP and GLP 1 in stimulating insulin secretion in healthy human subjects is difficult to resolve. Circulating levels of GIP following nutrient ingestion are some fourfold to fivefold higher than GLP 1, although in molar terms, GLP 1 has been shown to be a more potent insulin secretagogue than GIP [8]. Most current radioimmunoassays for GIP and GLP 1 measure precursors and inactive metabolites in addition to the biologically active hormone, making interpretation of physiological postprandial levels of the hormones difficult. A study using GIP-receptor antagonists in genetically obese mice concluded that GIP might be responsible for as much as 80 percent of the incretin effect in these animals [21]. However, similar studies in humans involving GLP 1 receptor antagonists [33] have
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shown that GLP 1 is responsible for a substantial part of the insulin response to oral glucose. Recent studies in humans, involving infusion of physiological concentrations of the biologically active hormones while circulating glucose levels were clamped at fasting, or slightly raised in order to mimic the postprandial state, have concluded that the two hormones contribute almost equally to the incretin effect of a meal, and do so in an additive manner [34]. This finding has been corroborated in recent experiments in mice with a double knock-out of both GIP and GLP 1 receptors [35], where preliminary results are consistent with the additive effects of the two hormones. However, GLP 1 is additionally very effective in minimizing changes in postprandial glycemia because of its capacity to delay gastric emptying and inhibit glucagon secretion (see next section). Thus, in the physiological setting of meal ingestion where whole-body glucose metabolism is considered, the insulinotropic effect of GLP 1 can be obscured by these effects, demonstrating that the regulation of circulating glucose levels via the enteroinsular axis does not operate solely via the effects of the incretin hormones on insulin secretion.
III. EXTRAPANCREATIC EFFECTS OF GIP AND GLP 1 A. GIP — THE OBESITY HORMONE? GIP receptor mRNA has been found in a variety of tissues outside the pancreas, including stomach, intestine, brain, heart, and adipose tissue. The function of GIP in many of these tissues remains unclear, but a role of GIP in adipose-tissue metabolism and a possible function in the development of obesity has recently generated much interest. Fat is a potent secretagogue of GIP in humans, and functional GIP receptors have been identified on adipocytes [36]. Twenty-four-hour secretory patterns of GIP in humans closely parallel those of plasma triglyceride, suggesting a possible role in postprandial lipid clearance and metabolism [26], a hypothesis strengthened by the finding that infusion of GIP promotes the clearance of chylomicron triacylglycerol (TAG) in dogs [37]. Consistent with this hypothesis, hypertriglyceridemic subjects have been shown to exhibit disordered postprandial GIP secretion [38]. In various adipose-tissue preparations in vitro, GIP augments insulin-stimulated glucose transport [39], increases fatty-acid synthesis [40], and reduces glucagonsstimulated lipolysis [41], demonstrating a direct insulin-like anabolic role. In man, accumulation of TAG in adipose tissue from dietary fat sources is quantitatively much more important than de novo lipogenesis. Adipose tissue lipoprotein lipase (LPL) plays a key regulatory role in postprandial TAG clearance by hydrolyzing chylomicron and very low density lipoprotein (VLDL) TAG and liberating fatty acids for uptake and storage within the adipocyte. GIP, in common with insulin, increases LPL activity in rat adipose-tissue explants, whereas GLP 1 is without effect [42]. The magnitude of the postprandial GIP response in humans is dependent on the size of the fat, as well as the carbohydrate load [43], and progressive increases in postprandial postheparin LPL activity in parallel with plasma GIP have been found when the fat content of the meal is increased [43]. These findings are consistent with GIP acting as a major hormonal signal linking meal size with LPL
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activity in the physiological control of postprandial lipemia, in addition to its effects on postprandial glycemia. These actions of GIP have led to the hypothesis that the hormone might play a role in the etiology of obesity. GIP secretion is sensitive to chronic changes in diet, in particular, to changes in the dietary fat content; diets high in fat content increase intestinal K cell number [44], GIP expression, and circulating GIP levels [45]. Obesity is typically associated with hyperinsulinemia, and the anabolic activity of GIP could combine with insulin to promote adipose tissue fat deposition. The gene encoding GIP could be considered a thrifty gene, maximizing nutrient storage and valuable to our hunter/gatherer forebears. However, this feature of GIP physiology could be maladaptive in people consuming energy-dense, fat-rich Western diets, and could contribute towards their obesity (Figure 2.2). The hypothesis has gained much recent support from studies of GIP-receptor knock-out mice (GIPR–/–) in which GIPreceptor expression is disrupted. In contrast to normal control animals, these mice did not gain weight or become obese when placed on a high-fat diet. Food intake was not significantly different between the two groups, but the GIPR–/– mice exhibited a higher energy expenditure and appeared to oxidize triglycerides preferentially. In addition, crossing hyperphagic, genetically obese ob/ob mice with GIPR–/– mice reduced the severity of obesity by 23 percent in their homozygous offspring. These Hyperphagia (high fat diet)
Elevated GIP (K-cell hyperplasia)
GIP receptors Actions on adipose tissue
Increased fat stores Obesity
GIP receptors Hyperinsulinaemia (beta-cell hyperplasia)
Insulin resistance
Glucose intolerance
Hyperglycaemia Diabetes
FIGURE 2.2 Scheme linking overnutrition to the development of obesity, insulin resistance, and type 2 diabetes, via GIP. From Gault, VA, O’Harte, FPM, and Flatt, PR, Glucosedependent insulinotropic polypeptide (GIP): antidiabetic and antiobesity potential? Neuropeptides, 37, 253, 2003. With permission from Elsevier.
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findings collectively indicate that GIP is an important hormone in lipid metabolism, which links overnutrition with the development of obesity.
B. GLP 1 — A SPECTRUM
OF
ANTIDIABETIC ACTIONS
GLP 1 is established as a physiological incretin, promoting insulin secretion and exerting trophic effects on the pancreas. However, it has other extrapancreatic biological actions, which could be highly desirable in the context of treating type 2 diabetes. GLP 1 delays gastric emptying [46], slowing down glucose absorption and thus reducing postprandial glucose excursions. It is also a potent inhibitor of glucagon secretion, and is able to lower glucose levels in insulin-requiring diabetic patients with no residual Β cell activity (hence, no capacity for insulin secretion) by attenuating the hyperglycemic action of glucagons [47]. GLP 1 has also been shown to enhance glucose uptake and glycogen storage in liver and muscle [48]. All of these actions would contribute towards GLP 1’s hypoglycemic effect in addition to its insulinotropic action. Moreover, GLP 1 is, in addition, a short-term inhibitor of appetite and food intake, and may contribute to glucose homeostasis by reducing food intake itself [49]. This satiety effect of GLP 1 would be desirable to support attempts at weight reduction in type 2 diabetic subjects, many of whom are also obese. The finding that glucose-stimulated GLP 1 secretion is reduced in obese subjects [50] is of obvious importance in its putative role as a satiety factor. The above spectrum of antidiabetic actions place GLP 1 in a potentially good position as a therapeutic agent in the treatment of diabetes.
IV. THE ENTEROINSULAR AXIS IN DIABETES The importance of the enteroinsular axis in healthy individuals gave rise to the possibility that an incretin defect might be partially responsible for the metabolic abnormalities observed in type 2 diabetes. Several studies showed that the incretin effect (as studied by comparing isoglycemic oral and IV glucose loads) is reduced or abolished in these individuals [51]. Work in this area initially centered on the possibility of impaired GIP secretion, but early publications reached no consensus, as normal, increased, and decreased GIP secretion have all been reported in type 2 diabetes [52]. Some of these conflicting results could be attributed to the varying degrees of cross-reactivity that GIP assays displayed with biologically inactive forms of the hormone. A recent study has found normal or marginally impaired GIP secretion in diabetics drawn from a population with a wide spectrum of the disease [53]. However, similar studies with GLP 1 have shown a significant impairment of GLP 1 secretion in diabetes, which was related to impaired B cell function, regardless of whether the biologically-active intact hormone, or the metabolites of GLP 1, were measured [53]. Studies of identical twins, discordant for type 2 diabetes, have shown that GLP 1 responses are lower in the diabetic twin, and they are also normal in the first degree relatives of diabetic subjects [54]. This implies that the impaired GLP 1 secretion observed in diabetes is a consequence rather than a cause of the disease.
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However, when the biological effects of IV infusions of GIP or GLP 1 in type 2 diabetic subjects was studied, the findings did not reflect the secretory defects of the two hormones in these individuals. While the insulinotropic effect of GLP 1 was similar to that of control subjects, the insulinotropic effect of GIP was almost lost in type 2 diabetes [55]. These findings point to a GIP receptor or postreceptor defect at pancreatic Β cell level in type 2 diabetes. Defective expression of the GIP receptor has been observed in animals with genetically determined diabetes [56]. Polymorphisms in the coding region of the GIP-receptor gene have also been reported, but these have not been associated with either defective signaling or diabetes [57]. However, studies in healthy, first-degree relatives of diabetic patients showed a reduced insulinotropic effectiveness of GIP in comparison to healthy subjects without a family history of diabetes, suggesting that the GIP defect could possibly be a genetically determined, primary defect [58]. The mechanism of diminished GIP responsiveness in diabetics remains unclear. It appears to be severe, but confined to late-phase insulin secretion only, a finding that makes defective GIP-receptor expression an unlikely explanation [59]. Recent work with diabetic patients who do not conform to the classic obese type 2 pattern [60] has suggested that the defect is primarily a consequence rather than a cause of the diabetic state, although a genetic component cannot be ruled out. The impairment of both the secretion of GLP 1 and the responsiveness of GIP in type 2 diabetes explains the findings of a severely diminished or absent incretin effect in these patients. It also has implications for the use of these hormones in the treatment of diabetes, as can be seen in the following section.
V. THERAPEUTIC ASPECTS OF GIP AND GLP 1 A. TYPE 2 DIABETES MELLITUS The potent insulinotropic actions of GIP and GLP 1 and their strict glucose dependency, thereby avoiding hypoglycemia, make these hormones potentially important agents in the treatment of type 2 diabetes. GLP 1’s other antihyperglycemic actions (inhibition of glucagon secretion, gastric emptying, food intake, etc.) additionally make it particularly suited to an antidiabetic role. However, there are two major difficulties associated with using these hormones as therapeutic agents, 1) their extremely rapid degradation in circulation (particularly GLP 1), and 2) the diminished responsiveness of diabetic individuals to the insulinotropic action of GIP. This latter difficulty has resulted in most work on the therapeutic potential of the incretins in type 2 diabetes, focusing on the possible use of GLP 1 or its analogues. Continuous IV infusion of GLP 1 can effectively normalize glucose concentrations in type 2 diabetes [61], but simple subcutaneous injections are ineffective, as > 90 percent of the peptide is rapidly degraded under these circumstances [62]. However, recent studies using minipumps to deliver subcutaneous GLP 1 continuously have demonstrated a clinically significant improvement in plasma glucose and HbA1C, together with modest weight loss, over a six-week period [63] (Figure 2.3). This mode of delivery is not, however, ideal for everyday treatment.
Plasma glucose (mmol/l)
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FIGURE 2.3 Plasma glucose profiles and weight losses in type 2 diabetics before and following a six-week course of GLP 1 infusions. From Zander, M, et al., Effect of a 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 359, 824, 2002.
The observation that GLP 1 secretion is diminished in diabetics has prompted the investigation of dietary strategies to increase endogenous GLP 1 secretion. Increasing large-bowel fermentation by means of lactulose (as a model of resistant starch carbohydrate) or with viscous fiber (psyllium) is ineffective in raising GLP 1 levels [64, 65], as is the manipulation of the mono-unsaturated acid/polyunsaturated fatty acid (MUFA/PUFA) content of the diet [66]. However, the alpha-glycosidase inhibitor acarbose, used in the treatment of both type 1 and type 2 diabetes, which delays the upper-intestinal absorption of sucrose, diminishes GIP, but markedly potentiates GLP 1 secretion [67] (Figure 2.4). The therapeutic efficacy of acarbose in diabetes could be partly due to this ability to augment GLP 1 secretion. More recent strategies to enhance the action of GLP 1 in diabetes have centered around extending its biologically active half-life in the plasma by circumventing the inactivation of GLP 1 (and GIP) by DPP-IV. This has been tackled by a two-pronged approach: 1) the use of DPP-IV inhibitors, and 2) the development of degradationresistant GLP 1 and GIP analogues. Treatment with DPP-IV inhibitors promote marked improvements in glycemic control in both animal models of diabetes and in human diabetic studies [68]. A major advantage to this approach lies in the ability to administer DPP-IV inhibitors orally; however, there is also an intrinsic disadvantage due to a lack of specificity of the DPP-IV enzyme. DPP-IV exerts physiological actions on a wide range of regulatory peptides in addition to GLP 1 and GIP. Its pharmacological inactivation may therefore have other clinical consequences beyond
GIP (pmol l–1)
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FIGURE 2.4 Plasma GIP and GLP 1 in healthy subjects following a 100 g oral sucrose load, with () or without () the addition of the alpha-glycosidase inhibitor acarbose. (From Ranganath, LR, et al., Diabetic Med., 15, 120, 1998. With permission.)
its antidiabetic action, and these will need to be carefully evaluated before the clinical efficacy of DPP-IV inhibitors can be confirmed. The other approach, namely the development of specific DPP-IV-resistant GLP 1 analogues modified at the N-terminus around the enzyme cleavage site, has proved to be more promising. A number of analogues are effective in improving glucose tolerance and insulin secretion in animal models of diabetes [69]. Studies are currently in progress to extend the half-lives of these analogues still further by the attachment of acyl side-chains to selected residues; these bind to albumin and thus delay renal clearance of the analogues. More convenient forms of delivery of the peptides are also being explored, such as nasal sprays and transdermal patches, to avoid the need for frequent injections or continuous infusion of the analogues. A final approach has been the utilization of DPP-IV-resistant receptor agonists. One such, exendin-IV, a naturally occurring agonist found in the saliva of the Gila monster lizard, is an effective antidiabetic agent in a wide range of animal studies, and is currently undergoing clinical trials in type 2 diabetes [70]. While most interest in the therapeutic potential of incretins in diabetes has centered around DPP-IV-resistant GLP 1, some studies have been carried out on DPP-IV-resistant GIP analogues. GIP analogues have some potential advantages over GLP 1 in that enhanced activity is generally easier to achieve with GIP than with GLP 1 analogues, and the lack of any significant effects of GIP on gastric emptying can be advantageous when treating diabetics with neurological complications. A number of N-terminally modified GIP analogues have been developed and characterized that have a greater potency than GIP in stimulating insulin secretion and improving glucose tolerance in diabetic animal models [9], but their therapeutic
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potential in human type 2 diabetes, which is characterized by GIP insensitivity, remains to be proven.
B. OBESITY The evidence that GIP might have a role in the etiology of obesity has supported the concept of using GIP-receptor antagonists to treat obesity. Receptor antagonists based on fragments of the full-length hormone have been developed [7, 9], together with antisera that bind either to GIP itself or to the GIP receptor. These are all very effective in blocking the insulinotropic action of GIP, but the effects of chronic administration on body weight have yet to be reported [71]. The concept of GIP antagonists as antiobesity agents is an attractive one, but the antagonistic effects of such compounds on the other actions of GIP also need to be considered. Thus, chronic treatment with a GIP-receptor antagonist might worsen glucose tolerance, and interfere with postprandial triglyceride disposal, leading to increased circulating triglyceride levels and hence increased cardiovascular-disease risk. The beneficial effects of fat loss may outweigh such deleterious effects, but a note of caution should be sounded regarding the potential loss of GIP’s other beneficial actions. It remains to be seen whether GIP antagonists with spectra of biological activities that specifically target adipose tissue can be developed, thus maximizing antiobesity activity while minimizing unwanted side effects. The effect of GLP 1 in increasing satiety, hence diminishing food intake, has hitherto received very little attention in terms of its potential use as an antiobesity agent. The vast, built-in redundancy of hypothalamic satiety mechanisms, together with the observation that GLP 1-receptor knock-out mice do not become obese, indicates that GLP 1 might not be indispensable for normal appetite regulation. However, the finding that chronic GLP 1 administration in type 2 diabetes not only improves glucose tolerance but also has modest but significant beneficial effects in terms of weight loss [63] (Figure 2.3) is clearly of great interest, as the majority of type 2 diabetic individuals are overweight. Improvement of insulin sensitivity resulting from weight loss would confer an additional therapeutic advantage in these patients.
VI. CONCLUSIONS The enteroinsular axis plays an important role in promoting insulin secretion in response to food intake, and its impairment in type 2 diabetes makes a significant contribution to the impairment of glucose tolerance and insulin secretion in these individuals. Although GIP and GLP 1 initially gained recognition as insulin secretogogues, it is their trophic actions on the pancreas, together with their extrapancreatic actions, that have recently generated most interest. The tight control of GIP and GLP 1 secretion by both the size and nutrient content of a meal provides a mechanism whereby diet is linked to the metabolic fate of nutrients. GLP 1 is able to control the rate of delivery of nutrients for absorption via modulation of gastric emptying and at a higher level may affect nutrient intake itself by acting as a satiety factor. GIP regulates the postprandial disposal and deposition of lipid with its insulin-like actions on adipose tissue, in addition to its effects on carbohydrate metabolism.
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The therapeutic potential for GLP 1 or its related analogues to act as antidiabetic agents is just beginning to be realized, with encouraging clinical results. While GIP is less likely to be effective in this respect, the hypothesis that increased GIP action links overnutrition to the development of obesity points to the possible therapeutic value of GIP-receptor antagonists in the treatment of obesity. Both therapeutic aspects are areas with exciting future possibilities.
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18. Trumper, A, et al., Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling, Mol. Endocrinol., 15, 1559, 2001. 19. Trumper, A, et al., Mechanisms of mitogenic and anti-apoptotic signaling by glucosedependent insulinotropic polypeptide in beta (INS-1) cells, J. Endocrinol., 174, 233, 2002. 20. Gallwitz, B, et al., GLP 1/GIP chimeric peptides define the structural requirements for specific ligand-receptor interaction of GLP 1, Regul. Pept., 63, 17, 1996. 21. Gault, VA, et al., Evidence that the major degradation product of glucose-dependent insulinotropic polypeptide, GIP (3-42), is a GIP receptor antagonist in vivo, J. Endocrinol., 175, 525, 2002. 22. Kieffer, TJ, McIntosh, CH, and Pederson, RA, Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagons-like peptide-1 in vitro and in vivo by dipeptidyl peptidase IV, Endocrinology, 136, 3585, 1995. 23. Ehses, JA, et al., Glucose-dependent insulinotropic polypeptide activates the Raf-Mek 1/2-ERK 1/2 module via a cyclic AMP-dependent protein kinase/Rap1-mediated pathway, J. Biol. Chem., 277, 37088, 2002. 24. Ehses, JA, et al., A new pathway for glucose-dependent insulinotropic polypeptide receptor signaling: evidence for the involvement of phospholipase A2 in GIP-stimulated insulin secretion, J. Biol. Chem., 276, 23667, 2003. 25. D’Alessio, DA and Ensinck, JW, The insulinotropic gut hormone glucagon-like peptide-1, Fehmann, HC and Göke, B, Eds., Karger, Basel, p. 132, 1997. 26. Elliott, RM, et al., Glucagon-like peptide (7-36) amide and glucose-dependent insulinotropic polypeptide secretion in response to nutrient ingestion in man: acute post prandial and 24h secretion patterns, J. Endocrinol., 138, 159, 1993. 27. Holst, JJ, Glucagon-like peptide 1 (GLP 1): an intestinal hormone signaling nutritional abundance, with an unusual therapeutic potential, Trends. Endocrinol. Metab., 10, 229, 1999. 28. Weir, GC et al., Glucagon-like peptide-1 (7-37) actions on the endocrine pancreas, Diabetes, 38, 338, 1989. 29. Fehmann, HC and Habener, JF, Insulinotropic glucagon-like peptide-1 (7-37) stimulation of proinsulin gene expression and proinsulin biosynthesis in insulinoma beta TC-1 cells, Endocrinology, 130, 159, 1992. 30. Zhou, J, et al., Glucagon-like peptide-1 and exendin-4 convert pancreatic AR42J cells into glucagon- and insulin-producing cells, Diabetes, 48, 2358, 1999. 31. Perfetti, R, et al., Glucagon-like peptide-1 induces cell proliferation and pancreaticduodenum homeobox-1 expression and increases endocrine cell mass in the pancreas of old, glucose-intolerant rats, Endocrinology, 141, 4600, 2000. 32. Knudsen, LB and Pridal, L, Glucagon-like peptide-1(9-36)amide is a major metabolite of glucagon-like peptide-1(7-36) amide after in vivo administration to dogs and it acts as an antagonist on the pancreatic receptor, Eur. J. Pharmacol., 318, 429, 1996. 33. Edwards, CM, et al., Glucagon-like peptide-1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39, Diabetes, 48, 86, 1999. 34. Vilsboll, T, et al., Both GLP 1 and GIP are insulinotropic at basal and postprandial glucose levels and contribute nearly equally to the incretin effect of a meal in healthy subjects, Regul. Pept., 114, 115, 2003. 35. Preitner, F, et al., Disruption of both GIP and GLP 1 signalling pathways in the mouse leads to glucose intolerance Diabetes, 51, A66, 2002. 36. Yip, RCG, et al., Functional GIP receptors are present on adipocytes, Endocrinology, 139, 4004, 1998.
40
Nutrition and Diabetes: Pathophysiology and Management 37. Wasada, T, et al., Effect of gastric inhibitory polypeptide on plasma levels of chylomicron triglyceride in dogs, J. Clin. Invest., 68, 1106, 1981. 38. Gama, R, et al., Postprandial elevation of gastric inhibitory polypetide concentrations in hypertriglyceridaemic subjects, Clin. Sci., 93, 343, 1997. 39. Starich, GH, Bar, RS, and Mazzaferri, EL, GIP increases insulin receptor affinity and cellular sensitivity in adipocytes, Am. J. Physiol., 249, E603, 1985. 40. Oben J, et al., Effect of the entero-pancreatic hormones gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue J. Endocrinol., 130, 267, 1991. 41. Dupré, J, et al., Inhibition of actions of glucagons in adipocytes by gastric inhibitory polypeptide, Metabolism, 25, 1197, 1976. 42. Knapper, JM, et al., Investigations into the actions of glucose-mediated insulinotropic polypeptide and glucagons-like peptide-1(7-36) amide on lipoprotein lipase activity in explants of rat adipose tissue, J. Nutr., 125, 183, 1995. 43. Murphy, MC, et al., Postprandial lipid and hormone responses to meals of varying fat content: modulatory role of lipoprotein lipase? Eur. J. Clin. Nutr., 49, 579, 1995. 44. Bailey, CJ, et al., Immunoreactive gastric inhibitory polypeptide and K cell hyperplasia in obese hyperglycaemic (ob/ob) mice fed high fat and high carbohydrate cafeteria diets, Acta. Endocrinol. (Copenh.), 112, 224, 1986. 45. Morgan, LM, et al., Modification of gastric inhibitory polypeptide secretion in man by a high fat diet, Br. J. Nutr., 59, 373, 1988. 46. Wettergren, A, et al., Trucated GLP 1 (proglucagon 78-107 amide) inhibits gastric and pancreatic functions in man, Dig. Dis. Sci., 38, 665, 1993. 47. Creutzfeldt, WO, et al., Glucagonostatic actions and reduction of fasting hyperglycemia by exogenous glucagon-like peptide 1(7-36) amide in type I diabetics, Diabet. Care, 19, 580, 1996. 48. O’Harte, FPM, et al., Effects of non-glycated and glycated glucagon-like peptide1(7-36) amide on glucose metabolism in isolated mouse abdominal muscle, Peptides, 18, 1327, 1997. 49. Verdich, C, et al., A meta-analysis of the effect of glucagon-like peptide-1(7-36)amide on ad libitum energy intake in humans, J. Clin. Endocrinol. Metab., 86, 4382, 2001. 50. Ranganath LR, et al., Attenuated GLP 1 secretion in obesity: Cause or consequence? Gut 38, 916, 1996. 51. Nauck, M, et al., Reduced incretin effect in type 2 (non-insulin dependent) diabetes, Diabetologia, 28, 46, 1986. 52. Krarup, T, Immunoreactive gastric inhibitory polypeptide, Endocr. Rev., 9, 122, 1988. 53. Toft-Neilsen, MB, et al., Determinants of the impaired secretion of glucagon-like peptide-1 secretion in type 2 diabetic patients, J. Clin. Endocrinol. Metab., 86, 3717, 2001. 54. Vaag, AA, et al., Gut incretins in identical twins discordant for non-insulin dependent diabetes mellitus (NIDDM) — evidence for decreased glucagon-like peptide-1 secretion during oral glucose ingestion in NIDDM twins, Eur. J. Endocrinol., 135, 425, 1996. 55. Nauck, MA, et al., Preserved incretin activity of glucagon-like peptide 1 [7-36 amide] but not of synthetic human gastric inhibitory polypeptide in patients with type-2 diabetes mellitus, J. Clin. Invest., 91, 301, 1993. 56. Lynn, FC, et al., Defective glucose-dependent insulinotropic polypeptide receptor expression in diabetic fatty Zucker rats, Diabetes, 50, 1004, 2001. 57. Holst, JJ, Gromada, J, and Nauke, MA, The pathogenesis of NIDDM involves a defective expression of the GIP receptor, Diabetologia, 40, 984, 1997.
The Enteroinsular Axis
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58. Meier, JJ, et al., Reduced insulinotropic effect of gastric inhibitory polypeptide in first degree relatives of patients with type 2 diabetes, Diabetes, 50, 2497, 2001. 59. Vilsboll, T, et al., Defective amplification of the late phase insulin response to glucose by GIP in obese type 2 diabetic patients, Diabetologia, 45, 1111, 2002. 60. Vilsboll, T, et al., The pathophysiology of diabetes involves a defective amplification of the late phase insulin response to glucose by GIP — regardless of aetiology or phenotype, J. Clin. Endocrinol. Metab., 88, 4897, 2003. 61. Rachman, J, et al., Near-normalisation of diurnal glucose concentrations by continuous administration of glucagon-like peptide 1 (GLP 1) in subjects with NIDDM, Diabetologia, 40, 205, 1997. 62. Deacon, CF, et al., Both subcutaneously and intravenously administered glucagonlike peptide-1 are rapidly degraded from the NH2 terminus in type II diabetic patients and in healthy subjects, Diabetes, 44, 1126, 1995. 63. Zander, M, et al., Effect of a 6-week course of glucagon-like peptide-1 on glycemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study, Lancet, 359, 824, 2002. 64. Frost, G, Brynes, A, and Leeds, A, Effect of large bowel fermentation on insulin, glucose, free fatty acids and glucagon-like peptide 1 (7-36) amide in patients with coronary heart disease, Nutrition, 15, 183, 1999. 65. Frost, GS, et al., The effects of fiber enrichment of pasta and fat content on gastric emptying, GLP 1, glucose and insulin responses to a meal, Eur. J. Clin. Nutr., 57, 293, 2003. 66. Brynes, AE, et al., Diet-induced change in fatty acid composition of plasma triacylglycerols is not associated with change in GLP 1 or insulin sensitivity in people with type 2 diabetes, Am. J. Clin. Nutr., 72, 1111, 2000. 67. Ranganath, LR, et al., Delayed gastric emptying occurs following acarbose administration and is a further mechanism for its antihyperglycaemic effect. Diabetic Med., 15, 120, 1998. 68. Ahren, B, et al., Inhibition of dipeptidyl peptidase IV improves metabolic control over a 4-week study period in type 2 diabetes, Diabet. Care, 25, 869, 2002. 69. Gault, VA, Flatt, PR, and O’Harte, FPM, Glucose-dependent insulinotropic polypeptide analogues and their therapeutic potential for the treatment of obesity-diabetes, Biochem. Biophs. Res. Comm., 308, 207, 2003. 70. Perry, T, and Greig, NH, The glucagon-like peptides: a double-edged therapeutic sword? Trends in Pharm. Sci., 24, 377, 2003. 71. Kieffer, TJ, GIP or not GIP? That is the question, Trends in Pharm. Sci., 24, 110, 2003.
3
Achieving a Healthy Body Weight: Diet and Exercise Interventions for Type 2 Diabetes Connie W. Bales, Ph.D., R.D., and Jama L.Purser, P.T., Ph.D.
CONTENTS I. Introduction to the Problem: The Critical Link Between Diabetes and Excess Body Weight ...............................................................................44 II. Health Benefits of Diet and Exercise..........................................................44 A. Prevention ............................................................................................45 B. Management of Existing Disease .......................................................45 III. Lifestyle Interventions: Indications and Goals ...........................................45 A. Weight-Reduction Diets ......................................................................46 1. Indications and Body-Weight Goals for Optimal Health.............46 2. Calorie-Reduction Diets................................................................46 3. Low-Fat Diets................................................................................48 4. Low Carbohydrate and Other Nontraditional Dietary Approaches .......................................................................48 5. Comments on Overall Diet Composition .....................................49 B. Exercise Interventions .........................................................................49 1. Aerobic Exercise ...........................................................................51 2. Resistance Training .......................................................................51 3. Combination Training ...................................................................52 IV. Concluding Comments on Maintenance of Weight Loss and Improved Fitness............................................................................................52 References................................................................................................................53
43
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Nutrition and Diabetes: Pathophysiology and Management
I. INTRODUCTION TO THE PROBLEM: THE CRITICAL LINK BETWEEN DIABETES AND EXCESS BODY WEIGHT The problem of obesity has reached epidemic proportions in the United States (see also other chapters by Boan and McMahon), and evidence of its negative impact on health is rapidly accumulating. Excessive body mass, defined as a body-mass index (BMI) over 25 kg/m2 (overweight; OW) and ≥ 30 kg/m2 (obese; OB) is linked with an increased risk for a number of serious chronic diseases, including cardiovascular disease (CVD), hypertension, and some cancers, as well as type 2 diabetes (1–3). The relationship between OW/OB and diabetes is exceedingly strong, with the prevalence of type 2 diabetes increasing along with OW/OB in a dose-dependent manner (3). In fact, as many as 90 percent of all type 2 diabetic individuals fit the OW/OB BMI criteria (4). Thus, OW/OB and type 2 diabetes are “inextricably linked” (5), the term “diabesity” having been coined by Astrup and Finer (6) to emphasize the close connection between the two disorders. The need to deal with the obesity problem by restoring optimal body mass and composition is well recognized for all segments of the adult population, but it is particularly critical for individuals with type 2 diabetes. The risk to mortality posed by obesity is greatly enhanced by the coexistence of diabetes; moreover, diabetes treatment can interfere with the ability to achieve and maintain a healthy body mass. OW/OB may also directly impact glycemic control. Due to greater hepatic or peripheral insulin resistance, type 2 diabetic patients who are OW/OB can have a reduced response to antidiabetic therapy compared with normal-weight patients, necessitating higher doses of antihyperglycemia medications (7). In addition, the risk of CVD — a major cause of mortality and morbidity in individuals with diabetes — is heightened due to OW/OB-linked hypertension and dyslipidemia. Recognizing the need for prompt, effective interventions to disrupt the cycle of OW/OB and diabetes, the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition have jointly developed and recently released a statement on the use of lifestyle modification to prevent and manage type 2 diabetes (8). The statement emphasizes the importance of lifestyle intervention as the principal therapy for OW and OB patients. In this chapter, we focus on the lifestyle modifications (diet and exercise) recommended in the statement. The utilization of weight-loss medications and bariatric surgery to aid weight loss in type 2 diabetes is discussed separately elsewhere in the book, and comprehensive reviews on the subject are available (9–10).
II. HEALTH BENEFITS OF DIET AND EXERCISE As already acknowledged, lifestyle interventions can play a critical role in preserving the health of individuals prone to developing type 2 diabetes. Interventions that reduce OW/OB can prevent the development of the disease in persons with prediabetes, and for those with established disease, a moderate weight loss helps improve glycemic control and reduces CVD risk.
Achieving a Healthy Body Weight
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A. PREVENTION In the case of both OW/OB and type 2 diabetes, prevention is by far the best approach, requiring significantly less expense and effort than therapeutic interventions. Compared to individuals with a BMI of 18.5 to 24.9, persons with a BMI > 35 are 20 times as likely to develop diabetes (2, 11). As little as a 5 percent weight loss has been shown in clinical trials to prevent obese subjects with glucose intolerance from developing type 2 diabetes (6). Unfortunately, in the face of affluent lifestyles and copious amounts of readily accessible and highly palatable foods, the motivation for preventing obesity is often absent, as evidenced by current trends toward more rather than less OW/OB in the U.S. population (12). Without the presence of discernable health impairments, many individuals lack the motivation to incorporate diet and exercise regimens into their daily routines. Labor-saving devices and time constraints that favor a sedentary lifestyle also contribute to the prevalence of positive energy balance. For ready-to-change individuals (13), however, preventive nutrition measures offer dramatically beneficial effects. Results from the Diabetes Prevention Program (14) indicated a reduced four-year incidence of type 2 diabetes in men and women with glucose intolerance in response to weight reduction (7 percent loss in year one) and increased physical activity (150 minutes brisk walking/week). Tuomilehto et al. (15) followed 522 OW/OB subjects randomly assigned to a control group or a diet/physical activity intervention and reported reductions in the incidence of diabetes directly commensurate with lifestyle changes.
B. MANAGEMENT
OF
EXISTING DISEASE
It is well recognized that OW/OB complicates the management of type 2 diabetes via increased insulin resistance and blood-glucose levels (16). For persons with type 2 diabetes who are OW/OB, targeting efforts to reach a healthy BMI (ideally ≤ 25 kg/m2) is the most important goal of lifestyle interventions (17, 18). When combined with increased activity, weight loss can dramatically enhance insulin sensitivity and glycemic control (8). Improvements occur in insulin action and blood-glucose concentrations, and required doses of diabetes medications may be reduced. Reductions in fasting glucose levels correspond directly to the amount of weight reduction (8,19). Alternatively, if excess weight is not reduced, glycemic control is likely to deteriorate over time, in as little as 12 months (7).
III. LIFESTYLE INTERVENTIONS: INDICATIONS AND GOALS In order to achieve a healthy body weight and body composition, persons with diabetes who are OW/OB need to have a medically supervised program that includes a calorie-restricted (weight reduction; WR) diet and an individualized exercise program that emphasizes long-term maintenance of total body mass and preservation of muscle tissue (20).
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Nutrition and Diabetes: Pathophysiology and Management
A. WEIGHT-REDUCTION DIETS By restoring a healthier body weight, dietary treatment (WR) in OW/OB individuals can provide significant clinical benefits. Unfortunately, the nature of diabetes and its treatment can hinder weight loss and even promote weight gain. This is because the progressive dysfunction of pancreatic B cells and increasing insulin resistance necessitate increasingly higher insulin dosages. This, in turn, promotes weight gain, and in a negative vicious cycle, makes weight loss even more difficult to achieve than for the nondiabetic obese individual (20). 1. Indications and Body-Weight Goals for Optimal Health For all OW and OB individuals who have type 2 diabetes or strong risk factors for the disease, WR is recommended. The ideal body-weight goal is to achieve a BMI of < 25 kg/m2, but it is important to set a realistic weight-loss goal that is likely to be both achievable and sustainable. As previously noted, a weight loss as small as 5 percent to 10 percent of baseline can lead to significant, positive effects on health and yet not be overwhelming as an initial goal (4, 8, 21, 22). This benefit is realized regardless of the initial weight at the time WR is initiated. 2. Calorie-Reduction Diets In designing a WR diet, both the amount of calories and distribution of energyyielding macronutrients need to be considered. A negative energy balance needs to be reached in order for weight loss to occur. Obviously, energy intake (amount of calories consumed) must be brought moderately below energy expenditure (and thus energy requirement) over time so as to achieve a safe but consistent negative balance. To determine a precise calorie prescription, energy requirements (total energy expenditures; TEE) can be calculated using published equations such as the Harris Benedict equations (23): Males: Calculated BMR = [66.5 + (13.75 × wt [kg]) + (5.003 × ht [cm]) – (6.775 × age [yr])] × PA Females: Calculated BMR = [655.1 + (9.563 × wt [kg]) + (1.850 × ht [cm]) – (4.676 × age [yr])] × PA To determine the TEE, adjustments need to be made for activity levels, as listed below: Sedentary (little or no exercise): BMR × 1.2 Lightly Active (light exercise/sports 1–3 days/week): BMR × 1.375 Moderately Active (moderate exercise/sports 3–5 days/week): BMR × 1.55
Achieving a Healthy Body Weight
47
Very Active (hard exercise/sports 6–7 days/week): BMR × 1.725 Extra Active (very hard daily exercise/sports and physical job or twice-daily training): BMR × 1.9 The TEE can also be calculated using the predictive equations derived from studies with doubly-labeled water and recently published by the Food and Nutrition Board of the Institute of Medicine (24). The following equations were developed for use in overweight individuals aged 19 years and older: Males: TEE = 864 – 9.72 × age [yr] + PA × 14.2 x wt [kg] + 503 × ht [m] Females: TEE = 387 – 7.31 × age [yr] + PA × (10.9 × wt [kg] + 660.7 × ht [m] Where PA is the physical activity coefficient: PA = 1.00 if PAL is estimated to be ≥1.0 <1.4 (Sedentary) PA = 1.11 if PAL is estimated to be ≥1.4 <1.6 (Low Active) PA = 1.25 if PAL is estimated to be ≥1.6 <1.9 (Active) PA = 1.48 if PAL is estimated to be ≥1.9 <2.5 (Very Active) A calorie-intake decrease of 500–1000 Kcal/day will usually result in a moderate but steady weight loss (1–2 lb/wk or 0.45–0.90 kg/wk). Table 3.1 provides some estimated Kcal reductions based on body-mass ranges. Generally, WR regimens should supply a minimum of ≥ 1000–1200 Kcal/d for women and ≥ 1200–1600 Kcal/d for men to assure that status of other nutrients is not compromised.
TABLE 3.1 Example Recommended Calorie Intakes for Weight Reduction by Body Weight and Body Mass Indexa Body Weight (lb)(kg) 170–199 200–249 250–299 300–349 ≥ 350 a b
77–90 90–113 113–136 136–158 ≥ 158
BMI (kg/mb)b
Energy Intake Ranges (Kcal/d)
26–28 28–35 35–45 45–50 ≥ 50
1000–1200 1200–1500 1500–1800 1800–2000 2000
Table adapted from references 8, 25. BMI was calculated assuming a height of 5′8″.
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Nutrition and Diabetes: Pathophysiology and Management
The optimal macronutrient (fat/protein/carbohydrate) distribution for weight reduction has not been resolved but is currently a matter of active debate (26). In recognition of the high caloric density of dietary fat and its relatively low satiety value compared to isocaloric amounts of carbohydrate and protein, a low-fat diet has been most typically employed for WR in diabetes, as well as in the general OW/OB population. However, the recent success of high-protein/high-fat/low-carbohydrate diets for WR has called this conventional approach into question. 3. Low-Fat Diets The accepted approach for the diabetic diet has generally included a relatively highcarbohydrate, low-fat (25 percent to 30 percent of Kcal from fat) distribution (27). While there are a variety of approaches to WR, this macronutrient distribution describes the conventional WR therapy for OW/OB. Randomized, controlled trials and other interventional studies of WR have found that decreasing dietary-fat intakes leads to decreased total energy intake and weight loss (28–30). Pirozzo et al. (31) systematically reviewed six randomized, controlled trials that compared a low-fat diet with another type of WR diet. The intervention and follow-up durations were 3–18 months and 6–18 months, respectively. The efficacy of low-fat diets was equal to but not greater than other WR diets with regards to sustained weight loss. However, only one of the six trials focused on subjects with type 2 diabetes (32). Very-lowfat diets have not been extensively studied but could be a concern because of the concomitant increase in carbohydrate intake that inevitably occurs when dietary-fat content is very low. High carbohydrate intakes could worsen lipid profiles by increasing triglycerides and lowering HDL cholesterol levels (33). 4. Low Carbohydrate and Other Nontraditional Dietary Approaches Among the general public, as well as those with type 2 diabetes, there has been a recent increased interest in the use of low-carbohydrate diets for OW/OB intervention. Klein et al. (8) summarizes five randomized trials in adults (34–38), comparing subjects assigned to a low-fat diet (~ 25 percent to 30 percent Kcal from fat and 55 percent to 60 percent Kcal from carbohydrate) to subjects randomly assigned to a low-carbohydrate, high-protein, high-fat diet (~ 25 percent to 40 percent of Kcal from carbohydrate). Subjects on the low-carbohydrate diet lost more weight in the short term (six months) but not the long term (12 months). In addition, glycemic control was found to be better (35, 37) and some serum lipids were improved. While these studies may offer promising dietary alternatives for those who are OW/OB, additional studies of long-term safety and efficacy are needed before low-carbohydrate diets are recommended as a WR strategy for OW/OB individuals with type 2 diabetes. Other dietary strategies may also offer promise. It has been recently suggested that a high-monounsaturated-fat diet would help avoid the risk of plasma triacylglycerol- and glucose-elevating effects of a high-carbohydrate diet, while still
Achieving a Healthy Body Weight
49
providing less saturated fat and cholesterol than a low-carbohydrate/high-fat regimen (27). 5. Comments on Overall Diet Composition Regardless of the approach for creating a dietary energy deficit, in the case of WR for individuals with type 2 diabetes, the advice of a nutritionist/registered dietitian should be sought for the design and individualization of the dietary plan. In these patients, maintenance of a healthy body mass may require long-term calorie restriction to some degree even for weight maintenance. So, it is important that the diet plan does not limit the intakes of essential nutrients (e.g., protein, vitamins, minerals) and that the diet provides a wide variety of nutritious foods in the long term. Any need for nutritional supplements (e.g., vitamins or minerals not consumed at adequate levels from the diet) should also be identified at this point. A diet history or typical diet record or recall may be collected to provide a profile of the usual intake and food preferences so that these can be taken into account in the diet plan whenever possible. Noting the need for individualization of dietary approaches, the joint recommendation of the American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition for type 2 diabetic patients needing to lose weight is to achieve a 500–1000 Kcal/d energy deficit and to choose a dietary intake pattern that is consistent with current recommendations to ameliorate comorbidities associated with obesity (8). A summary of other dietary recommendations to enhance overall health and minimize CVD risk includes the following: Saturated fat: Limit to less than 10 percent of total Kcal per day Cholesterol: Limit to ≤ 300 mg/day Fiber: Consume 20–35 g/day dietary fiber, both soluble and insoluble Sodium: If not hypertensive, sodium intake should be in the range of 2400–3000 mg/day Alcohol: Men, limit to two drinks/day; women, limit to one drink/day, consumed with food Vitamins and minerals: Insure adequate intakes from wide variety of dietary sources that meet recommended intake levels (Table 3.2).
B. EXERCISE INTERVENTIONS Programs for WR using dietary modification are more likely to succeed if physical activity is included as an integral component. Physical activity consumes calories and thus contributes to the energy deficit; it is particularly helpful for maintaining weight loss and preventing weight regain by providing motivation for long-term compliance with the diet (4, 40–42). It also promotes the selective preservation of lean body mass (LBM) during weight loss. Additional benefits that may accrue from regular physical activity include improved glycemic control, lowering of blood pressure, and a reduction in overall CVD risk (43). Specifically, it can lower the risk
2.4 2.4 2.4 2.4 2.4 2.4
1.3 1.5 1.5
Vitamin B12 μg) (μ
1.3 1.7 1.7
Vitamin B6 (mg)
1000 1200 1200
1000 1200 1200
Calciumc (mg)
320 320 320
420 420 420
Magnesium (mg)
18 8 8
8 8 8
Iron (mg)
8 8 8
11 11 11
Zinc (mg)
900 900 900
900 900 900
Copper μ) (μ
25 20 20
35 30 30
Chromium2 μg) (μ
55 55 55
55 55 55
Selenium μg) (μ
130 130 130 130 130 130
56 56 56 46 46 46
700 700 700
900 900 900 5 10 15
5 10 15 15 15 15
15 15 15 90 90 90
120 120 120
75 75 75
90 90 90
1.1 1.1 1.1
1.2 1.2 1.2
1.1 1.1 1.1
1.3 1.3 1.3
14 14 14
16 16 16
400 400 400
400 400 400
b
Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes, The National Academies Press, Washington, D.C., 2002–2003, 39. 0.80g/kg/day c Adequate Intakes (AIs) represent the recommended average daily intake level based on observed or experimentally determined approximations. AIs are used when there is insufficient information to determine an RDA.
a
Men 31–50 51–70 > 70 Women 31–50 51–70 > 70
Gender Proteinb Carbohydrate Vitamin A Vitamin Db Vitamin E Vitamin Kb Vitamin C Thiamin Riboflavin Niacin Folacin μg RAE) μg) μg) μg) Age (y) (g) (g) (μ (μ (mg) (μ (mg) (mg) (mg) (mg) (μ
Men 31–50 51–70 > 70 Women 31–50 51–70 > 70
Gender Age (y)
TABLE 3.2 Selected Dietary Reference Intakes for Adults Aged ≥ 31 Yearsa
50 Nutrition and Diabetes: Pathophysiology and Management
Achieving a Healthy Body Weight
51
of developing type 2 diabetes (44) and improve mortality in individuals with the disease (45). 1. Aerobic Exercise Aerobic exercise contributes to the energy deficit, improves cardiovascular fitness and lipid profiles, and also enhances the preservation of LBM and bone-mineral density. This benefit accrues for individuals with type 2 diabetes, as well as the general OW/OB population. Before embarking on an exercise program, OW/OB individuals with type 2 diabetes should be assessed as to the need for exercise stress testing (46), according to the discretion of their primary-care physician. Once readiness for training has been confirmed, a program of 30–45 minutes of moderate-intensity aerobic activity (40 percent to 60 percent maximum oxygen uptake or 50 percent to 70 percent maximum heart rate) three to five days per week is typically recommended with a gradual increase in duration and frequency of the activity (8, 47). For sedentary individuals who are quite inactive at the onset, the initial exercise should be of short duration and allow for a gradual progression to the target duration and intensity. 2. Resistance training Strengthening exercise (achieved through resistance training; RT) is known to increase muscle mass and strength and thus contributes to the preservation of these attributes during WR dieting. Moreover, RT improves a number of metabolic factors, especially insulin sensitivity. RT improves insulin action (48–51) whether measured by reduced insulin response to an oral-glucose tolerance test or with the euglycemic, hyperinsulinemic clamp. In fact, improved insulin sensitivity is one of the most important benefits of strength training. Castaneda et al. (52) have demonstrated this in adults with type 2 diabetes in only 16 weeks, and Wiley and Singh (53) note that RT can improve insulin sensitivity and glycemic control in elderly patients with diabetes. A typical training regimen might be calibrated to the one-repetition maximum (1 RM), the greatest resistance that can be safely moved in one repetition of a given exercise. An individual might begin with 8–12 repetitions at ~ 75 percent of this amount, which can be varied based on individual needs, preferences, and safety. An initial warm-up series of 8–12 repetitions at ≤ 50 percent of the 1 RM might then proceed with several sets of 70 percent 1 RM directed to target muscles and muscle groups. Resistance can be applied with free weights, cuff weights, exercise machines, or with differential grades of resistance using elastic therapeutic bands. A reasonably comprehensive program might include exercise to quadriceps, hamstrings, hip abductors and adductors, gluteals, calf muscles, pectorals, triceps, deltoids, latissimus dorsi, biceps, abdominals, and erector spinae (46). Exercise regimens can be gradually adjusted and recalibrated to the 1 RM as strength gains are noted. In addition, variations in the program can be incorporated by altering the number of sets or repetitions, the frequency or length of rest periods,
52
Nutrition and Diabetes: Pathophysiology and Management
or by incorporating the use of lighter weights (≤ 50 percent) with shorter rest periods between sets (sometimes referred to as circuit training). 3. Combination Training Ideally, for the joint purposes of enhancing weight reduction, preserving and possibly building lean mass, and improving cardiovascular and metabolic parameters, an optimal exercise regimen should incorporate a mixture of aerobic and resistance training, as the two types of exercise might have separate and different, as well as interactive, protective effects for the individual with type 2 diabetes. An exercise regimen might, for example, include some form of aerobic exercise three times weekly, supplemented by resistance training twice per week.
IV. CONCLUDING COMMENTS ON MAINTENANCE OF WEIGHT LOSS AND IMPROVED FITNESS Specific recommendations for weight-loss interventions for individuals with type 2 diabetes and OW/OB are summarized in Table 3.3. But it is recognized that for individuals who are OW/OB, achieving and maintaining an optimal body mass can be an uphill battle even in the absence of type 2 diabetes complications. While some patients are successful in maintaining at least some of their weight-loss achievement in the long term (54), dietary recidivism seems to be the rule rather than the exception. Thus, while many different dietary schemes show good success in the short term, most OB patients are unable to fully maintain their lower body weights in the long term. As an additional challenge, OB patients who have type 2 diabetes may be more resistant to the maintenance of weight loss because antidiabetic drugs, such as insulin and sulfonylurea, often promote weight gain. The progressive nature of diabetes means that even with successful monotherapy (e.g., management by diet/weight loss) glycemic control may deteriorate over time, necessitating the addition of
TABLE 3.3 Recommendations for OW/OB Individuals with Type 2 Diabetes and Those At Risk for the Disease 1.
2.
3. 4.
Weight loss is recommended for all those with type 2 diabetes mellitus whose BMI exceeds 25 kg/m2; the intervention strategy should include a reduced calorie intake and increased physical activity. The target BMI for this population is 25 kg/m2 or less; but even a modest weight loss of 5 percent to 10 percent of initial body mass will help prevent the development of diabetes and enhance metabolic control for those in whom the disease is already established. In most cases, a calorie-restricted diet should include no fewer than 1000 Kcal/day for women and 1200 Kcal/day for men. A program of regular, moderate-intensity exercise, including both aerobic exercise and resistance training, should be employed and maintained in order to preserve and increase lean-muscle mass, to assist long-term weight management, and to decrease the risk of CVD.
Achieving a Healthy Body Weight
53
pharmacologic treatments, including insulin (20), as discussed in the chpater by Lien and Feinglos in Section II of this book. In patients with longstanding disease or pronounced pancreatic β-cell dysfunction, moderate weight loss may not be sufficient to achieve satisfactory glycemic control. There may be a need for more intensive, ongoing intervention, including an escalation of calorie restriction to a very low-calorie diet, e.g., 800 Kcal/day or less (4, 55). In this event, a routine vitamin/mineral supplement and routine nutritional monitoring should be employed, and indications of medical complications, including gallstones (56), should be monitored. Weight-loss-promoting medications may need to be considered in some cases when calorie reduction and exercise do not result in sufficient weight loss, i.e., BMI ≥ 30 or BMI ≥ 27 plus OW/OB-related comorbid conditions. Bariatric surgery may be considered with a BMI ≥ 40 or BMI ≥ 35 plus comorbid conditions (47). Achieving a healthy body weight can be a daunting task for OW/OB individuals with type 2 diabetes, requiring encouragement and guidance from the health-care team and strong social support from family and friends. Invariably, the potential benefits are nothing short of remarkable, having few negative side effects and providing a number of indirect benefits (improved self-esteem, sense of control) in addition to wide-ranging improvements in health and mortality. Even if pharmacologic agents are needed to achieve full glycemic control, lifestyle interventions can help minimize necessary doses and maximize health benefits.
REFERENCES 1. Sturm, R, The effects of obesity, smoking, and drinking on medical problems and costs. Obesity outranks both smoking and drinking in its deleterious effects on health and health costs, Health Aff., 21, 245, 2002. 2. Mokdad, AH, et al., The continuing epidemics of obesity and diabetes in the United States, J. Am. Med. Assoc., 286, 1195, 2001. 3. Must, A, et al., The disease burden associated with overweight and obesity, J. Am. Med. Assoc., 282, 1523, 1999. 4. Tremble JM and Donaldson, D, Is continued weight gain inevitable in type 2 diabetes mellitus? J. R. Soc. Health 119, 235, 1999. 5. Campbell, L and Rossner, S, Management of obesity in patients with Type 2 diabetes, Diab. Med., 18, 345, 2001. 6. Astrup, A and Finer, N, Refining Type 2 diabetes: ‘diabesity’ or ‘obesity dependent diabetes melllitus’? Obesity Rev., 1, 57, 2000. 7. Yki-Jarvinen, H, Ryysy, L, Kauppila, M, et al., Effect of obesity on the response to insulin therapy in noninsulin-dependent diabetes mellitus, J. Clin. Endocrinol. Metab., 82, 4037, 1997. 8. Klein S, Sheard, NF, Pi-Sunyer X, et al., Weight management through lifestyle modification for the prevention and management of type 2 diabetes: rationale and strategies. A statement of American Diabetes Association, the North American Association for the Study of Obesity, and the American Society for Clinical Nutrition, Am. J. Clin. Nutr., 80, 257, 2004. 9. Leung, WY, et al., Weight management and current options in pharmacotherapy: orlistat and sibutramine, Clin. Ther., 25, 58, 2003.
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Nutrition and Diabetes: Pathophysiology and Management 10. Brolin, RE, Bariatric surgery and long-term control of morbid obesity, JAMA, 288, 2793, 2002. 11. Field, AE, et al., Impact of overweight on the risk of developing common chronic diseases during a 10-year period, Arch. Intern. Med., 161, 1581, 2001. 12. Flegal, KM, Carroll, MD, Ogden, CL, and Johnson, CL, Prevalence and trends in obesity among U.S. adults, 1999-2000. JAMA 288,1723-1727, 2002. 13. Greene, GW, et al., Dietary applications of the stages of change model, J. Am. Diet. Assoc., 99, 673, 1999. 14. Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346, 393, 2002. 15. Tuomilehto J, Lindstrom J, Eriksson, JG, et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N. Engl. J. Med., 344, 1343, 2001. 16. Maggio, CA and Pi-Sunyer, FX, The prevention and treatment of obesity. Application to type 2 diabetes, Diabet. Care, 20, 1744, 1997. 17. Anderson, JW, et al., Carbohydrate and fiber recommendations for individuals with diabetes: a quantitative assessment and meta-analysis of the evidence, J. Am. Coll. Nutr., 23, 5, 2004. 18. Hanefeld, M and Sachese, G, The effects of orlistat on body weight and glycemic control in overweight patients with type 2 diabetes: a randomized placebo-controlled trial, Diabet. Obes. Metab., 4, 415, 2002. 19. UKPDS Group, UK Prospective Diabetes Study 7: response of fasting plasma glucose to diet therapy in newly presenting type II diabetic patients, Metabolism, 39, 905, 1990. 20. Albu, K and Raja-Khan, N, The management of the obese diabetic patient, Primary Care, 30, 465, 2003. 21. Vidal, J, Updated review on the benefits of weight loss, Int. J. Obes. Relat. Metab. Disord., 26 (Suppl.), S525, 2002. 22. Anderson, JW and Kona, EC, Obesity and disease management: effects of weight loss on co-morbid conditions, Obes. Res., 9 (Suppl.), 326S, 2001. 23. Harris, J and Benedict, F, A biometric study of basal metabolism in man, Carnegie Institution, Washington, D.C., 1919. 24. Food and Nutrition Board, Institute of Medicine, Energy, in Dietary Reference Intakes for Energy, Carbohydrates, Fiber, Fat, Protein and Amino Acids (Macronutrients), The National Academies Press, Washington, D.C., 149, 2002. 25. Klein, S, Wadden, T, and Sugarman, HJ, AGA technical review on obesity, Gastroenterology, 123, 882, 2002. 26. Astrup A, Meinert Larse T, and Harpe A, Atkins and other low-carbohydrate diets: hoax or an effective tool for weight loss? Lancet, 364, 897, 2004. 27. Garg, A, High-monounsaturated-fat diets for patients with diabetes mellitus: a metaanalysis, Am. J. Clin. Nutr., 67, 577S, 1998. 28. Wing, RR and Jeffery, RW, Food provision as a strategy to promote weight loss, Obes. Res., 9, 271S, 2001. 29. Yu-Poth, S, et al., Effects of the National Cholesterol Education Program’s Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis, Am. J. Clin. Nutr., 69, 632, 1999. 30. Saris, WH, Astrup, A, Prentice, AM, et al., Randomized controlled trial of changes in dietary carbohydrate/fat ratio and simple vs complex carbohydrates on body weight and blood lipids: the CARMEN study. The Carbohydrate Ratio Management in European National diets, Int. J. Obes. Relat. Metab. Disord., 24, 1310, 2000.
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31. Pirozzo, S, Summerbell, C, Cameron, C, and Glasziou, P, Should we recommend low-fat diets for obesity? Obes. Rev., 4, 83, 2003. 32. Pascale, RW, Wing, RR, Butler, BA, et al., Effects of a behavioral weight loss program stressing calorie restriction versus calorie plus fat restriction in obese individuals with NIDDM or a family history of diabetes. Diabet. Care, 18, 124, 1995. 33. Garg A, Bantle JP, Henry RR, et al. Effects of varying carbohydrate content of diet in patients with non-insulin-dependent diabetes mellitus, JAMA, 271, 1421, 1994. 34. Foster, GD, Wyatt, HR, Hill, JO, et al., A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348, 2082, 2003. 35. Samaha, FF, Iqbal, N, Seshadri P, et al., A low-carbohydrate as compared with a lowfat diet in severe obesity, N. Engl. J. Med., 348, 2074, 2003. 36. Brehm, BJ, Seely, RJ, Daniels, SR, et al., A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women, J. Clin. Endocrinol. Metab., 88, 1617, 2003. 37. Stern, L, Iqbal, N, Seshadri, P, et al., The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one year follow-up of a randomized trial, Ann. Intern. Med., 140, 778, 2004. 38. Yancy, WS, Jr., Olsen, MK, Guyton, JR, et al., A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia: a randomized, controlled trial, Ann. Intern. Med., 140, 769, 2004. 39. Food and Nutrition Board, Institute of Medicine, Dietary Reference Intakes, The National Academies Press, Washington, D.C., 1–7, 2002–2003. 40. NIH, NHLBI, and North American Association for the Study of Obesity, The practical guide. Identification, evaluation, and treatment of overweight and obesity in adults, NIH, Bethesda, MD, 2000. 41. Wing, R. and Hill, JO, Successful weight loss maintenance, Ann. Rev. Nutr., 21, 323, 2001. 42. Doucet, E, Imbeaul, P, Almeras, N, and Tremblay, A, Physical activity and low-fat diet: is it enough to maintain weight stability in the reduced–obese individual following weight loss by therapy and energy restriction? Obes. Res., 7, 323, 1999. 43. Stetson, B and Mokshagundam, SP, Nutrition and lifestyle change in older adults with diabetes mellitus, in Handbook of Clinical Nutrition and Aging, Bales, CW and Ritchie, CS, Eds., Humana Press, Totowa, NJ, 2004, chap. 21. 44. Wei, M, et al., The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men, Ann. Intern. Med., 130, 89, 1999. 45. Church, TS, et al., Exercise capacity and body composition as predictors of mortality among men with diabetes, Diabet. Care, 27, 83, 2004. 46. ACSM, American College of Sports Medicine Position Stand on the recommended quantity and quality of exercise for developing and maintaining cardiorespiratory and muscular fitness and flexibility in healthy adults, Med. Sci. Sports Exercise, 30, 975, 1998. 47. National Institutes of Health, NHLBI, and NIDDK, Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults, NIH, Bethesda, MD, 1998. 48. Miller, WJ, Sherman, WM, and Ivy, JL, Effect of strength training on glucose tolerance and post-glucose insulin response, Med. Sci. Sports Exercise, 16, 539, 1984. 49. Dunstan, DW, Daly, RM, Owen, N, et al., High-intensity resistance training improves glycemic control in older patients with type 2 diabetes, Diabet, Care, 25, 1729, 2002. 50. Eriksson, JG, Exercise and the treatment of type 2 diabetes mellitus, Sports Med., 27, 381, 1999.
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Nutrition and Diabetes: Pathophysiology and Management 51. Rice, B, Janssen, I, Hudson, R, et al., Effects of aerobic or resistance exercise and/or diet on glucose tolerance and plasma insulin levels in obese men, Diabet. Care, 22, 684, 1999. 52. Castaneda, C, Layne, JE, Munoz-Orians, L, et al., A randomized controlled trial of resistance exercise training to improve glycemic control in older adults with type 2 diabetes, Diabet. Care, 25, 2335, 2002. 53. Wiley, KA and Singh, MA, Battling insulin resistance in elderly obese people with type 2 diabetes: bring on the heavy weights, Diabet. Care, 26,1580, 2003. 54. Wing, RR, Behavioral interventions for obesity: recognizing our progress and future challenges, Obes. Res., 11 (Suppl.), 3S, 2003. 55. Dhindsa, P, Scott, AR, and Donnelly, R, Metabolic and cardiovascular effects of verylow-calorie diet therapy in obese patients with Type 2 diabetes in secondary failure: outcomes after 1 year, Diabetic Med., 20, 319, 2003. 56. Weinsier, RL, Wilson, LJ, and Lee J, Medically safe rate of weight loss for the treatment of obesity: A guideline based on risk of gallstone formation, Am. J. Med., 98, 115, 1995.
4
Metabolic Syndrome: Recognition, Etiology, and Physical Fitness as a Component William E. Kraus, M.D. and Cris A. Slentz, Ph.D.
CONTENTS I . The Metabolic Syndrome ............................................................................57 II. Overview of Current Controversies with Definition of the Metabolic Syndrome ......................................................................................58 III. Cross-Sectional Studies of the Importance of Physical Fitness and Exercise to the Diagnosis and Etiology of Metabolic Syndrome..........60 IV. Metabolic Syndrome and Exercise..............................................................63 V. Exercise Training and Individual Components of Metabolic Syndrome ...64 A. Exercise-Training Effects on Blood Pressure.....................................64 B. Exercise-Training Effects on Triglycerides ........................................66 C. Exercise-Training Effects on HDL Cholesterol..................................66 D. Exercise-Training Effects on Fasting Plasma Glucose.......................67 E. Exercise-Training Effects on Insulin Sensitivity ................................69 F. Exercise Training Effects on Waist Circumference............................70 VI. Rationale for Including Cardiorespiratory Fitness in Metabolic Syndrome ......................................................................................71 VII. Future Directions for Research ...................................................................73 References................................................................................................................73
I. THE METABOLIC SYNDROME The general concept of the metabolic syndrome, which describes a clustering of metabolic abnormalities associated with increased risk of cardiovascular disease, diabetes, and hypertension, has been recognized for many years.1–4 Despite a definition of syndrome by the World Health Organization (WHO)5, the most commonly used definition is relatively new. In 2002, the National Cholesterol Education Program, in its Adult Treatment Program III (ATP III),6 presented a definition of 57
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metabolic syndrome that is commonly accepted in the U.S as a working model of the condition. However, the relative novelty of the condition to the general medical and lay audiences and only recent acceptance of a working definition means that there have been few studies of the prevalence, incidence, and response of metabolic syndrome to commonly available lifestyle interventions, such as exercise training. Several excellent reviews of metabolic syndrome exist.7–10 Hence, rather than presenting yet again a review of the topic of metabolic syndrome, in this chapter we will discuss several controversies that continue to plague the field and provide compelling lines of evidence that establish the strong relation between the metabolic syndrome, physical activity, and regular exercise. First, we will present evidence from cross-sectional studies that have consistently reported significant, inverse associations between levels of cardiorespiratory fitness or physical activity and the prevalence of metabolic syndrome (as defined in the ATP III report). Second, we will review the only published study of which we are aware that has analyzed (in a post hoc manner) the effect of exercise training on the metabolic syndrome as currently defined.11 Third, we will briefly present evidence of the relationship between exercise and physical activity and each of the five individual components of the metabolic syndrome. In the course of this discussion, several areas of controversy will become apparent. Where possible, we primarily will point to results from meta-analyses (e.g., blood pressure and exercise). Alternatively, we will reference expert review articles when meta-analyses are not available. In some cases we also discuss data from some key individual studies, relying more heavily on data from randomized, controlled trials (RCTs).
II. OVERVIEW OF CURRENT CONTROVERSIES WITH DEFINITION OF THE METABOLIC SYNDROME The current diagnostic criteria for metabolic syndrome are detailed in Table 4.1. Although the current ATP III definition provides a useful and accessible formula for
TABLE 4.1 ATP III Criteria Risk Factor
Defining Level
Metabolic syndrome is diagnosed when three or more of the following are present. Waist circumference Men > 102 cm (> 40 inches) Women > 88 cm (> 35 inches) Triglycerides ≥ 150 mg/dL HDL cholesterol Men < 40 mg/dL Women < 50 mg/dL Blood pressure ≥ 130/ ≥ 85 mm Hg Fasting glucose ≥ 110 mg/dL
Metabolic Syndrome
59
diagnostic purposes, it is not clear that it has much predictive capacity, thus limiting its clinical utility. Most consider metabolic syndrome to be a prediabetic state, as the various components of the condition are invariably associated with some degree of insulin resistance. However, there are relatively little to no definitive data on the conversion rate of individuals with metabolic syndrome to frank diabetes. Also, although the ATP III guidelines provide a useful working definition, it is clear that the five diagnostic criteria are not independent. For example, low-serum HDL cholesterol and high-serum triglycerides tend to track together in individuals. This makes the current scoring mechanism (i.e., the need to have three of the five diagnostic criteria) seem somewhat artificial and negatively impacts its predictive utility. Thus, there is room for further refining the clinical definition of metabolic syndrome. One potential improvement would be to provide differential weighting of the individual diagnostic conditions by providing a scoring system that incorporates the relative predictive capacity for future events or conversion to diabetes of the various components. Another would be to refine the predictive capacity through inclusion of additional diagnostic criteria, such as elevated high-sensitivity C-reactive protein (hsCRP), or, as we argue further on, through an assessment of cardiorespiratory fitness. There are other, less obvious issues with the current definition. The ATP III and WHO (Tables 4.1 and 4.2) include elevated blood pressure as part of the diagnostic criteria. Although most would agree that elevated waist circumference, fasting serum glucose, low-serum HDL cholesterol, and high-serum triglycerides tend to all be a
TABLE 4.2 WHO Criteria Risk Factor
Defining Level
Metabolic syndrome is diagnosed when the individual has: diabetes, IFG, IGT, or HOMAa insulin resistance AND AT LEAST TWO of the following: Waist-to-Hip Ratio Men Women Triglycerides HDL Men Women Urinary albumin excretion rate Blood pressure a
> 0.90 > 0.85 ≥ 150 mg/dL < 35 mg/dL < 39 mg/dL > 20 μg/min ≥ 140/90 mm Hg
IFG — impaired fasting glucose; IGT – impaired glucose tolerance; HOMA [resting determination of insulin sensitivity = (fasting glucose × 0.055551) × (fasting insulin/22.1)].
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part of the same metabolic substrate for insulin resistance and diabetes mellitus, this is less clear for hypertension. More specifically, it is not apparent whether hypertension is another relatively common cardiovascular risk factor that tends to occur more frequently than not with other relatively common risk factors (associated with the prediabetic state) or whether, in fact, it is part of a metabolic substrate that is characteristic of individuals on the path to developing diabetes. When all five criteria are considered, we and others have noticed that there are striking differences in the prevalence of qualifying criteria among individuals of difference ethnicities. For example, in African Americans, hypertension is more likely to be a qualifying criterion than it is in Caucasians. Conversely, in Caucasians, lipid abnormalities predominate (studies of targeted risk reduction interventions through defined exercise [STRRIDE] data; Table 4.3).12,13 Waist-circumference measures, although attempting to account for differences in women and men, clearly do not account for other differences in body habitus that might influence the normalization of this measure. For example, should a waist circumference of 92 cm be equally applicable in a woman that is 152 cm (60 in) tall as it is in a woman that is 183 cm (72 in) tall? Further, gender differences can be striking in the contribution of waist circumference to metabolic abnormalities. We have observed that women have less visceral fat (unpublished data), lower triglycerides, and much lower serum concentrations of small dense atherogenic low-density LDL cholesterol than do men, even given similar waist circumferences (STRRIDE data; Table 4.3).12 Similar observations can be made for African Americans when compared with Caucasians, i.e., at nearly identical waist circumferences, African Americans have lower visceral fat (unpublished observations) and lower triglycerides compared to Caucasians. Thus, more precision may be achievable in the diagnosis of metabolic syndrome if the criteria were differentially weighted by height, gender, and ethnicity. Finally, as we will argue, there are likely other measures, relatively easily obtained clinically, that contribute to the clinical picture of insulin resistance and may be mechanistically involved in its etiology. These include cardiorespiratory fitness, (e.g., time to exhaustion on a maximal treadmill exercise test) and concentrations of specific lipoprotein subspecies, such as small dense LDL cholesterol.
III. CROSS-SECTIONAL STUDIES OF THE IMPORTANCE OF PHYSICAL FITNESS AND EXERCISE TO THE DIAGNOSIS AND ETIOLOGY OF METABOLIC SYNDROME Cross-sectional studies have consistently found that higher levels of cardiorespiratory fitness or physical activity are associated with decreased risk of morbidity and mortality from diabetes,14,15 cardiovascular disease,16,17 hypertension,18,19 cancer,16 and metabolic syndrome.20,21 In 1999, data from the Aerobics Center Longitudinal Study (ACLS) of the Cooper Clinic in Dallas, Texas, were analyzed for the relationship between cardiorespiratory fitness and metabolic syndrome.20 This study was published before the ATP III definition of metabolic syndrome was available and, as a result, it used a slightly different definition of metabolic syndrome. In this study,
143 49.8 16.9 42.3 46.0 ± ± ± ± ±
± + ± ± ± ± ± 80.8 11.1 11.5 29.0 64.8
25.3 0.78 326 31.2 34.8 45.0 5.75
± 12.4 ± 0.36 ± 5.09 ± 13.5
112 47.4 20.0 35.9 22.5
124 21.0 1345 16.2 50.3 56.1 1.59
37.8 ± 11.9 8.67 ± 0.34 19.8 ± 4.87 18.0 ± 13.0
185 ± 30.5
± ± ± ± ±
75.8 10.4 10.8 27.2 60.7
176 53.9 18.3 50.5 71.2
± ± ± ± ±
77.4 10.6 11.0 27.8 62.0
± 23.8 121 ± 24.3 + 0.73 20.5 + 0.75 ± 305 1414 ± 312 ± 29.3 34.7 ± 29.9 ± 32.6 41.9 ± 33.3 ± 42.2 40.1 ± 43.0 ± 5.40 3.91 ± 5.51
42.4 ± 11.6 8.90 ± 0.33 19.3 ± 4.78 23.1 ± 12.6
187 ± 29.9 .0001 .0001 .0001 .0001
0.0002 0.0019 0.2107 0.0121 0.0006
0.0074 < .0001 0.0634 <.0001 0.0034 <.0001 0.9585
< < < <
< .0001
M> F M> F
M> F M> F
F> M F> M M> F M> F M> F F> M
F> M F> M M> F F> M
F>M
< .0001 < .0001 0.5084 0.0001 < .0001
0.7239 0.0022 0.0557 0.0112 0.5438 0.0212 < .0001
0.1855 0.0004 0.8559 0.2034
0.2466
Race Difference
W> B W> B
W> B W>B
B> W W> B
B>W W> B W> B
B> W
Note: Data expressed as adjusted mean ± SD; Data determined by analysis of covariance adjusting for differences in age and BMI; No interactions between gender and race were observed; ‡ ANCOVA performed using ranked data.
77.9 10.7 11.1 28.0 62.5
Trilyceride (mg/dL) ‡ VLDL size (nm) Small VLDL (mg/dL Tg) Medium VLDL (mg/dL Tg) Large VLDL (mg/dL Tg) ‡ ± ± ± ± ±
131 21.2 1351 14.3 35.0 78.1 3.70
LDL-C (mg/dL) 126 ± 24.4 LDL size (nm) 21.4 + 0.75 LDL particle (nmol/L) 1250 ± 314 Small LDL (mg/dL Chol) ‡ 8.50 ± 30.1 Medium LDL (mg/dL Chol) ‡ 30.1 ± 33.5 Large LDL (mg/dL Chol) ‡ 85.9 ± 43.4 IDL (mg/dL Chol) ‡ 1.08 ± 5.55 85.7 43.6 17.4 26.0 5.98
52.8 9.05 17.1 35.7
207 ± 31.9
12.0 0.34 4.91 13.0
53.0 9.17 17.3 35.6
HDL-C (mg/dL) HDL size (nm) Small HDL (mg/dL Chol) Large HDL (mg/dL Chol) ± ± ± ±
195 ± 30.8
Cholesterol (mg/dL)
Black Women White Women Black Men White Men Gender n = 40 n = 108 n = 29 n =1 08 Difference
TABLE 4.3 Lipoprotein Subclass Distributions by Group and Gender/Race Statistical Comparisons
Metabolic Syndrome 61
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the variables associated with insulin resistance identified by Kaplan22 as part of the “deadly quartet” included systolic BP (≥ 140 mmHg), hypertriglyceridemia (≥ 150 mg/dl), hyperglycemia (fasting glucose ≥ 110 mg/dl), and central adiposity (waist circumference ≥ 100 cm for both men and women). They did not include HDL cholesterol in this study due to its strong correlation with TG. A total of 15,534 men and 3898 women were included in the study. Cardiorespiratory fitness was assessed by time to exhaustion on a treadmill-exercise test, and fitness categories were based on age and gender-normative data. Finally, the association between fitness and clustering of metabolic abnormalities was assessed using proportional odds logit models. For the men, the age-adjusted, cumulative-odds ratio for abnormal markers of metabolic syndrome was 10.1 (C.I. 9.1–11.2, P < 0.0001) when comparing the least-fit with the most-fit men, and was 3.0 (95 percent C.I. 2.7–3.4; P < 0.0001) when comparing the least fit with the moderately fit. For women, the odds ratio was 4.9 (C.I. 3.8–6.3; P < 0.0001) when comparing the least-fit to the most-fit women, and was 2.7 (C.I. 2.7–3.4; P < 0.0001) when comparing the least fit to the moderately fit. These data provide very strong evidence that a highly significant relation exists between cardiorespiratory fitness and clustering of factors of the metabolic syndrome. In another study of the relationship between metabolic syndrome, physical activity and fitness by Carroll et al., 23 similar findings were reported. This study, only in men presenting for preventive assessment at a private hospital in the United Kingdom (n = 711), reported age-adjusted odds ratios for metabolic clustering of 0.28 (95 percent C.I., 0.14–0.57) for moderate fitness versus low fitness and 0.12 (95 percent C.I. 0.05–0.32) for high fitness versus low fitness (P < 0.0001). They also reported that even after exclusion of obesity in the metabolic syndrome definition, the relationship between cardiorespiratory fitness and metabolic syndrome was still significant. Similar relationships were observed for physical-activity measures obtained via recall questionnaire. The confidence level for a trend between physical activity and metabolic syndrome was less (P < 0.05) than it was for cardiorespiratory fitness and metabolic syndrome (P < 0.0001). This is likely due to the nature of the measure, as physical-activity questionnaires are inherently less accurate than the more highly reproducible time to exhaustion on an exercise test. More recently, Irwin et al. 24 examined the relationships between fitness and metabolic syndrome in a smaller sample of women of three ethnicities (African American, n = 49; Native American, n = 46; and Caucasian, n = 51). In this study, the current ATP III definition for metabolic syndrome was used. Physical activity was determined prospectively from detailed subject records that included all physical activity performed during two consecutive four-day periods. Cardiorespiratory fitness was determined from maximal treadmill time during a graded exercise test. They reported significant inverse relations between metabolic syndrome and higher levels of moderate-intensity physical activity (P < 0.01), vigorous-intensity physical activity (P < 0.01), and maximal treadmill time (P < 0.0004) among an ethnically diverse population of women. This appears to be the first study of these relationships in minority women. Importantly, they found that while all associations were statistically significant, the strongest association was between metabolic syndrome and maximal treadmill time. They suggested that cardiorespiratory fitness was a more
Metabolic Syndrome
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objective, albeit indirect, measure of physical activity, and as such is a more accurate exposure variable. It is important to note that physical activity records are generally a reflection of recent activity levels, whereas cardiorespiratory fitness likely reflects a much longer-term effect of regular habitual physical activity. Highlighting the consistency and generalizability of the relationship between physical activity, cardiorespiratory fitness, and metabolic syndrome are similar data reported by Lakka et al. 25 in Finnish men, and by Panagiotakos et al.26 in Greek men and women. In the Lakka study, the relationship between physical activity and metabolic syndrome and between cardiorespiratory fitness and metabolic syndrome was significant, and the magnitude and level of significance was once again much greater for the relation between cardiorespiratory fitness and metabolic syndrome than for physical activity and metabolic syndrome. In fact, total leisure-time physical activity was found to be significantly related to metabolic syndrome when adjusted for age only, or for age and multiple other factors (P < 0.03). Neither low-intensity physical activity nor moderate and vigorous physical activity was significantly related with metabolic syndrome using either statistical model. However, cardiorespiratory fitness was inversely related to metabolic syndrome (P < 0.001) for both the age-adjusted model and for the model that adjusted for age, smoking, alcohol consumption, and socioeconomic status. They found that the least-fit men were almost seven times more likely to have the metabolic syndrome than the most-fit men even when major confounders were controlled. Furthermore, Lakka found, even after controlling for body-mass index, that the least-fit men had a nearly fourfold likelihood of having the metabolic syndrome when compared with the most-fit men, suggesting a strong, independent relationship between cardiorespiratory fitness and prevalence of metabolic syndrome. The observation that cardiorespiratory fitness independent of body-mass index is a very strong predictor of metabolic risk, diabetes risk, and overall cardiovascular risk is supported by numerous studies from the Aerobics Center Longitudinal Study of Dallas.27-30 In aggregate, these findings imply that cardiorespiratory fitness should be included as a defining variable of the metabolic syndrome. In fact, one of the conclusions of Lakka et al.25 was that the measurement of peak oxygen consumption (VO2) (a measure highly correlated with time to exhaustion in an exercise test) in sedentary men with cardiovascular risk factors might provide an efficient means for targeting individuals who would benefit from interventions to prevent the metabolic syndrome and its consequences. Presumably, these relationships hold as strongly in women as in men, although the data is not as extensive in women.
IV. METABOLIC SYNDROME AND EXERCISE The relatively recent recognition of the metabolic syndrome as a clinically definable entity implies that few studies are available that address the specific effects of exercise training on the prevalence of metabolic syndrome. To our knowledge, there is only one exercise-training study that has published data analyzed (post hoc) based on the new ATP III definition of metabolic syndrome. This study is the Heritage Family Study11. The Heritage Family Study was a multicenter study, including a large number of individuals across a large age range (18–65 yr) in African American and Caucasian men
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and women. Complete data were available on 621 subjects who completed the exercise training. Of these, 105 had metabolic syndrome as defined by ATP III. The race and gender distribution coupled with the wide age range of study participants in this trial makes the findings likely generalizable to a large portion of the U.S. adult population. Furthermore, the research design emphasized close attention to the details of measurement and quality control within and between sites, strengthening the validity of the conclusions.31 Of pertinence, the exercise exposure was very carefully monitored and standardized with the data presented representing those individuals who completed 95 percent or more of the prescribed exercise sessions. In the Heritage Family Study, of the 105 subjects who had the ATP III definition of metabolic syndrome (waist circumference, fasting, triglycerides, HDL-C and glucose, and blood pressure), nearly one third (30.5 percent, 32 of the 105) were no longer defined as having metabolic syndrome after the exercise-training program of 20 weeks. This was a highly physiologically, clinically, and statistically significant effect. It is particularly impressive, given that the exercise stimulus was of a fairly modest weekly amount (likely very similar total amount of exercise as approximately 30 min of moderate-intensity exercise six days per week) and was of a relatively modest training duration. In Figure 4.1, the prevalence of individual risk factors and the prevalence of metabolic syndrome is shown with both before and after prevalence rates. Of the five risk factors, all except the prevalence of low HDL-C were significantly decreased with exercise training. In individuals with a clustering of metabolic syndrome risk factors (i.e., three or more risk factors), the prevalence of metabolic syndrome was even more substantially reduced with the exercise-training intervention than any of the individual risk factors. In Table 4.4, the prevalence percentages for each of the five risk factors are shown individually for each subject subgroup (black men, white men, black women, and white women). The consistency of the exercise effects on metabolic syndrome across race and gender subgroups and over a large range of ages emphasize, as did the previous cross-sectional studies, the strong generalizability of these effects.
V. EXERCISE TRAINING AND INDIVIDUAL COMPONENTS OF METABOLIC SYNDROME A discussion of the effects of individual exercise training studies on each of the five individual components of the metabolic syndrome is beyond the scope of this review. Instead, we will summarize the effects by briefly discussing reviews and metaanalyses, and in some cases a few key exercise training studies.
A. EXERCISE-TRAINING EFFECTS
ON
BLOOD PRESSURE
Numerous meta-analyses of the effect of aerobic exercise on blood pressure have been published, and the results have been consistent. Fagard18 performed a metaanalysis on 44 RCTs and concluded that aerobic exercise reduces blood pressure and that the lowering effect was greater in hypertensives (–7/–6 mm Hg) than normotensives (–3/–2 mm Hg). Further, he concluded that the evidence in support of these findings achieved the highest level of confidence rating, i.e., a “Category
Metabolic Syndrome
* * * *
%
100 90 80 70 60 50 40 30 20 10 0
65
*
High TG
Low HDL-C
High BP
High Glucose
Pre-Training
High WC
Metabolic Syndrome
Post-Training
FIGURE 4.1 Prevalence of individual risk factors before and after 20 wk of aerobic exercise training in the HERITAGE Family Study among 105 participants with the metabolic syndrome at baseline. *P < 0.05 pretraining versus posttraining. Reprinted with permission from Med. Sci. Sport Exerc., 35:1703–09, 2003.
TABLE 4.4 Prevelance (%) of Risk Factors Pre- and Post Training Among 105 Participants in the HERITAGE Family study Classified as Having the Metabolic Syndrome at Baseline High TG
Low HDL
High BP
High Glucose
High WC
Black men Pre 93 Post 79
100 100
71 43
43 29
43 43
White men Pre 76 Post 63
98 93
46 42
24 7
93 76
Black women Pre 26 Post 13
100 96
87 65
35 30
100 91
White women Pre 81 Post 62
100 93
26 22
15 19
100 93
A” level, indicating that the conclusion was based on a rich body of data from well-designed, randomized clinical trials providing a consistent pattern of results. In addition to this general finding, this report looked at the effects of the individual components of exercise training: intensity, frequency, and individual session duration. Fagard concluded that the beneficial aerobic-exercise effect was not dependent
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on exercise intensity (between 40 percent 70 percent of maximal exercise performance) and that the effect was similar for frequencies of three to five times per week and for session durations of 30–60 minutes. In a somewhat larger and more recent meta-analysis, also on RCTs (n = 54), Whelton et al.32 concluded that aerobic exercise decreased diastolic and systolic blood pressure in both hypertensive and normotensive individuals. The effect was somewhat larger in the hypertensives (–5/–4 mm Hg) than the normotensives (–4/–2 mm Hg). Additional analyses revealed that the beneficial exercise effects were observed in Caucasians and Asians for both systolic and diastolic blood-pressure reductions. In African Americans, a significant beneficial effect was found for systolic, but not diastolic, blood pressure. Importantly, only two studies met the analysis criteria and were included in the analysis for exercise effect and diastolic blood pressure in African Americans, suggesting the need for additional studies in minorities. Several other meta-analyses have been conducted over the years, and all have reported a significant exercise effect on blood pressure.32–35 In spite of the finding of a consistent, beneficial effect of exercise on blood pressure in numerous metaanalyses, important ethnic differences exist for health parameters in general, yet a relatively small number of studies of exercise and blood pressure were found in both African Americans and Asians. While no analysis was presented for the separate effects of exercise on blood pressure in women and men, seventeen of the fifty-one trials that reported sex distribution included predominantly women (≥ 80 percent), while only 10 were predominantly men.
B. EXERCISE-TRAINING EFFECTS
ON
TRIGLYCERIDES
One of the more extensive reviews of the effects of exercise on lipids and lipoproteins was conducted by Durstine and Haskell.36 First, in analyzing several cross-sectional studies comparing inactive controls to either endurance athletes, runners, crosscountry skiers, tennis players, or individuals with longer treadmill test times, they concluded that generally active individuals have lower triglyceride concentrations. With regard to exercise-training studies, they reported that training also generally reduced the triglyceride levels if the baselines were elevated. They also found that the degree of reduction in triglycerides was related to both the baseline amount of triglyceride elevation and to the volume of exercise training, but that in women, these findings were not as consistent. In a more recent meta-analysis of fifty-one studies, of which twenty-eight were randomized controlled trials, Leon and Sanchez37 reported an overall 3.7 percent average decrease in triglycerides (P < 0.05). They also reported that men generally had a greater reduction then women. However, in general, they concluded that the blood-lipid response to exercise, including the triglyceride response, was quite variable, confirming similar observations from previous reviewers.
C. EXERCISE-TRAINING EFFECTS
ON
HDL CHOLESTEROL
Durstine and Haskell36 reported that in cross-sectional studies endurance athletes have 20 percent to 30 percent higher levels of HDL cholesterol when compared to
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67
inactive controls. Cross-sectional studies also suggest a dose-response relationship between amount of exercise and HDL-C concentrations. However, exercise-training studies, according to Durstine and Haskell, have not been as consistent, as many studies have reported a significant training benefit on HDL-C levels, while many other studies did not find the effect to be significant. Leon and Sanchez,37 in their meta-analysis, reported a marked inconsistency of the effects of aerobic-exercise training on blood lipids in general, and they suggested that the most frequent finding was of a significant (P < 0.05) increase in HDL-C. However, this significant beneficial effect was reported in only 24 of the 51 studies (47 percent) included in the review. The exercise-induced change in HDL-C ranged from a decrease of 5.8 percent to an increase of 25 percent. Nevertheless, overall there was an average increase of 4.6 percent across the studies (P < 0.05). Some help in understanding the variability in the lipid response has recently been reported in an eight-month exercise training study by Kraus et al.38 In the first randomized controlled study of the effect of two different amounts of exercise training on HDL-C, they reported that only the larger amount of exercise (an amount of exercise calorically equivalent to ~ 17 miles of jogging per week) was found to have a significantly increased HDL-C, compared to an inactive control group. The two lower amounts of exercise training (both calorically equivalent to ~ 11 miles per week, one group at a moderate exercise intensity and the other group at a more vigorous exercise intensity) had small, nonsignificant, increases in HDL-C. Thus, the Kraus study confirmed the earlier analysis of Durstine and Haskell, which reported that cross-sectional studies suggested that there was a dose-response effect of exercise training on HDL-C improvement.
D. EXERCISE-TRAINING EFFECTS
ON
FASTING PLASMA GLUCOSE
In a recent meta-analysis of controlled clinical trials (11 randomized and three nonrandomized) on the effects of exercise training on glycemic control in individuals with type 2 diabetes, Boule and colleagues39 reported a significant (P < 0.001) beneficial exercise effect on glycosylated hemoglobin (HbA1c) (–0.66 percent) compared to the controls. The authors concluded that exercise training reduces HbA1c by an amount that should decrease the risk of diabetic complications. The difference found in this meta-analysis was close to the difference (–0.9 percent) between conventional and intensive glucose-lowering therapy reported in the United Kingdom Prospective Diabetes Study (UKPDS)40,41; an amount that was associated with significant improvement in clinical outcomes (development of microvascular and macrovascular complications of diabetes, including cardiovascular disease). The authors went on to speculate that exercise might result in a greater reduction in cardiovascular complications than with insulin or sulfonylureas since exercise has additional cardioprotective benefits and does not cause weight gain. We are not aware of a meta-analysis of the effects of exercise training in nondiabetics, most likely because HbA1c, a good, long-term measure of glucose control, is not often measured in nondiabetic subjects. Neither are we aware of a meta-analysis of the effects of exercise on fasting blood glucose in any population. There are a number of individual exercise studies in normal individuals that report
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fasting glucose11,42 and HbA1c43 are significantly improved with exercise training. Unfortunately, none of these studies had a control group. Additionally, there are many exercise-training studies in normal individuals where no decrease in fasting glucose is observed, presumably because these individuals already have normal and healthy fasting glucose levels44 (unpublished observations). In a comprehensive review by Ivy et al.,45 several lines of evidence are presented that support a key role of exercise and physical activity in prevention and treatment of diabetes. As diabetes is defined by fasting glucose, prevention of diabetes is defined by the prevention of increases in fasting serum glucose. Ivy and colleagues reviewed numerous epidemiological studies (cross-sectional, retrospective, and prospective designs) that provide strong support for the beneficial effect of physical activity in the prevention of type 2 diabetes. Studies on the population of Mauritius showed that the relationship between low levels of physical activity and increased prevalence of impaired fasting glucose and type 2 diabetes existed across both sexes and across the major ethnic groups on the island46–48 and that total physical activity was a significant, independent predictor even after controlling for several major confounders. Mayer-Davies et al.49 reported similar findings in a large, culturally and ethnically diverse sample of men and women. Kriska and colleagues reported the same relationship in Pima Indians.50 Manson et al.,51,52 in a prospective study, provided additional evidence of this relationship, including evidence of a doseresponse effect of increased exercise frequency and reduced risk of type 2 diabetes. Ivy et al. presented additional evidence in their review of bed-rest studies53–56 and exercise-detraining studies,57–59 which together revealed a rapid deterioration in insulin action and glucose tolerance (if the individual/population was glucose intolerant) with even short periods of bed rest or detraining. But, does exercise training improve glucose tolerance and prevent development of type 2 diabetes? Exercise training reliably improves insulin action in all subjects but does not affect glucose tolerance in normal individuals. However, in glucoseintolerant individuals, exercise does result in improvements in glucose tolerance. In a seven-day exercise-training study in ten men with mild type 2 diabetes or impaired glucose tolerance, Holloszy’s group60 found that two of three who had impaired glucose tolerance had a normal oral glucose-tolerance test after training. Of the seven men with type 2 diabetes, three had normal oral glucose-tolerance tests after training, two had only impaired fasting glucose, and two still had diabetic oral glucose-tolerance tests after seven days of training. The two who still had diabetic oral glucose-tolerance tests had relative hypoinsulinemia, whereas the other eight that improved with exercise all had mild to moderate hyperinsulinemia. The data suggest that when sufficient insulin reserve exists, exercise training has the potential to reverse glucose intolerance and even mild type 2 diabetes. Results from cross-sectional studies of young and old endurance athletes compared to young and old (lean and not lean) untrained individuals show that untrained individuals have decreased insulin action and decreased glucose tolerance compared to young and old athletes.61 The master athletes, compared to young athletes, had essentially identical insulin and glucose responses to an oral glucose-tolerance test, indicating that age need not result in impaired glucose tolerance. The authors suggested that earlier studies that had shown no improvement in insulin action or glucose
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tolerance generally used an insufficient exercise stimulus, waited too long after the final exercise bout, and used patients with relative insulin deficiency. When this group trained individuals for one year who were mildly diabetic without insulin deficiency and measured oral glucose-tolerance tests within 18 hours of the last bout of exercise, they found significantly improved glucose tolerance and insulin action and that fasting glucose levels were normalized.62 Data from Reitman et al.63 reported 6–10 weeks of intensive exercise lowered fasting glucose and improved glucose tolerance in obese type 2 diabetic individuals. Other studies in type 2 diabetic subjects support these findings.64,65 While the totality of the data are quite compelling, it is clear that a large, controlled, randomized study of the effects of exercise training in mild type 2 diabetic subjects would provide more definitive evidence for the potential reversal of type 2 diabetes with exercise training. One cannot discuss the effects of exercise training on progression to diabetes in individuals without mention of the results of the Diabetes Prevention Program.66 In this study, the effects of pharmacologic therapy (metformin) and lifestyle interventions (exercise training at the level of ACSM/CDC recommendations of 30 minutes per day most days of the week, diet, and weight loss for a total of 7 percent body weight) were compared with usual care. The results revealed that the lifestyle intervention reduced the risk of progression to diabetes in this population by 58 percent compared with usual care. The effects of metformin, although statistically and clinically significant, were less impressive in reducing rate of progression to diabetes, which it did by 31 percent compared to usual care. Granted, this trial did not study the effects of exercise alone, but it points out the utility of lifestyle interventions in individuals with metabolic syndrome.
E. EXERCISE-TRAINING EFFECTS
ON INSULIN
SENSITIVITY
The metabolic syndrome is conceptually the same as the insulin-resistance syndrome, and the names are essentially interchangeable. That some prefer the term insulin-resistance syndrome is due to the common understanding that an observable decrease in insulin sensitivity is the first detectable aberration in course toward metabolic syndrome. In fact, some deterioration in insulin sensitivity is generally observed prior to elevations in triglycerides levels, decreases in HDL-C concentrations, which in turn precede deterioration in fasting glucose, and glucose-tolerance measures, and perhaps even before clinically significant increases in body weight, body-mass index, and waist circumference are apparent. In fact, as a reflection of this understanding, the WHO includes a resting measure of insulin resistance in its definition of metabolic syndrome (Table 4.2). The relationship between exercise and insulin resistance is clear. In fact, one of the most consistent, beneficial effects of exercise is a statistically and physiologically significant improvement in insulin action. This beneficial effect can be observed in a broad range of exercise conditions and models: after only a few bouts of acute exercise,60,67 or with longer term exercise training68–71; with low-intensity or highintensity exercise (Figure 4.1 from Houmard et al., 200467,72); and in exercising animals71 and humans.68-70 In a classic study, Seals et al.61 observed that even young, lean, but sedentary individuals have nearly twice the insulin response to an
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* α
120
* α
100 Change SI (%)
80 60
*
40 20 0 –20
Control
Low/Mod Low/High High/High Group
FIGURE 4.2 Relative changes (%) (after training/before training) in insulin-sensitivity index derived from the intravenous glucosetolerance test (Si) in the control and exercise [lowvolume/moderate-intensity (Low/Mod); low-volume/high-intensity (Low/High); high-volume/high-intensity (High/High)] groups. Line at 0.0 represents no change. *Significant difference from control group, P < 0.05; Alpha symbol ó significant difference from the Low/Highgroup, P < 0.05. Reprinted with permission from J. Appl. Physiol., 96:101–106, 2004.
oral-glucose administration as young, lean, endurance athletes. Aging had no influence on this observation, as the results were the same when the young, lean, sedentary individuals were compared to older (mean age 60 years), lean, endurance athletes, demonstrating an improved insulin action in endurance athletes when compared with sedentary controls. In a study from our group,72 the data revealed that of the two groups performing the same amount of exercise (calorically equivalent to walking or jogging ~ 10 miles per week), the lower exercise-intensity group had a greater improvement in insulin sensitivity (Figure 4.2). This may specifically be due to a beneficial effect of low-intensity exercise, which is known to oxidize more fat than the same amount of more vigorous exercise. Alternatively, it may be due to the higher exercise frequency and total time of weekly exercise required by the low amount/moderate-intensity group to expend the same amount of calories through exercise. Whether this same observation holds for individuals with frank diabetes remains an open question and a potential area for future investigation.
F. EXERCISE TRAINING EFFECTS
ON
WAIST CIRCUMFERENCE
In randomized, controlled trials that provided a significant increase in exercise volume, either through a large, weekly amount of exercise for a short time period (4900 Kcal/wk for 12 weeks; Ross et al.44), or a smaller, weekly amount over a long time period (980 Kcal/wk for 48 weeks; Binder et al.73), or both (2000 Kcal/wk for 36 weeks; Slentz et al.74), statistically and physiologically significant decreases in waist circumference have been observed. In the randomized, controlled exercisetraining study by Kraus’ group,74 two amounts of exercise (low dose, ~ 1200 Kcal/wk, and high dose, ~ 2000 Kcal/wk) combined with a control (no extra Kcal/wk through exercise) revealed a clear, strong volume of exercise effect on reductions in abdominal obesity as measured by waist circumference (Figure 4.3). In this study,
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71
Δ Waist Cir (%)
2 0 –2 –4 –6
Control
Low-amount Low-amount High-amount moderate-intensity vigorous-intensity vigorous-intensity
FIGURE 4.3 Effects of exercise amount and intensity on mean percent changes in waist circumference. * Indicates P < 0.05 compared with controls. Error bars show SE.
even the low-dose exercise groups had significant reductions in waist circumference compared to the inactive control group. Clearly, when a significant exercise-training stimulus is provided, waist circumference and abdominal obesity are reduced.
VI. RATIONALE FOR INCLUDING CARDIORESPIRATORY FITNESS IN METABOLIC SYNDROME Lakka et al. suggested that a sedentary lifestyle and especially poor cardiorespiratory fitness are not only associated with metabolic syndrome but could be considered central, defining features of metabolic syndrome.25 Further, they suggested that measurement of peak VO2 in sedentary men with risk factors could provide a means of identifying individuals who would most benefit from interventions, especially lifestyle interventions, in individuals at risk of developing diabetes mellitus. Numerous studies have revealed a clear, independent relationship between exercise capacity (cardiorespiratory fitness) and cardiovascular events and all causes of deaths in men.16,17,75–82 And in a recent study by Gulati et al.,83 the authors reported a strong, independent relationship between exercise capacity as a predictor of death in asymptomatic women, which they observed was stronger than what had been previously established among men. Even after adjusting for traditional cardiovascular risk factors via the Framingham Risk Score (a point system assessing risk, which includes total cholesterol, HDL-C, age, systolic blood pressure, diastolic blood pressure, smoking, and the presence or absence of diabetes), they found that the adjusted hazards ratios (with 95 percent CI) of death associated with MET levels of < 5, 5 to 8, and > 8 were 3.1 (2.0 to 4.7), 1.9 (1.3 to 2.9), and 1.00, respectively. Data from the Cooper Clinic had revealed similar, albeit not as strong, relationships between cardiorespiratory fitness and cardiovascular disease mortality16 in women. Further, Weinsier et al.,84 using U.S. data, and Prentice and Jeb,85 using U.K. data, extensively reviewed the data concerning the question of whether the obesityand-diabetes epidemic is primarily due to overeating or lack of physical activity (the “gluttony versus sloth” debate). Both have cautiously concluded that, even given the
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difficulty in measuring changes in caloric consumption or physical activity over the past decades, it is clear that physical inactivity is a major culprit in the obesity epidemic. They go on to suggest that perhaps physical inactivity is the major culprit. This concept is supported by studies from the 50s in carefully performed studies in animals86 and humans.87 Meyers et al. observed that at significant physical activity levels, increases or decreases in physical activity were matched with increases or decreases in food intake. However, below certain minimal levels of physical activity, further decreases in physical activity were not met by further decreases in food intake, but rather by increases in food intake and consequent body weight. They interpreted the data to suggest that a minimal level of physical activity might be necessary for appropriate appetite control. Recent data from our group provides support for this theory. In our study,74 inactive controls gained weight over a sixmonth period, whereas two different low-dose exercise-training groups (equivalent to ~ 12 miles/wk of walking or jogging) lost weight and a higher dose (equivalent to ~ 17 mile/wk) lost even more body mass. The data suggest that below a certain level, appetite control is not appropriately balanced, and weight gain occurs. If these suggestions are correct, then the extreme levels of physical inactivity present in today’s society may be at the root of the obesity-and-diabetes epidemic in that these levels of inactivity may directly lead to the inability to balance food intake with decreasing physical-activity levels, resulting in continuous weight gain and progression from metabolic syndrome to diabetes. As reviewed previously, physical-activity levels are poorly measured, whereas cardiorespiratory fitness is a relatively easily measured, reliable, and accurate clinical assessment that is a good surrogate for physical activity. Studies show that both moderate and vigorous-intensity activity can lead to increases in cardiorespiratory fitness.38,88 Finally, in a particularly compelling article entitled “Exercise capacity: The prognostic variable that doesn’t get enough respect,” Mark and Lauer discuss what they refer to as “one of the most potent prognostic variables,”89 i.e., exercise capacity/cardiorespiratory fitness. The article is precipitated by the Gulati et al.83 study (see discussion above) reported in the same issue, along with numerous studies that have come before this. Mark and Lauer argue that the overwhelming amount of data support the role of exercise capacity as a potent prognostic indicator of future health for both men and women and for both symptomatic and asymptomatic individuals. We believe that the accumulated evidence provides strong rationale for including cardiorespiratory fitness as one of the major defining diagnostic components of the metabolic syndrome. Furthermore, by including cardiorespiratory fitness in the definition of metabolic syndrome, individuals and physicians would more likely focus directly on physical activity and fitness as measures of health. This would also demand attention to methods for increasing physical activity and cardiorespiratory fitness as an effective, therapeutic intervention for metabolic syndrome and the prevention of progression to type 2 diabetes. A direct emphasis on physical activity and cardiorespiratory fitness certainly will have significant consequences on the prevalence of metabolic syndrome, obesity, progression to type 2 diabetes, and cardiovascular disease in the U.S. population.
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VII. FUTURE DIRECTIONS FOR RESEARCH It seems clear that regular exercise/physical activity has beneficial effects both for preventing and treating type 2 diabetes and metabolic syndrome. Particularly promising areas of research are: (a) the most effective amounts and intensities of exercise that lead to these benefits in individuals with diabetes; (b) investigating the unique role that resistance-training exercise may have on insulin sensitivity and metabolic syndrome; and (c) the interactions between exercise, environment, and genetics. We are currently in the early phases of a study of the separate and combined effects of aerobic and resistance exercise on individuals with aspects of the metabolic syndrome (central obesity, dyslipidemia, and sedentary lifestyle). We anticipate that such lines of investigation hold great promise for improving our effectiveness in diagnosing individuals with metabolic syndrome on the road to type 2 diabetes and in ultimately preventing its development in susceptible individuals.
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Nutrition and Diabetes: Pathophysiology and Management 13. Despres, J, Couillard, C, Gagnon, J, et al., Race, visceral adipose tissue, plasma lipids and lipoprotein lipase activity in men and women, the HERITAGE family study, Arter. Thromb. Vasc. Biol., 20:1932–38, 2000. 14. Wei, M, Gibbons, L, Mitchell, T, Kampert, J, Lee, C, and Blair, S, The association between cardiorespiratory fitness and impaired fasting glucose and type 2 diabetes mellitus in men, Ann. Intern. Med .,130:89–96, 1999. 15. Wei, M, Gibbons, L, Kampert, J, Nichaman, M, and Blair, S, Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes, Ann. Intern. Med., 132:605–11, 2000. 16. Blair, S, Kohl, HI, Paffenbarger, RJ, Clark, D, Cooper, K, and Gibbons, L, Physical Fitness and all-cause mortality. A prospective study of healthy men and women, JAMA, 262:2395–2401, 1989. 17. Blair, S, Kohl, HI, Barlow, C, Paffenbarger, RJ, Gibbons, L, and Macera, C, Changes in physical fitness and all-cause mortality. A prospective study of healthy and unhealthy men, JAMA, 273:1093–98, 1995. 18. Fagard, R, Exercise characteristics and the blood pressure response to dynamic physical training, Med. Sci. Sports Exerc., 33:S484–492, 2001. 19. Blair, S, Kohl, HI, Barlow, C, and Gibbons, L, Physical fitness and all-cause mortality in hypertensive men, Ann. Med., 23:307–12, 1991. 20. Whaley, M, Kampert, J, Kohl, HI, and Blair, S, Physical fitness and clustering of risk factors associated with the metabolic syndrome, Med. Sci. Sports Exeric., 31:287–93, 1999. 21. Katzmarzyk, PT, Church, T, and Blair, S, Cardiorespiratory fitness attenuates the effects of metabolic syndrome on all-cause and cardiovascular disease mortality in men, Archives Intern. Med., 164:1092–97, 2004. 22. Kaplan, N, The Deadly Quartet: upper body obesity, glucose intolerance, hypertriglyceridemia and hypertension, Archives Intern. Med., 149:1514–20, 1989. 23. Carroll, S, Cooke, C, and Butterly, R, Metabolic clustering, physical activity and fitness in nonsmoking, middle-aged men, Med. Sci. Sports Exerc., 32:2079–86, 2000. 24. Irwin, M, Ainsworth, B, Mayer-Davis, E, Addy, C, Pate, R, and Durstine, J, Physical activity and the metabolic syndrome in a tri-ethnic sample of women, Obes. Res., 10:1030–1037, 2002. 25. Lakka, T, Laaksonen, D, Lakka, H, et al., Sedentary lifestyle, poor cardiorespiratory fitness, and the metabolic syndrome, Med. Sci. Sports Exerc., 35:1279–1286, 2003. 26. Panagiotakos, D, Pitsavos, C, Chrysohoou, C, et al., Impact of lifestyle habits on the prevalence of the metabolic syndrome among Greek adults from the ATTICA study, Am. Heart J., 2004; 147:106–12, 2004. 27. Lee, C, Jackson, A, and Blair, S, US weight guidelines: is it also important to consider cardiorespiratory fitness? Internat. J. Obes. Relat. Metab. Disord., 22:2–7, 1998. 28. Wei, M, Kampert, J, Barlow, C, et al., Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight, and obese men, JAMA, 282:1547–53, 1999. 29. Farrell, S, Braun, L, Barlow, C, Cheng, Y, and Blair, S, The relation of body mass index, cardiorespiratory fitness and all-cause mortality in women, Obes. Res., 2002; 10:417–23, 2002. 30. Lee, C, Blair, S, and Jackson, A, Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men, Am. J .Clin. Nutr., 69:373–80, 1999.
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31. Gagnon, J, Province, M, and Bouchard, C, The HERITAGE Family study: quality assurance and quality control, Ann. Epidemiol., 6:520–29, 1996. 32. Whelton, S, Chin, A, Xin, X, and He, J, Effect of aerobic exercise on blood pressure: a meta-analysis of randomized, controlled trials, Ann. Intern. Med., 136:493–503, 2002. 33. Halber, J, Silagy, C, Finucane, P, Withers, R, Hamdorf, P, and Andrews, G, The effectiveness of exercise training in lowering blood pressure: a meta-analysis of randomised controlled trials of 4 weeks or longer, J. Human Hypertens., 11:641–49, 1997. 34. Kelley, G and Sharpe, K, Aerobic exercise and resting blood pressure in older adults: a meta-analytic review of RCT's, J. Gerontol. Series A-Bio. Sci. Med. Sci. 56:298–303, 2001. 35. Kelley, G, Aerobic exercise and resting blood pressure among women: a metaanalysis, Prev. Med., 28:264–75, 1999. 36. Durstine, J and Haskell, W, Effects of exercise training on plasma lipids and lipoproteins, Exerc. Sport Sci. Rev., 22:477–524, 1994. 37. Leon, A and Sanchez, O, Response of blood lipids to exercise training alone or combined with dietary intervention, Med. Sci. Sports Exerc., 33:S502–515, 2001. 38. Kraus, W, Houmard, J, Duscha, B, et al., Effects of the amount and intensity of exercise on plasma lipoproteins, N. Engl. J. Med., 347:1483–92, 2002. 39. Boule, N, Haddad, E, Kenney, G, Wells, G, and Sigal, R, Effects of exercise on glycemic control and body mass in Type 2 Diabetes mellitus, JAMA, 286:1218–27, 2001. 40. Group UPDS, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes, Lancet, 352:837–53, 1998. 41. Group UPDS, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes, Lancet, 352:854–65, 1998. 42. Arciero, P, Vukovich, M, Holloszy, J, Racette, S, and Kohrt, W, Comparison of shortterm diet and exercise on insulin action in individuals with abnormal glucose tolerance, J. Appl. Physiol., 86:1930–35, 1999. 43. Walker, K, Piers, L, Putt, R, Jones, J, and O’Dea, K, Effects of regular walking on cardiovascular risk factors and body composition in normoglycemic women and women with Type 2 diabetes, Diabet. Care, 22:555–61, 1999. 44. Ross, R, Dagnone, D, Jones, P, et al., Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men: a randomized, controlled trial, Ann. Intern. Med., 133:92–103, 2000. 45. Ivy, J, Zderic, T, and Donovan, F, Prevention and treatment of non-insulin-dependent diabetes mellitus, Exerc. Sport Sci. Rev., 27:1–35, 1999. 46. Dowse, G, Zimmet, P, Gareeboo, H, et al., Abdominal obesity and physical inactivity as risk factors for NIDDM and impaired glucose tolerance in Indian, Creole, and Chinese Mauritians, Diabet. Care, 14:271–82, 1991. 47. Pereira, M, Kriska, A, Joswiak, M, et al., Physical inactivity and glucose tolerance in the multiethnic island of Mauritius, Med. Sci. Sports Exerc., 27:1626–34, 1995. 48. Zimmet, P, Collins, V, Dowse, G, et al., The relation of physical activity to cardiovascular disease risk factors in Mauritians, Am. J. Epidemiol., 134:862–75, 1991. 49. Mayer-Davis, E, D’Agostino, R, Karter, A, Haffner, S, Rewers, M, Saad, M, Bergman, R, Intensity and amount of physical activity in relation to insulin sensitivity: the Insulin Resistance Atherolsclerosis Study, JAMA, 279:669–674, 1998.
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Nutrition and Diabetes: Pathophysiology and Management 50. Kriska, A, LaPorte, R, Pettitt, D, et al., The association of physical activity with obesity, fat distribution and glucose intolerance in Pima Indians, Diabetologia, 36:863–869, 1993. 51. Manson, J, Nathan, D, Krolewski, A, Stampfer, J, Willett, W, and Hennekens, C, A prospective study of exercise and incidence of diabetes among U.S. male physicians, JAMA, 268:63–67, 1992. 52. Manson, J, Rimm, E, Stampfer, J, et al., Physical activity and incidence of NIDDM in women, Lancet, 338:774–778, 1991. 53. Lipman, R, Raskin, P, Love, T, Triebwasser, J, Lecocq, F, and Schnure, J, Glucose intolerance during decreased physical activity in man, Diabetes, 21, 1972. 54. Lipman, R, Schnure, J, Bradley, E, and Lecocq, F, Impairment of peripheral glucose utilization in normal subjects by prolonged bed rest, J. Lab. Clin. Med., 76:221–30, 1970. 55. Misbin, R, Moffa, A, and Kappy, M, Insulin binding to monocytes in obese patients treated with carbohydrate restriction and changes in physical activity, J. Clin. Endocrinol. Metab., 56:273–78, 1983. 56. Stuart, C, Shamgraw, R, Prince, M, Peters, E, and Wolfe, R, Bed-rest-induced insulin resistance occurs primarily in muscle, Metabolism, 37:802–06, 1988. 57. Heath, G, Gavin, J, Hinderliter, J, Hagberg, J, Bloomfield, S, and Holloszy, J, Effects of exercise and lack of exercise on glucose tolerance and insulin sensitivity, J. Appl. Physiol., 55:512–17, 1983. 58. King, D, Dalsky, G, Clutter, W, et al., Effects of exercise and lack of exercise on insulin sensitivity and responsiveness, J. Appl. Physiol. 64:1942–46, 1988. 59. Mikines, K, Sonne, B, Tronier, B, and Galbo, H, Effects of training and detraining on insulin action in trained men, J. Appl. Physiol., 66:704–11, 1989. 60. Rogers, M, Yamamoto, C, King, D, Hagberg, J, Ehsani, A, and Holloszy, J, Improvement in glucose tolerance after 1 wk of exercise in patients with mild NIDDM, Diabet. Care, 11:613–18, 1988. 61. Seals, D, Hagberg, J, Allen, W, et al., Glucose tolerance in young and older athletes and sedentary men, J. Appl. Physiol., 56:1521–25, 1984. 62. Holloszy, J, Schultz, J, Kusnierkiewicz, J, Hagberg, J, and Eshani, A, Effects of exercise on glucose tolerance and insulin resistance: brief review and preliminary results, Acta. Med. Scand., 711:55–65, 1986. 63. Reitman, J, Vasquez, B, Klimes, I, and Nagulesparan, M, Improvement of glucose homeostasis after exercise training in NIDDM, Diabet. Care, 7:434–441, 1984. 64. Schneider, S, Amorosa, A, Khachadurian, A, and Ruderman, N, Studies on the mechanism of improved glucose control during regular exercise in type 2 (noninsulin-dependent) diabetes, Diabetologia, 26:355–360, 1984. 65. Dela, F, Larsen, J, Mikines, K, Ploug, T, Petersen, L, and Galbo, H, Insulin-stimulated muscle glucose clearance in patients with NIDDM: effects of one-legged physical training, Diabetes, 44:1010–20, 1995. 66. Group DPPR, Reduction in the incidence of Type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346:393–403, 2002. 67. Braun, B, Zimmermann, B, and Kretchmer, N, Effects of exercise intensity on insulin sensitivity in women with NIDDM, J. Appl. Physiol., 78:300–306, 1995. 68. Hawley, J and Houmard, J, Introduction — Preventing insulin resistance through exercise: a cellular approach, Med. Sci. Sports Exerc., 36:1187–1190, 2004. 69. Berggren, J, Hulver, M, Dohm, G, and Houmard, J, Weight loss and exercise: implications for muscle lipid metabolism and insulin action, Med. Sci. Sports Exerc., 36:1191–95, 2004.
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70. Bruce, C and Hawley, J, Improvements in insulin resistance with aerobic exercise training: a lipocentric approach, Med Sci. Sports Exerc, 36:1196–1201, 2004. 71. Ivy, J, Muscle insulin resistance amended with exercise training: role of GLUT4 expression, Med. Sci. Sports Exerc., 36:1207–11, 2004. 72. Houmard, J, Tanner, C, Slentz, C, Duscha, B, McCartney, J, and Kraus, W, Effect of the volume and intensity of exercise training on insulin sensitivity, J. Appl. Physiol, 96:101–06, 2004. 73. Binder, E, Birge, S, and Kohrt, W, Effects of endurance exercise and hormone replacement therapy on serum lipids in older women, J. Am. Geriatr. Soc., 44:231–36, 1996. 74. Slentz, C, Duscha, B, Johnson, J, et al., Effects of the amount of exercise on body weight, body composition, and measures of central obesity, Arch. Intern. Med., 164:31–39, 2004. 75. Ekelund, L, Haskell, W, Johnson, J, et al., Physical fitness as a predictor of cardiovascular mortality in asymptomatic North American men: the Lipid Research Clinics Mortality Follow-up Study, N. Engl. J. Med., 319:1379–1384, 1988. 76. Meyers, J, Prakash, M, Froelicher, V, Do, D, Partington, S, and Atwood, J, Exercise capacity and mortality amount men referred for exercise testing, N. Engl. J. Med., 346:793–801, 2002. 77. Weiner, D, Ryan, T, Parsons, L, et al., Long-term prognostic value of exercise testing in men and women from the Coronary Artery Surgery Study (CASS) registry, Am. J. Card., 75:865–70, 1995. 78. Wei, M, Kampert, J, Barlow, C, et al., Relationship between low cardiorespiratory fitness and mortality in normal-weight, overweight and obese men, JAMA, 282:1547–53, 1999. 79. Slattery, M and Jacobs, DJ, Physical fitness and CVD mortality: the US Railroad Study, Am. J. Epidemiol., 127:571–80, 1988. 80. Peters, R, Cady, LJ, Bischoff, D, et al., Physical fitness and subsequent myocardial infarction in healthy workes, JAMA, 249:3052–56, 1993. 81. Wyns, W, Musschaert-Beauthier, E, van Domburg, R, et al., Prognostic value of symptom limited exercise testing in men with a high prevalence of coronary artery disease, Eur. Heart J., 6:939–45, 1985. 82. Roger, V, Jacobsen, S, and Pellikka, P, Prognostic value of treadmill exercise testing: a population-based study in Olmsted county, Minnesota, Circulation, 98:2836–41. 83. Gulati, M, Pandey, D, Arnsdorf, M, et al., Exercise capacity and the risk of death in women: The St. James Women Take Heart Project, Circulation, 108:1554–59, 2003. 84. Weinsier, R, Hunter, G, Heini, A, Goran, M, and Sell, S, The etiology of obesity: relative contribution of metabolic factors, diet & physical activity, Am. J. Med., 105:145–150, 1998. 85. Prentice, A, and Jebb S, Obesity in Britain: gluttony or sloth? Br. Med. J., 311:437–39, 1995. 86. Mayer, J, Marshall, N, Vitale, J, Christensen, J, Mashayekhi, M, and Stare, F, Exercise, food intake and body weight in normal rats and genetically obese adult mice, Am. J. Physiol., 177:544–48, 1954. 87. Mayer, J, Purnima, R, and Mitra, K, Relation between caloric intake, body weight, and physical work: studies in an industrial male population in West Bengal, Am. J. Clin. Nutr., 4:169–175, 1956.
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5
Metabolic Alterations in Muscle Associated with Obesity John P. Thyfault, Ph.D. and G. Lynis Dohm, Ph.D.
CONTENTS I. Introduction..................................................................................................79 II. Muscle Mitochondria and Uncoupling Protein in Obesity.........................80 III. Insulin Resistance in Obesity ......................................................................81 A. Blunted Muscle Insulin-Signal Transduction in Obesity ...................81 B. Activation of PKC May Cause Insulin Resistance ............................83 C. Relationship of Skeletal-Muscle Insulin Resistance and Intramyocellular Lipid Accumulation.................................................83 D. Inflammatory Pathways and Insulin Action in Obesity .....................85 E. Mechanisms Causing Insulin Resistance in Obesity..........................85 IV. Lipid Metabolism in Obesity ......................................................................85 A. Fatty-Acid Oxidation in Skeletal Muscle ...........................................86 B. Fatty-Acid Transport into Skeletal Muscle.........................................88 C. Metabolic Inflexibility Associated with Obesity ................................89 References................................................................................................................91
I. INTRODUCTION The obesity epidemic in developed countries brings into focus a need to understand the causes and the consequences of obesity. In this chapter we will review the role of muscle in the altered metabolism that is seen with obesity. The first part of the chapter will be a description of the differences in muscle carbohydrate, lipid, and energy metabolism between lean and obese individuals. In many cases, the changes in muscle metabolism that are observed in obese people can be directly linked to diseases, such as diabetes, that are increased by obesity. However, in cross-sectional studies that compare lean and obese subjects, one doesn’t know if the differences are caused by obesity or if they are themselves a cause for the individual to become obese. It is clear that there are genetic factors that predispose some people to become obese more easily than others. If we understood the metabolic differences that
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predispose people to become obese, we might be able to intervene with effective treatment. Thus, in a later section of the chapter, we present evidence for a hypothesis that disturbances in muscle-lipid metabolism may cause a person to be predisposed to become obese. We hope that the speculation presented will provide testable hypotheses that may lead to understanding the underlying mechanisms of obesity. Muscle is certainly an important organ to consider with regard to obesity, since it accounts for approximately 42 percent of the body mass87 and approximately 70 percent to 80 percent of the glucose of a meal goes to muscle. At rest, muscle accounts for about 25 percent of whole-body-oxygen consumption, while during a marathon, 90 percent of the energy expended goes to support muscular contraction. Thus, it is important to know the differences in muscle carbohydrate, lipid, and energy metabolism in obese individuals if we are to understand the causes and consequences of obesity.
II. MUSCLE MITOCHONDRIA AND UNCOUPLING PROTEIN IN OBESITY Energy contained in the food we eat is preserved in the chemical potential of adenosine triphosphate (ATP) after carbohydrates, lipids, and proteins are oxidized to carbon dioxide and water. Oxidation takes place inside mitochondria, and the energy of electron transfer through the electron-transport chain is maintained by extrusion of protons from the matrix, producing an electrochemical gradient across the inner mitochondrial membrane. Dissipation of the protein gradient through the F1 ATPase complex of the inner membrane then leads to ATP synthesis. It has long been known that brown adipose tissue has a high capacity for heat production, because the mitochondria of this tissue contains a protein called uncoupling protein (UCP1), which dissipates the proton gradient through the inner membrane, with the energy being released as heat instead of ATP synthesis. Since obesity is associated with energy imbalance, it was speculated that more uncoupling protein might protect against obesity. Evidence to support this hypothesis was provided by an experiment in which UCP1 was overexpressed in skeletal muscle. The UCP1 overexpressing transgenic mice were resistant to weight gain and obesity when placed on a high-fat diet.66 However, since UCP1 is normally only found in brown adipose tissue, and humans have little or no brown adipose tissue, the significance of UCP1 in human obesity is questionable. After the cloning of two proteins with high homology to UCP1 (UCP2 and UCP3), there was renewed interest in whether uncoupling proteins might be a factor in obesity. Both UCP2 and UCP3 were confirmed to cause uncoupling of oxidative phosphorylation. UCP2 is ubiquitously expressed, while UCP3 is primarily expressed, in muscle. UCP2 and UCP3 have been extensively studied, but there is no clear link between these uncoupling proteins and obesity.44 The physiological function of uncoupling proteins is somewhat puzzling. UCP3 expression is paradoxically increased by fasting and acute exercise, but these responses are secondary to the release of fatty acids, which are potent regulators of UCP3 transcription. Thus, there seems to be a link between lipid metabolism and
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the expression of UCP3 in muscle.95 Since altered lipid metabolism is related to insulin resistance (see later sections of this chapter), uncoupling proteins may play an indirect role in the changes in metabolism seen in obesity. In addition to producing ATP, mitochondria are also a major source of reactiveoxygen species, which can cause DNA damage and peroxidation of membrane lipids. Recent evidence suggests that one of the functions of uncoupling proteins in muscle may be to prevent the proton gradient across the inner mitochondrial membrane from becoming too high, which would lead to the production of harmful reactiveoxygen species.40,95 Damage to mitochondrial membranes and mitochondrial DNA by reactive-oxygen species may be responsible for the defects that have been observed in muscle mitochondria of diabetic and aged individuals.57,80 In fact, impaired mitochondrial activity may play a much larger role in disease than previously recognized, since insulin-resistant offspring of patients with type 2 diabetes were also recently found to have reduced capacity for oxidative phosphorylation.81
III. INSULIN RESISTANCE IN OBESITY The metabolic syndrome is a condition characterized by hyperinsulinemia, hypertension, visceral obesity, dyslipidemia, and glucose intolerance, which leads to increased risk of coronary-artery disease and type 2 diabetes. The National Health and Nutrition Examination Survey (NHANES III) indicated that 45 percent of the U.S. population over age 50 has metabolic syndrome, and, because of the increase in the prevalence of obesity, the incidence of the metabolic syndrome has increased by 60 percent over the last decade. Obesity is generally accompanied by insulin resistance, which is manifest as fasting hyperinsulinemia. In addition, an elevated area under the curve for insulin values during an oral glucose-tolerance test is usual for insulin-resistant, obese individuals, and glucose utilization is markedly depressed in euglycemic insulinclamp studies.58,59 Stimulation of glucose transport by insulin is markedly blunted in muscle of obese individuals.27,34,59,82 This observation likely explains the decreased in vivo glucose disposal observed in insulin-resistant individuals, because muscle is the primary tissue for glucose disposal, and glucose transport into muscle is the ratelimiting step for glucose utilization.33, 35, 86, 88
A. BLUNTED MUSCLE INSULIN-SIGNAL TRANSDUCTION
IN
OBESITY
The inability of insulin to stimulate glucose transport in muscle of obese individuals raises the question as to whether this effect is caused by a defect in the glucosetransport system (i.e., glucose transporter 4 [GLUT4] translocation and activation) or in the insulin signaling system (i.e., insulin-signal transduction). To differentiate between these alternative mechanisms for insulin resistance, a number of experiments have been conducted to test whether glucose transport could be stimulated in insulin-resistant muscle if a signal other than insulin were presented. Exercise and muscle contraction have been shown to stimulate glucose transport by causing translocation of glucose transporters to the cell surface, analogous to the stimulation by insulin.36 Maximal stimulation of transport by insulin and exercise are additive,
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suggesting that the two stimuli act through different signaling pathways. Several groups have investigated stimulation of glucose transport in the insulin-resistant muscle of obese rats and have observed normal stimulation by muscle contraction, even though insulin stimulation was severely impaired.16,28 Kennedy et al.60 confirmed this finding in human subjects. This suggests that the glucose-transport system, (i.e., translocation and activation of glucose transporters) can respond if an alternative signal is transmitted. In our in vitro human-muscle preparations we have not been able to study muscle contraction, but stimulation of transport by hypoxia occurs by the same signaling pathway as contraction; stimulation by insulin and hypoxia are additive, but stimulation by contraction and hypoxia are not additive.20 The finding that stimulation of transport by hypoxia was normal in muscle of obese patients seems to confirm that the glucosetransport system is intact in insulin-resistant muscle.7 Likewise, we have observed that stimulation of transport by alkaline conditions was normal in muscle of obese patients,19 suggesting that several stimuli can stimulate transport in insulin-resistant muscles. Another line of evidence that a defect in insulin signaling causes insulin resistance comes from our experiments with serine/threonine and tyrosine protein phosphatase inhibitors. These experiments were based on the fact that insulin initiates a cascade of tyrosine and serine/threonine kinase activations. Therefore, inhibiting the opposing phosphatases mimics insulin action, but without the need for the defective step in the signaling pathway. The serine/threonine phosphatase inhibitor, okadaic acid, and the tyrosine phosphatase inhibitors phenylarsine oxide and vanadate all produced robust stimulation of glucose transport in insulin-resistant muscle of obese patients.19 A more direct set of observations that demonstrate a defect in the insulinsignaling pathway of insulin-resistant muscle come from studies in which the early steps in the signaling pathway were measured in normal and insulin-resistant muscle. Goodyear et al.38 found that autophosphorylation of the insulin receptor, phosphorylation of IRS-I, and activation of PI 3-kinase were all depressed in incubated human muscle from obese, insulin-resistant patients. Brozinick et al.17 demonstrated that protein kinase B (PKB/Akt) activation is also depressed in insulin-resistant muscle of obese individuals. Further evidence that the proximal steps in insulin signaling are depressed in obesity is demonstrated by the experiments of Leng et al.65 They found that in muscle of lean animals both insulin and muscle contraction activate the enzymes of the MAP kinase pathway (c-Jun NH2-terminal kinase [JNK], p38 MAPK, and extracellular signalrelated kinase [ERK 1 and 2]). Insulin stimulation of the MAPK enzymes was blunted in obese muscle, but contraction caused a normal response. This seems to suggest that the distal-signaling proteins respond normally if stimulated, and the depressed-insulin response in obese muscle was due to defects in the proximal steps. The insulin receptor tyrosine-kinase activity is depressed in muscle of obese individuals.4,53,76,77 In Pima Indians, insulin receptor autophosphorylation correlated well with glucose disposal,109 and the correlations were also found in cultured myoblasts.110 The mechanism that decreases insulin receptor tyrosine kinase activity has been investigated. We observed that removing phosphates from the receptors of obese individuals with alkaline phosphatase restored tyrosine-kinase activity,53,112 suggesting that phosphorylation of insulin receptors on serine or threonine residues
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might be the cause of inactivation. Hyperphosphorylation and inactivation of the insulin receptor has also been observed in insulin-resistant muscle of patients with polycystic-ovary syndrome30 and gestational diabetes. 97 Serine/threonine phosphorylation of IRS-1 may also be a potential mechanism for the inactivation of insulin-signal transduction.111Infusing rats with fatty acids for 3–4 hours caused decreased insulin receptor and IRS-1 tyrosine phosphorylation in response to insulin. IRS-1 was phosphorylated on serine 307 which makes it a less favorable substrate for the insulin receptor kinase.48
B. ACTIVATION
OF
PKC MAY CAUSE INSULIN RESISTANCE
Protein kinase C (PKC) can directly phosphorylate and inactivate the insulin receptor.67 Likewise, overexpression of PKC isoforms in cultured cells causes phosphorylation of the insulin receptor and insulin resistance.14,22 These findings led to the hypothesis that PKC causes insulin resistance in skeletal muscle.23 Several groups have reported that PKC activity and protein were increased in muscle of animals with insulin resistance.6,29,45,64,93,94 To determine if one of the PKC isoforms is increased in insulinresistant muscle and causes serine/threonine phosphorylation of the insulin receptor, we measured the protein content of eight PKC isoforms in the membrane fractions of muscles from lean and obese patients. The only PKC isoform that was increased in the membrane of insulin-resistant muscle (obese) was PKCβ. Basal PKCβ was higher in the in vitro incubated muscle of obese individuals, and insulin increased PKCβ in the membrane fraction in muscle of obese, but not lean, patients.53 To demonstrate a cause-and-effect relationship between PKC activity and insulin action, we incubated human-muscle strips in the presence and absence of PKC activators and inhibitors. In insulin-resistant muscle, the PKC inhibitor GF109203X enhanced insulin stimulation of glucose transport. In insulin-sensitive muscle, incubation with the PKC activator dPPA caused insulin-stimulated glucose transport to be depressed.25 These data suggest that a PKC activator can cause insulin resistance and that a PKC inhibitor can reverse insulin resistance. Other research groups have made observations that also implicate PKC in the development of lipid-induced insulin resistance. Griffen et al.,41 using a rat model, induced insulin resistance with a 5 h lipid/heparin infusion and observed a 50 percent reduction in insulin-stimulated IRS-1-associated PI-3 kinase activity, blunted IRS1 tyrosine phosphorylation, and a fourfold increase in PKC activity. In humans, Itani et al.52 also employed a lipid/heparin infusion and reported that insulin-stimulated glucose disposal was reduced by 43 percent, and skeletal-muscle diacylglycerol mass and PKC activity were increased fourfold. These findings not only imply that PKC activation causes skeletal-muscle insulin resistance, but also demonstrate an association between lipid accumulation (diacylglycerols) and PKC activation.
C. RELATIONSHIP OF SKELETAL-MUSCLE INSULIN RESISTANCE INTRAMYOCELLULAR LIPID ACCUMULATION
AND
It is well-established that intramyocellular triacylglycerol (IMTG) accumulation is associated with skeletal-muscle insulin resistance.10,56,73 However, it is unlikely that
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triacylglycerols are the culprit for reduced skeletal-muscle insulin action, but more likely they are an inert marker of other lipid intermediates known to suppress insulin sensitivity. An increase in the intramyocellular concentration of lipid intermediates such as fatty acyl-CoAs,50 ceramides,3,39 and diacylglycerols52 not only correlate with insulin resistance but also directly and indirectly alter insulin signaling.92 Considerable evidence linking increased skeletal-muscle lipid content to insulin resistance has been derived from animal studies employing acute and chronic high-fat diets.24 Fatty acid-induced insulin resistance appears to occur in concert with increased fatty acyl-CoAs.24 Moreover, insulin sensitivity is restored by treatments that reduce intramyocellular lipid accumulation (i.e., low-fat feeding and fasting).78 Similar findings have been observed in humans. Bachmann et al.8 reported significant increases in intramyocellular lipid content and reductions in insulin sensitivity following intravenous-lipid infusion. Ellis et al.31 demonstrated a negative correlation between insulin-mediated glucose disposal and fatty acyl-CoA content in skeletal muscle from a group of older men. Our laboratory observed blunted insulin-mediated glucose disposal in skeletal muscle from moderately and morbidly obese patients that was accompanied by elevated levels of intramyocellular fatty acyl-CoAs.50 After weight loss, insulin sensitivity was restored, and fatty acyl-CoA levels were also normalized.49 Thus, fatty acyl-CoAs, or a derived lipid, are related to, and possibly responsible for, muscle-insulin resistance. Various intramyocellular lipid intermediates, such as fatty acyl-CoAs, ceramides, and diacylglycerols, inhibit specific steps in the insulin-signaling cascade.92 Ceramides activate a protein phosphatase that dephosphorylates Akt/PKB, resulting in inhibition of GLUT4 translocation and glycogen synthesis21, 68. Diacylglycerols have been implicated in the activation of PKC in various tissues.24,92,99 Fatty acyl-CoAs have been shown to directly activate PKC in brain tissue15, 98, but these observations have yet to be observed in skeletal muscle. In models of high-fat exposure, intramyocellular fatty acylCoAs are elevated in concert with increased PKC activation.52 Moreover, fatty acylCoAs are also implicated in the indirect activation of PKC, as they are precursors for diacylglycerols formation. Diacylglycerol levels are elevated in many models of insulin resistance92, and these intermediates directly activate PKC,63,75 One of the difficulties with the lipotoxicity hypothesis of insulin resistance is the apparent paradox of increased IMTG in muscle of highly trained athletes, who are very insulin sensitive.37 However, the recent report by He, et al.43 may help to understand the role of muscle lipids in insulin resistance. They measured the size and quantity of mitochondria and lipid droplets in muscle from obese patients before and after weight loss and an endurance-exercise trial. After weight loss and exercise, the subjects improved insulin sensitivity by approximately 40 percent, but there was no change in the amount of intramuscular lipid. However, the mitochondria were larger, the lipid droplets were smaller, and the change in size of both mitochondria and lipid droplets correlated with the improvement in insulin sensitivity. They speculate that the smaller lipid droplets have a larger surface area that provides access for hydrolysis and utilization. In addition, the ratio of mitochondria to lipid droplets would also be important in the improved utilization of fat, which was characteristic of the subjects after weight loss and exercise.
Metabolic Alterations in Muscle Associated with Obesity
D. INFLAMMATORY PATHWAYS
AND INSULIN
ACTION
IN
85
OBESITY
The proinflammatory cytokine tumor necrosis factor alpha (TNFα) has also been proposed as a link between adiposity and the development of insulin resistance.47 TNFα initiates an inflammatory response by stimulating IκB kinase-β (IκK-β). Serine phosphorylation of inhibitor protein of κB (IκB) triggers ubiquitination and degradation of IκB, and, eventually, activation of the nuclear factor κB (NF-κB), a transcription factor involved in immune and inflammatory responses. TNFα is highly expressed in adipose tissue, and infusion of TNFα into rats caused insulin resistance, while neutralization of the cytokine with antibodies to TNFα reversed insulin resistance in obese rats. The insulin resistance induced by TNFα can be prevented by treatment with the salicylate, which is known to inhibit IκKβ. Treatment of adipocytes and skeletal muscle with TNFα causes insulin resistance by decreasing insulin-induced IRS-1 tyrosine phoshorylation and activation of IRS-1-associated PI 3-kinase. This is likely caused by phosphorylation of serine 307 of the IRS-1 protein. The serine kinase that is directly responsible for the phosphorylation of IRS-1 has not been determined with certainty, but candidates include c-Jun N-terminal kinase (JNK),47 PKC,61 and IκKβ.26 The insulin resistance induced by muscle lipids may also be mediated through inflammatory pathways.79 Kim et al.61 found that infusion of fatty acids into rats caused insulin resistance and decreased insulin signaling in skeletal muscle. Lipidinduced insulin resistance could be prevented by pretreating the rats with salicylate, a known inhibitor of IκK-β. Likewise, fatty-acid infusion in an IκKβ knock-out mouse did not produce insulin resistance as it did in wild-type controls.
E. MECHANISMS CAUSING INSULIN RESISTANCE
IN
OBESITY
Although the mechanisms that cause insulin resistance in muscle are not known with certainty, there appear to be some generally accepted concepts that form the basis of a model that serves as the basis for future hypothesis testing. In response to either TNFα or intramuscular lipids (fatty acyl-CoA, diacylglycerol, or ceramides), there is activation of a serine kinase (PKC, JNK, or IκKβ) and inactivation of a protein phosphatase (PP2A), such that IRS-1 and the insulin receptor become serine phosphorylated. These events then depress insulin-signal transduction to cause insulin resistance. Figure 5.1 displays a representation of insulin signaling in a muscle cell.
IV. LIPID METABOLISM IN OBESITY Obesity is associated with an increased storage of triglycerides in skeletal muscle (IMTG), accumulation of lipid intermediates (long-chain fatty acyl-CoAs, diacylglycerols, and ceramides) and subsequent insulin resistance. The question then presents itself: Why is there an accumulation of muscle lipids in obesity?
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Insulin Receptor
TNFα Receptor Ikk β
IRS-1/2 tyrosine Phos IRS-1/2 serine Phos
JNK
+
– PKC (θ or βll)
PI 3 Kinase IMTG GLUT4
Fatty Acyl-CoA
DAG
FIGURE 5.1 Proposed mechanism(s) for insulin resistance in skeletal muscle. DAG, diacylglycerols: IMTG, intramyocellular triacylglycerols; PKC, protein kinase C; JNK, c-Jun N terminal kinase; IKK, IkB kinase-; IRS-1/2, insulin receptor substrate 1 and 2; P13K, phosphatidylinositol 3-kinase; GLUT4, glucose transporter 4; (+), activation; (–), inhibition.
A. FATTY-ACID OXIDATION
IN
SKELETAL MUSCLE
When fatty acids are transported into skeletal muscle they are partitioned into one of two pathways: synthesis, resulting in formation of IMTG, or oxidation, resulting in energy production. Under normal conditions, most fatty acids are shunted towards oxidation, but evidence demonstrates this is not always the case in obesity. A reduced ability to oxidize free fatty acids is a probable explanation for an accumulation of IMTGs and lipid intermediates found in the skeletal muscle of obese individuals. Obesity is also associated with a large surplus of fat, both in storage, adipose tissue, and in circulation (plasma free fatty acids). Therefore, decreased fat oxidation in skeletal muscle likely plays a role in dislipidemia and obesity. Several studies have examined the impact of obesity on lipid metabolism at the whole-body level. Some studies show no difference or an increase in fat oxidation in obese compared to nonobese subjects,46,54,104,107 however, other studies have demonstrated that rates of whole-body fat utilization are lower in obese than nonobese subjects.85,113 Because these measures were obtained at the whole-body level, it is difficult to ascertain the effect of other tissues, including liver and adipose, on these results. Kelley et al.55 examined fatty-acid uptake and indirect calorimetry across the leg in a large sample of obese and nonobese subjects. This model allowed for a measure of metabolism across the muscle of the leg without a large degree of interference from other tissues. Respiratory quotient (RQ, obtained from arterio-venous samples) was significantly higher in obese than nonobese subjects, indicating reduced fattyacid utilization with obesity. Basal RQ values also correlated indirectly with the insulin sensitivity of the subjects, demonstrating that fat utilization could play a role in IMTG accumulation and insulin resistance. Fat oxidation in skeletal muscle involves several enzymes, but one of key importance is carnitine palmitoyltransferase 1 (CPT-1). Upon entry of the muscle cell, long-chain fatty acids are first converted to fatty acyl-CoAs in the cytosol and then transported across the outer mitochondrial membrane by the enzyme CPT-1. The
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activity or ability of CPT-1 to transport fatty acyl-CoAs into the mitochondria is believed to be the rate-limiting step of fat oxidation in skeletal muscle.89 Malonyl coenzyme A (malonyl CoA), the product of acetyl coenzyme A carboxylase (ACC), allostericaly binds to and inhibits CPT-1 activity,74 thereby inhibiting transport of fatty acyl-CoAs into the mitochondria. The importance of the malonyl CoA–CPT1 interaction upon rates of fat oxidation has been demonstrated in response to many stimuli.84,89,90 Transgenic mice that lack the ACC enzyme (no production of malonyl CoA) have increased rates of fat oxidation and reduced rates of fat storage1. In addition, the same ACC knockout mice are resistant to weight gain and maintain normal insulin sensitivity in response to a high-fat diet.1 An in vivo human study demonstrated that hyperglycemia/hyperinsulinemia decreases long-chain fatty acid oxidation through increasing muscle malonyl-CoA content, but had no effect upon oxidation of medium-chain fatty acids that enter the mitochondria independently of CPT-1.83 The regulation of CPT-1 by malonyl CoA is thus an important regulator of fatty-acid oxidation and also plays a role in metabolic flexibility, which is discussed later. Additional studies have examined this and other enzymes that are important for skeletal-muscle fat oxidation in obesity. Initial work from our laboratory examined fatty-acid oxidation at the in vitro level in muscle from obese and nonobese subjects. Using a whole homogenate preparation from vastus-lateralis biopsies, we found that obese muscle has a reduced rate of lipid oxidation, as well as reduced CPT-1 and citrate synthase activity.62 In addition, CPT-1 and citrate synthase activities were both inversely correlated with levels of adiposity. Studies from other groups have found similar results, mainly that citrate synthase activity and β-hydroxyacyl CoA dehydrogenase (β-HAD) activity are depressed in muscle from obese/insulin-resistant subjects.100,101,113 In relation to this, muscle from obese/insulin-resistant subjects has been shown to have increased activities of glycolytic enzymes. Simoneau et al. 101 found that the ratio between glycolytic and oxidative enzyme activities within skeletal muscle correlated negatively with insulin sensitivity. These data led us to hypothesize that skeletal muscle from obese subjects possessed a decrement in fatty-acid oxidation, leading to lipids being shunted to the synthetic pathway, resulting in an accumulation of IMTGs and subsequent insulin resistance. Our lab has also examined lipid metabolism in intact muscle strips (rectus abdominus) obtained from nonobese, moderately overweight, and extremely obese subjects.50 Incubating intact muscle strips allowed for the tracking of labeled palmitate into synthesis or oxidation. As expected, muscle from extremely obese subjects displayed a decrement in lipid oxidation (58 percent) when compared to muscle from nonobese. The lipids entering extremely obese muscle were preferentially partitioned toward triglyceride synthesis at a rate twofold higher than that found in nonobese muscle (calculated from a ratio of oxidation/storage). However, muscle from moderately overweight individuals had rates of lipid oxidation and synthesis that were equal to that from nonobese muscle. Interestingly, muscle from moderately overweight individuals had the same increased levels of lipid metabolite content (long-chain fatty acyl-CoA) and the same levels of insulin resistance that is observed in muscle from the extremely obese. Therefore, depressed rates of lipid oxidation
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could not be the only mechanism causing IMTG accumulation in skeletal muscle from obese subjects.
B. FATTY-ACID TRANSPORT
INTO
SKELETAL MUSCLE
When examining substrate usage by cellular systems it is important that there be a match between rates of substrate uptake and rates of substrate metabolism. Therefore, an increased rate of fatty-acid uptake may be a potential mechanism responsible for IMTG accumulation in obese skeletal muscle. We and others have reported that obesity is associated with hyperlipidemia.71 As a result, fatty-acid uptake may be increased in obese skeletal muscle due to oversupply and increased rates of fattyacid uptake. It was once thought that fatty acids entered the muscle cell solely through passive diffusion. It is now apparent that fatty acids can also enter through a protein-mediated mechanism.2,11,12 The proteins involved in the process include: fatty-acid-binding protein-plasma membrane (FABPpm), which is associated with the plasma membrane,102 and fatty-acid translocase (FAT/CD36), which is found both at the sarcolemma and in intracellular pools.2 In addition, a third protein, fatty-acid transporter protein 1 (FATP1), is thought to be involved in the process, but it is less understood and may act as an acyl-CoA synthase.2,91 Transport of fatty acids into the cell is a dynamic process upregulated by both contraction and insulin stimulation. Contraction and insulin both activate the translocation of FAT/CD36 from intracellular stores to the plasma membrane.11,70 During the same conditions, rates of fatty-acid uptake are elevated, demonstrating that FAT/CD36 is the primary protein involved in facilitated transport. Stimulation of fatty-acid transport by insulin and muscle contraction occur through different mechanisms and are additive.11 Therefore, there are two mechanisms regulating fatty-acid transport in muscle: acute regulation through translocation of FAT/CD36 (following insulin and contraction) and chronic regulation through increased expression of transporter proteins.11 There is ample evidence suggesting that muscle fatty-acid transport is altered with insulin resistance. Studies examining aging and insulin resistance have shown that skeletal muscle from older animals has increased rates of palmitate uptake in response to insulin compared to young animals.105 Obese, insulin-resistant Zucker rats have also been shown to have elevated rates of fatty-acid transport.106 Although expression of transporter proteins was not elevated in obese Zucker rats, sarcolemmal concentrations of FAT/CD36 are elevated, and translocation of FAT/CD36 back to intracellular stores is seemingly impaired. A recent study from Bonen et al.13 examined fatty-acid transport in skeletal muscle from human subjects who were obese, type 2 diabetic, and healthy controls. They showed that fatty-acid transport was fourfold higher in obese and type 2 diabetic skeletal muscle, which was associated with increased IMTG content. They also found that increased fatty-acid transport was not associated with an increased expression of FAT/CD36 or FABPpm. However, they did find that sarcolemmal content of FAT/CD36, but not FABPpm, were higher in the muscle of obese and type 2 diabetic patients compared to controls. So, as with the muscle from obese Zucker rats, human obesity and type 2 diabetes is
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associated with increased FAT/CD36 at the sarcolemma, which forces rapid entry of fatty acids into muscle. This provides an interesting complexity in insulin-resistant muscle where GLUT4 (glucose transporters) are unable to readily translocate from intracellular pools to the sarcolemma, and FAT/CD36 (fatty-acid transporters) are unable to leave the sarcolemma and return to intracellular pools. As suggested by Bonen et al.,13 this results in a juxtaposed relationship between glucose and fattyacid transporters, creating an environment for insulin resistance and increased stores of IMTGs and other lipid metabolites. We can only speculate on the series of events that leads to insulin resistance in skeletal muscle. However, it is certain that increased levels of IMTG and concurrent lipid metabolites trigger skeletal-muscle insulin resistance. Why lipids accumulate in skeletal muscle of obese/insulin-resistant individuals is not completely understood. However, there is ample evidence demonstrating that increased rates of fattyacid uptake alone or in combination with decreased rates of fatty-acid oxidation play a significant role.
C. METABOLIC INFLEXIBILITY ASSOCIATED
WITH
OBESITY
Healthy skeletal muscle adapts to differing concentrations of plasma substrates (carbohydrates and fats) and hormones (primarily insulin). When a substrate is in oversupply, healthy skeletal muscle is able to adjust and activate processes that are necessary for appropriate oxidation or storage. Accordingly, healthy muscle is also able to adjust substrate utilization in response to hormonal changes. This process has been termed metabolic flexibility and constantly occurs in daily life when conditions move from fasting to fed to fasting again. This term was coined by Kelley and colleagues55 following a study (previously mentioned) in which they measured differences in substrate utilization during basal- and insulin-stimulated conditions across the leg in obese and nonobese subjects. During fasting conditions, obese individuals had significantly higher rates of carbohydrate oxidation and decreased fat oxidation, which fit the hypothesis for reduced oxidative capacity in obese skeletal muscle. When moving from basal to euglycemic/hyperinsulinemic conditions, the nonobese subjects increased rates of carbohydrate oxidation and decreased fat oxidation, indicating an appropriate response to an increase of plasma glucose and insulin. This adaptation or flexibility did not occur in obese individuals. Figure 5.2 demonstrates rates of fat and carbohydrate oxidation as measured in the study by
basal
insulin
Fat Oxidation
basal
insulin
Carbohydrate Oxidation
FIGURE 5.2 Metabolic flexibility in Δ Obese and Lean-NonObese subjects during basal and insulin-stimulated conditions. Data derived from Kelley et al., Am. J. Physiol., 277, 1999.
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Kelley et al.55 Therefore, the obese subjects displayed metabolic inflexibility, as their skeletal muscle was unable to adapt to changes in their nutritional environment. Measures of muscle metabolism from our laboratory and others may provide insight into the metabolic inflexibility found with obesity. Lean skeletal muscle has higher basal- and insulin-stimulated glucose uptake than muscle from obese, and this could affect the ability of obese individuals to increase carbohydrate reliance during postabsorptive conditions. Preliminary data from our laboratory suggests another possible mechanism51. We have measured rates of fatty-acid uptake under basal- and insulin-stimulated conditions in skeletal muscle from lean and obese. Uptake values in obese muscle were twofold and threefold greater under basal- and insulin-stimulated conditions, respectively, compared to nonobese. Fatty-acid uptake was increased (twofold) in response to insulin in obese muscle, while this did not occur in lean muscle. This is interesting, as obesity is associated with an opposite response of insulin upon glucose uptake. Therefore, it is possible that altered rates of glucose and fatty-acid uptake affect cellular substrate availability and influence substrate reliance directly or through signaling events. A clear association can be linked between metabolic inflexibility and a defect in lipid oxidation measured with obesity. In normal conditions, an increase in dietary fat or plasma lipids is met with adaptations that increase lipid metabolism in skeletal muscle. In rodent studies, in which plasma fatty-acids levels are significantly increased (fasting, high-fat feedings, streptozotocin-induced diabetes) there is an equivalent increase in the expression and activity of lipid-metabolizing enzymes in skeletal muscle, including malonyl-CoA decarboxylase, CPT-1, β-HAD, pyruvate dehydrogenase kinase 4, and FAT/CD36.72,108 In healthy, nonobese humans, five days of a high-fat diet increased lipid oxidation (measured by RQ) during submaximal exercise and increased genes important for fat oxidation, including FAT/CD36, FABPpm, β-HAD, and CPT-1.18 In another study, nonobese subjects increased total daily fat oxidation (measured in indirect calorimetry chamber) after seven days of a high-fat diet.96 These data demonstrate that nonobese individuals can increase lipid oxidation when needed. Conversely, it appears that obese individuals lack an ability to increase lipid oxidation following dietary manipulation. Astrup et al.5 compared lipid oxidation between previously obese and lean women following three days of a high fat-diet (50 percent fat). Lean women adjusted rates of fat oxidation to the diet. However, previously obese (post weight loss) women could not increase fat oxidation, resulting in positive fat balance and storage. As previously mentioned, the CPT-1–malonyl-CoA interaction in skeletal muscle probably plays a role in metabolic flexibility. Plasma insulin and glucose dictate malonyl-CoA content in muscle. Therefore, the altered substrate utilization associated with obesity could be related to a dysregulation of muscle malonyl-CoA content. Preceding enzymatic dysregulation, the response of gene expression to changes in the nutritional environment may be malfunctioning in skeletal muscle of obese subjects. Peroxisome proliferators-activated receptors (PPARs) are the first genetic sensors known to respond to changes in lipids.32 PPARs are activated by changes in dietary fat and metabolic derivatives, and then enact their response by changing the expression of proteins regulating fat metabolism. The PPAR-α receptor has been shown to enhance skeletal-muscle lipid oxidation. Therefore, a defect in the PPAR-α
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response to lipids is a possible candidate for the reductions in lipid oxidation and the lack of metabolic flexibility in skeletal muscle from obese subjects. In conclusion, our in vitro skeletal-muscle studies show that obese skeletal muscle possesses defective rates of lipid oxidation. This leads to another question: Is defective lipid oxidation the “chicken” or the “egg” of obesity? Do preobese individuals possess muscle that is defective in metabolizing fat, or does this occur after the onset of obesity? We believe that defective lipid oxidation in skeletal muscle plays a likely role in the onset of obesity based on the following factors: 1) genetic work involving families and twins demonstrates that genetic factors at least predispose individuals to obesity,69 and that part of these genetic factors are related to energy expenditure, and, assumedly, defective lipid metabolism; 2) a short-term, prospective study in Pima Indians demonstrated that elevated RQ values were correlated with increased weight gain over four years103; 3) a study from our lab has shown that women who were previously extremely obese but had lost approximately 100 lbs (gastric-bypass surgery) had significantly lower rates of fat utilization during exercise compared with healthy women matched for BMI42; 4) recently, we have performed primary-cell cultures of muscle from lean and obese individuals, and we see the same defect in rates of lipid oxidation in cultured obese muscle that are measured in vitro,9 demonstrating a distinct phenotype that is unaltered when removing muscle from its environment; and 5) finally, in transgenic animal models where rates of lipid oxidation are elevated, animals are resistant to high-fat diets and do not gain weight, demonstrating that an increased metabolic capacity can withstand overfeeding.1 These studies provide evidence that a disturbance in muscle-lipid metabolism may lead to obesity. Currently, scientists are examining the effect of exercise and pharmacological treatments upon lipid metabolism in skeletal muscle. These studies will provide insight into the prevention of obesity and its related comorbidities.
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54. Kanaley, JA, MM Weatherup-Dentes, CR Alvarado, and G Whitehead, Substrate oxidation during acute exercise and with exercise training in lean and obese women, Eur. J. Appl. Physiol., 85:68–73, 2001. 55. Kelley, DE, B Goodpaster, RR Wing, and JA Simoneau, Skeletal muscle fatty acid metabolism in association with insulin resistance, obesity, and weight loss, Am. J. Physiol., 277:E1130–1141, 1999. 56. Kelley, DE and BH Goodpaster, Skeletal muscle triglyceride. An aspect of regional adiposity and insulin resistance, Diabet. Care, 24:933–941, 2001. 57. Kelley, DE, J He, EV Menshikova, and VB Ritov, Dysfunction of mitochondria in human skeletal muscle in type 2 diabetes, Diabetes, 51:2944–2950, 2002. 58. Kelley, DE and LJ Mandarino, Fuel selection in human skeletal muscle in insulin resistance: a reexamination, Diabetes, 49:677–683, 2000. 59. Kelley, DE, MA Mintun, SC Watkins, JA Simoneau, F Jadali, A Fredrickson, J Beattie, and R Theriault, The effect of non-insulin-dependent diabetes mellitus and obesity on glucose transport and phosphorylation in skeletal muscle, J. Clin. Invest., 97:2705–2713, 1996. 60. Kennedy, JW, MF Hirshman, EV Gervino, JV Ocel, RA Forse, SJ Hoenig, D Aronson, LJ Goodyear, and ES Horton, Acute exercise induces GLUT4 translocation in skeletal muscle of normal human subjects and subjects with type 2 diabetes, Diabetes, 48:1192–1197, 1999. 61. Kim, JK, YJ Kim, JJ Fillmore, Y Chen, I Moore, J Lee, M Yuan, ZW Li, M Karin, P Perret, SE Shoelson, and GI Shulman, Prevention of fat-induced insulin resistance by salicylate, J. Clin. Invest., 108:437–446, 2001. 62. Kim, JY, RC Hickner, RL Cortright, GL Dohm, and JA Houmard, Lipid oxidation is reduced in obese human skeletal muscle, Am. J. Physiol. Endocrinol. Metab., 279:E1039–1044, 2000. 63. Kishimoto, A, Y Takai, T Mori, U Kikkawa, and Y Nishizuka, Activation of calcium and phospholipid-dependent protein kinase by diacylglycerol, its possible relation to phosphatidylinositol turnover, J. Biol. Chem., 255:2273–2276, 1980. 64. Koya, D and GL King, Protein kinase C activation and the development of diabetic complications, Diabetes, 47:859–866, 1998. 65. Leng, Y, TL Steiler, and JR Zierath, Effects of insulin, contraction, and phorbol esters on mitogen-activated protein kinase signaling in skeletal muscle from lean and ob/ob mice, Diabetes, 53:1436–1444, 2004. 66. Li, B, LA Nolte, JS Ju, DH Han, T Coleman, JO Holloszy, and CF Semenkovich, Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice, Nat. Med., 6:1115–1120, 2000. 67. Liu, F and RA Roth, Identification of serines-1035/1037 in the kinase domain of the insulin receptor as protein kinase C alpha mediated phosphorylation sites, FEBS Lett., 352:389–392, 1994. 68. Long, SD and PH Pekala, Lipid mediators of insulin resistance: ceramide signalling down-regulates GLUT4 gene transcription in 3T3-L1 adipocytes, Biochem. J., 319 (Part 1):179–184, 1996. 69. Loos, RJ and C Bouchard, Obesity — is it a genetic disorder? J. Intern. Med., 254:401–425, 2003. 70. Luiken, JJ, DJ Dyck, XX Han, NN Tandon, Y Arumugam, JF Glatz, and A Bonen, Insulin induces the translocation of the fatty acid transporter FAT/CD36 to the plasma membrane, Am. J. Physiol. Endocrinol. Metab., 282:E491–495, 2002.
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Nutrition and Diabetes: Pathophysiology and Management 71. MacLean, PS, S Vadlamudi, KG MacDonald, WJ Pories, JA Houmard, and HA Barakat, Impact of insulin resistance on lipoprotein subpopulation distribution in lean and morbidly obese nondiabetic women, Metabolism, 49:285–292, 2000. 72. McAinch, AJ, JS Lee, CR Bruce, RJ Tunstall, JA Hawley, and D Cameron-Smith, Dietary regulation of fat oxidative gene expression in different skeletal muscle fiber types, Obes. Res., 11:1471–1479, 2003. 73. McGarry, JD, Banting lecture 2001: dysregulation of fatty acid metabolism in the etiology of type 2 diabetes, Diabetes, 51:7–18, 2002. 74. McGarry, JD, SE Mills, CS Long, and DW Foster, Observations on the affinity for carnitine, and malonyl-CoA sensitivity, of carnitine palmitoyltransferase I in animal and human tissues. Demonstration of the presence of malonyl-CoA in non-hepatic tissues of the rat, Biochem. J., 214:21–28, 1983. 75. Nishizuka, Y, Turnover of inositol phospholipids and signal transduction, Science, 225:1365–1370, 1984. 76. Nolan, JJ, G Freidenberg, R Henry, D Reichart, and JM Olefsky, Role of human skeletal muscle insulin receptor kinase in the in vivo insulin resistance of noninsulindependent diabetes mellitus and obesity, J. Clin. Endocrinol. Metab., 78:471–477, 1994. 77. Nyomba, BL, VM Ossowski, C Bogardus, and DM Mott, Insulin-sensitive tyrosine kinase: relationship with in vivo insulin action in humans, Am. J. Physiol., 258:E964–974, 1990. 78. Oakes, ND, KS Bell, SM Furler, S Camilleri, AK Saha, NB Ruderman, DJ Chisholm, and EW Kraegen, Diet-induced muscle insulin resistance in rats is ameliorated by acute dietary lipid withdrawal or a single bout of exercise: parallel relationship between insulin stimulation of glucose uptake and suppression of long-chain fatty acyl-CoA, Diabetes, 46:2022–2028, 1997. 79. Perseghin, G, Cellular mechanisms of insulin resistance by salicylate, Int. J. Obes., 27:S6–S11, 2003. 80. Petersen, KF, D Befroy, S Dufour, J Dziura, C Ariyan, DL Rothman, L DiPietro, GW Cline, and GI Shulman, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science, 300:1140–1142, 2003. 81. Petersen, KF, S Dufour, D Befroy, R Garcia, and GI Shulman, Impaired mitochondrial activity in the insulin-resistant offspring of patients with type 2 diabetes, N. Engl. J. Med., 350:664–671, 2004. 82. Petersen, KF, R Hendler, T Price, G Perseghin, DL Rothman, N Held, JM Amatruda, and GI Shulman, 13C/31P NMR studies on the mechanism of insulin resistance in obesity, Diabetes, 47:381–386, 1998. 83. Rasmussen, BB, UC Holmback, E Volpi, B Morio-Liondore, D Paddon-Jones, and RR Wolfe, Malonyl coenzyme A and the regulation of functional carnitine palmitoyltransferase-1 activity and fat oxidation in human skeletal muscle, J. Clin. Invest., 110:1687–1693, 2002. 84. Rasmussen, BB and WW Winder, Effect of exercise intensity on skeletal muscle malonyl-CoA and acetyl-CoA carboxylase, J. Appl. Physiol., 83:1104–1109, 1997. 85. Ravussin, E, Metabolic differences and the development of obesity, Metabolism, 44:12–14, 1995. 86. Ren, JM, BA Marshall, EA Gulve, J Gao, DW Johnson, JO Holloszy, and M Mueckler, Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle, J. Biol. Chem., 268:16113–16115, 1993. 87. Rolfe, DF and GC Brown, Cellular energy utilization and molecular origin of standard metabolic rate in mammals, Physiol. Rev., 77:731–758, 1997.
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88. Roussel, R, PG Carlier, JJ Robert, G Velho, and G Bloch, 13C/31P NMR studies of glucose transport in human skeletal muscle, Proc. Natl. Acad. Sci. U.S.A., 95:1313–1318, 1998. 89. Ruderman, NB, AK Saha, D Vavvas, and LA Witters, Malonyl-CoA, fuel sensing, and insulin resistance, Am. J. Physiol., 276:E1–E18, 1999. 90. Saha, AK, TG Kurowski, and NB Ruderman, A malonyl-CoA fuel-sensing mechanism in muscle: effects of insulin, glucose, and denervation, Am. J. Physiol., 269:E283–289, 1995. 91. Schaffer, JE and HF Lodish, Expression cloning and characterization of a novel adipocyte long chain fatty acid transport protein, Cell, 79:427–436, 1994. 92. Schmitz-Peiffer, C, Protein kinase C and lipid-induced insulin resistance in skeletal muscle, Ann. N.Y. Acad. Sci., 967:146–157, 2002. 93. Schmitz-Peiffer, C, CL Browne, ND Oakes, A Watkinson, DJ Chisholm, EW Kraegen, and TJ Biden, Alterations in the expression and cellular localization of protein kinase C isozymes epsilon and theta are associated with insulin resistance in skeletal muscle of the high-fat-fed rat, Diabetes, 46:169–178, 1997. 94. Schmitz-Peiffer, C, ND Oakes, CL Browne, EW Kraegen, and TJ Biden, Reversal of chronic alterations of skeletal muscle protein kinase C from fat-fed rats by BRL49653, Am. J. Physiol., 273:E915–921, 1997. 95. Schrauwen, P and MK Hesselink, Oxidative capacity, lipotoxicity, and mitochondrial damage in type 2 diabetes, Diabetes, 53:1412–1417, 2004. 96. Schrauwen, P, WD van Marken Lichtenbelt, WH Saris, and KR Westerterp, Changes in fat oxidation in response to a high-fat diet, Am. J. Clin. Nutr., 66:276–282, 1997. 97. Shao, J, PM Catalano, H Yamashita, I Ruyter, S Smith, J Youngren, and JE Friedman, Decreased insulin receptor tyrosine kinase activity and plasma cell membrane glycoprotein-1 overexpression in skeletal muscle from obese women with gestational diabetes mellitus (GDM): evidence for increased serine/threonine phosphorylation in pregnancy and GDM, Diabetes, 49:603–610, 2000. 98. Shoyab, M, Long-chain fatty acyl-coenzyme A’s activate both the ligand-binding and protein kinase activities of phorboid and ingenoid receptor, Arch. Biochem. Biophys., 236:435–440, 1985. 99. Shulman, GI, Cellular mechanisms of insulin resistance, J. Clin. Invest., 106:171–176, 2000. 100. Simoneau, JA, SR Colberg, FL Thaete, and DE Kelley, Skeletal muscle glycolytic and oxidative enzyme capacities are determinants of insulin sensitivity and muscle composition in obese women, FASEB. J., 9:273–278, 1995. 101. Simoneau, JA and DE Kelley, Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM, J. Appl. Physiol., 83:166–171, 1997. 102. Stremmel, W, G Strohmeyer, F Borchard, S Kochwa, and PD Berk, Isolation and partial characterization of a fatty acid binding protein in rat liver plasma membranes, Proc. Natl. Acad. Sci. U.S.A., 82:4–8, 1985. 103. Tataranni, PA, IT Harper, S Snitker, A Del Parigi, B Vozarova, J Bunt, C Bogardus, and E Ravussin, Body weight gain in free-living Pima Indians: effect of energy intake vs expenditure, Int. J. Obes. Relat. Metab. Disord., 27:1578–1583, 2003. 104. Tataranni, PA, DE Larson, and E Ravussin, Body fat distribution and energy metabolism in obese men and women, J. Am. Coll. Nutr., 13:569–574, 1994. 105. Tucker, MZ and LP Turcotte, Aging is associated with elevated muscle triglyceride content and increased insulin-stimulated fatty acid uptake, Am. J. Physiol. Endocrinol. Metab., 285:E827–835, 2003.
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106. Turcotte, LP, JR Swenberger, MZ Tucker, and AJ Yee, Increased fatty acid uptake and altered fatty acid metabolism in insulin-resistant muscle of obese Zucker rats, Diabetes, 50:1389–1396, 2001. 107. Weyer, C, S Snitker, R Rising, C Bogardus, and E Ravussin, Determinants of energy expenditure and fuel utilization in man: effects of body composition, age, sex, ethnicity and glucose tolerance in 916 subjects, Int. J. Obes. Relat. Metab. Disord., 23:715–722, 1999. 108. Young, ME, GW Goodwin, J Ying, P Guthrie, CR Wilson, FA Laws, and H Taegtmeyer, Regulation of cardiac and skeletal muscle malonyl-CoA decarboxylase by fatty acids, Am. J. Physiol. Endocrinol. Metab., 280:E471–479, 2001. 109. Youngren, JF, ID Goldfine, and RE Pratley, Decreased muscle insulin receptor kinase correlates with insulin resistance in normoglycemic Pima Indians, Am. J. Physiol., 273:E276–283, 1997. 110. Youngren, JF, ID Goldfine, and RE Pratley, Insulin receptor autophosphorylation in cultured myoblasts correlates to glucose disposal in Pima Indians, Am. J. Physiol., 276:E990–994, 1999. 111. Yu, C, Y Chen, GW Cline, D Zhang, H Zong, Y Wang, R Bergeron, JK Kim, SW Cushman, GJ Cooney, B Atcheson, MF White, EW Kraegen, and GI Shulman, Mechanism by which fatty acids inhibit insulin activation of insulin receptor substrate1 (IRS-1)-associated phosphatidylinositol 3-kinase activity in muscle, J. Biol. Chem., 277:50230–50236, 2002. 112. Zhou, Q, PL Dolan, and GL Dohm, Dephosphorylation increases insulin-stimulated receptor kinase activity in skeletal muscle of obese Zucker rats, Mol. Cell Biochem., 194:209–216, 1999. 113. Zurlo, F, PM Nemeth, RM Choksi, S Sesodia, and E Ravussin, Whole-body energy metabolism and skeletal muscle biochemical characteristics, Metabolism, 43:481–486, 1994.
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Nonsurgical Management of Obesity Jarol Boan, M.D., M.P.H.
CONTENTS I. Introduction..................................................................................................99 II. Definition .....................................................................................................99 III. Relationship Between Obesity and Diabetes ............................................100 IV. Challenges of Lifestyle Change in the Management of Obesity .............101 V. The Role of Exercise in the Management of Obesity ..............................103 VI. The Role of Drugs.....................................................................................104 VII. Conclusion .................................................................................................105 References..............................................................................................................106
I. INTRODUCTION The rapid increase in the prevalence of overweight and obesity in the U.S. represents a major health problem. Obesity is a worldwide epidemic, and after tobacco use, obesity is the second-leading preventable cause of death in the U.S.1 Obesity is the result of sustained positive-energy balance, and the current obesity epidemic is the result of interactions between genes and the environment (i.e., diet and exercise habits), as well as metabolic, social, behavioral, and psychological factors. Obesity has been associated with three conditions that are characterized by resistance to insulin-mediated glucose disposal: coronary heart disease, type 2 diabetes, and hypertension.2,3 It has been estimated that approximately 25 percent of the U.S. population has three or more of the following abnormalities: excess body weight, high triglyceride or low HDL cholesterol concentration, hypertension, or impaired fasting glucose.4
II. DEFINITION Obesity is defined as an excess of fat in the body, which increases body weight beyond physical and skeletal requirements. Because total body fat is hard to measure, obesity is determined by the body-mass index (BMI). BMI is defined as weight divided by height squared (weight/height2) and represents the degree of body fat that a person has. A short person carries weight differently than a tall person, making 99
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TABLE 6.1 Weight Classification — Body Mass Index (BMI) Underweight Normal Overweight Obesity Class Obesity Class II Obesity, extreme
<18.5 18.5–24.9 25.0–29.0 30.0–39.0 35.0–39.9 >40.0
comparisons of weight between two individuals in a population difficult. The BMI is a concept of weight that estimates the degree of body fat independent of height, gender, or ethnicity. Since increasing BMI is associated with increasing risks for comorbidities, every physician should be familiar with the common cut-off points. These are presented in Table 6.1.
III. RELATIONSHIP BETWEEN OBESITY AND DIABETES It is often assumed that obesity equals insulin resistance, since overweight people tend to become more insulin sensitive with weight loss.5 However, results from the European Group for the Study of Insulin Resistance have shown that only 25 percent of people who are overweight had evidence of insulin resistance.6 Epidemiological evidence suggests that persons in the upper tertile of insulin resistance (measured by insulin-mediated glucose disposal) are at a statistically, significantly increased risk for developing type 2 diabetes, coronary heart disease, or hypertension.7,8 Recently, several well-designed clinical trials suggest that changes in lifestyle can prevent the onset of diabetes. In the Finnish Study, 522 obese (mean BMI 31 kg/m2) subjects were randomized to receive brief or individualized lifestyle instruction. After 3.2 years, there was a 58 percent relative reduction in the incidence of diabetes in the intervention group with individualized instruction.9 Diabetes Prevention Program is a multicenter, three-arm trial that randomized 3234 people at risk for diabetes to either a placebo pill or metformin plus minimal diet and exercise education (yearly individual sessions with handouts), or an intensive lifestyle intervention (diet, exercise, and behavioral education in a 16-lesson, 24-week curriculum, followed by monthly sessions, with both individual and group sessions).10 The intensive lifestyle group lost more weight (–5.6 kg versus –2.1 kg versus 0.1 kg) and had lower diabetes incidence (14.4 percent versus 21.7 percent versus 28.9 percent) than the metformin group and the control group, respectively. Interestingly, these results were seen even though only 50 percent of participants in the intensive group achieved the goal of 7 percent or more weight loss at 24 weeks, and only 58 percent were adherent to the exercise recommendation (150 minutes per week) at the most recent visit (mean follow-up 2.8 years). The intensive group successfully reduced energy intake by an average of 150–200 Kcal per day compared with the
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other groups. These studies emphasize the importance of measuring clinical outcomes (e.g., incidence of diabetes) because the intensive intervention might have been considered only mildly successful if only weight loss were measured.
IV. CHALLENGES OF LIFESTYLE CHANGE IN THE MANAGEMENT OF OBESITY Lifestyle change (diet and exercise) remain the first-line therapy for many common disorders, including diabetes, obesity, hypertension, and hyperlipidemia. The reported prevalence of people trying to lose weight in a community-based survey was 28.8 percent for men and 43.6 percent for women.11 A recent, systematic review of the literature regarding obesity treatment by McTigue et al. showed that behavior and counseling (diet and exercise) result in average weight loss of 3 kg to 6 kg over 12 to 60 months.12 Since dieting is associated with a high failure rate, physicians are hesitant to recommend it as a treatment for improving obesity comorbidities. However, a recent review of long-term outcomes of dietary intervention showed a 15 percent success rate among 2131 patients followed for five years.13 Interventions most likely to be successful were high intensity (contact with the participant more often than monthly) and included more than one component (i.e., diet education, exercise education, behavioral therapy). Educating the patient is the main goal of diet counseling, and effectiveness of learning is important for a patient to adhere effectively to a diet. Unfortunately, learning is quite difficult, given the complexities of nutrition information and of food choices available to a patient. Moreover, learning the healthiest food selections has never been as difficult as it is today when even renowned nutrition researchers stage debates in prominent medical journals over what types of foods should be eaten. Patients are often confused about what to eat. Despite multiple studies, clinical guidelines, and public recommendations in support of lowering dietary fat, evidence from a systematic review suggests that low-fat diets are no better than other types of weight-reducing diets in achieving and maintaining weight loss over a 12- to 18month period.14 Recently, greater weight loss and improvement in serum lipids have been reported with a low-carbohydrate/high-fat diet (Atkins-type diet).15,16 It is not surprising that patients receive streams of conflicting diet information from health professionals, friends, television, radio, newspapers, and magazines. Expanding a patient’s knowledge of nutrition is only one of the barriers to overcome when trying to improve lifestyle change. Other barriers to diet modification include resource constraints, environmental factors, and cultural/social factors. A healthy diet may be considered more expensive and time-consuming to prepare than a less-healthy diet. Similarly, low socioeconomic communities may have less access to healthy food options and more access to unhealthy food options. Even the wealthiest communities, however, are bombarded with the environmental pressures of unhealthy food options and advertising in today’s world. Intermingled among these issues are cultural, ethnic, and social factors, which can make healthy-diet changes very difficult for patients and challenge health practitioners trying to assist patients in these endeavors. As an example of culture’s powerful influence on diet, eating
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habits are one of the latest of the features assimilated from the new culture in individuals who relocate from one country to another.17 Meal size is another example of how social factors influence diet changes; the size of the meal is positively correlated with the number of people present at the meal.18 Behavioral or psychological issues may constitute some of the greatest barriers to modifying diet. With maturation, one’s eating habits become ingrained as a part of one’s behavior. In order for a patient to change eating behaviors, the patient must be motivated to do so. Similar to other lifestyle modifications, several psychological models can be used to assess patient motivation to change and predict success, including the stages-of-change (Transtheoretical),19 health belief,20 locus of control,21 and self-efficacy22 models. For some people, food is often used to relieve stress or adapt to difficult situations. When these behaviors become maladaptive, eating disorders might result. Not surprisingly, obese people have a higher prevalence of two distinct eating disorders: binge-eating syndrome and night-eating syndrome. Binge eating is a feeling of loss of control while consuming an amount of food that is larger than most people would eat. Binge eating is twice as prevalent in obese patients than nonobese patients.23 Moreover, relative to obese patients who do not binge eat, binge eaters have higher BMIs, as well as higher rates of comorbid depression and anxiety.24 Among bariatricsurgery patients, the prevalence of preoperative binge eating ranges from 13 percent to 49 percent.25 Night-eating syndrome, first recognized by Stunkard in 1955, is defined by ingestion of 50 percent of the daily caloric intake after the evening meal, awakening at least once a night for three nights a week to eat, and morning anorexia. In morbidly obese patients, the prevalence of night-eating syndrome may be as high as 26 percent.26 Dieting or chronic restrained eating may be important triggers for these disorders, which often go unrecognized due to the surreptitious manner in which patients binge. These disorders are complex psychological illnesses; further studies are needed to define appropriate therapy in obese patients with these problems. In addition to eating disorders, another psychological disorder that can be a barrier to lifestyle change is depression, especially in obese patients. Obese people are particularly vulnerable to symptoms of low self-esteem and depression, and depression has been linked strongly with nonadherence.35–37 Possible contributors to low self-esteem include repeated unsuccessful weight-loss attempts, failure to measure up to the thin ideal promoted by the media, discrimination, increased physical pain, and decreased physical ability.27 Health-care providers must be aware of the possibility of depressive symptoms in obese patients, and should avoid stereotyping their patients as having personality disorders responsible for their obesity. Health professionals are not immune to discrimination of obese people28; discrimination has even been demonstrated in obesity specialists.29 Therefore, when working with obese patients, it is important for health-care providers to maintain an empathetic attitude; avoid accusatory, derogatory, or nihilistic remarks; and rather, work with the patient to identify barriers to adherence and work to overcome these barriers. Two of the factors most consistently associated with successful weight loss include attendance at follow-up sessions and self-monitoring (of dietary intake and body weight).30 Another predictor, duration of intervention, is actually derived more
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by comparing longer duration interventions with shorter ones, as opposed to examining factors within one intervention. These factors are reflected in many current, successful interventions, which have frequent follow-up over long durations and emphasize patient involvement in monitoring, but also in menu and food preparation.
V. THE ROLE OF EXERCISE IN THE MANAGEMENT OF OBESITY The current public-health recommendation for physical activity is for individuals to participate in 30 minutes of moderately intense physical activity on most days of the week.31 The reason that people do not lose weight with increased exercise alone is because they usually also increase their food intake. Therefore, exercise combined with energy restriction is recommended based on the rationale that physical activity will result in an increase in total energy expenditure. It appears that the key factor that explains the relationship between exercise and weight is the adoption of an active lifestyle to prevent weight gain and weight regain. Exercise has a powerful effect on insulin sensitivity. Studies in Pima Indians and persons of European ancestry demonstrated that physical fitness was as powerful a modulator of insulin resistance as was body weight; each variable accounted for approximately 25 percent of the differences in insulin-mediated glucose disposal in nondiabetic persons.32 Obese individuals with type 2 diabetes mellitus had an increase in insulin sensitivity following low-intensity bicycle riding.33 In nonobese, insulin-resistant relatives of type 2 diabetic subjects, moderate-intensity exercise had a 40 percent increase in insulin sensitivity.34 The Diabetes Prevention Program found that intensive exercise in combination with a change in diet could lower the risk of progressing to diabetes by 58 percent.35 Despite recommendations of exercise for prevention of weight gain and improvement of cardiovascular fitness and insulin sensitivity, the major challenge is adoption of a regular exercise pattern. Recent studies on the effectiveness of intermittent exercise (multiple 10- to 15-minute exercise sessions daily) suggest that intermittent exercise is a successful strategy for increasing the adoption of exercise in overweight individuals who are sedentary.36 The long-term, cumulative effect of small changes in activity level can be beneficial. By walking about 2000 extra steps a day, 100 extra calories can be burned a day. It appears that the key factor that explains the relationship between exercise and weight is the adoption of an active lifestyle to prevent weight gain and weight regain. Evidence from the National Weight Control Registry, a group of 1047 individuals who lost at least 30 pounds (13.6 kg) and maintained that loss for at least one year, supports this claim. In an analysis of successful weight maintainers, one hour or more of moderate to vigorous physical activity per day was the factor that led to a successfully maintained weight loss over an average of 6.9 years.37 Understanding how powerfully the environment influences behavior is necessary to understand why some people gain more weight than others in the same environment. Considerable interindividual differences in the trainability of cardiorespiratory endurance traits have been observed after exposure to identical training programs,
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suggesting genetic diversity accounts for the variability in weight gain.38 In twin studies, Bouchard et al. showed that the effect of exercise may be influenced by genetic differences between individuals. In his elegant studies, there was a 6.8 times greater change in body weight between pairs than within pairs of twins that were engaging in the same type and amount of physical activity.39 Energy expended during physical activity is highly variable, and it is the component of total energy expenditure over which an individual has the most control. It may represent 15 percent to 50 percent of the total 24-hour energy expended, depending on the activity of the individual. Increasing intensity and duration of activity will increase energy expenditure.
VI. THE ROLE OF DRUGS Weight-loss medications are indicated for patients with a BMI greater than 30 kg/m2 (27 kg/m2 with comorbidities) who have not achieved weight loss with lifestyle changes. Presently, two drugs (orlistat and sibutramine) are FDA approved and marketed as adjunctive treatment of obesity, albeit many compounds are being studied for the treatment of obesity. The pharmacological treatment of obesity receives substantial attention from research and development. It is estimated that the market for obesity treatments in the United States ranges from $735.5 million to $1.23 billion. One study has shown that sibutramine has helped obese patients on a four-week, very low-calorie diet maintain their weight loss for a period of 12 months.40 In the Sibutramine Trial in Obesity Reduction and Maintenance (STORM), 605 patients were followed for 24 months. Eighty-two percent of the patients on sibutramine achieved at least a 5 percent weight reduction and were able to maintain it for 18 months compared to 16 percent of patients on placebo.41 Predictors of an effective response with the use of sibutramine include a history of successful weight loss with lifestyle change alone, a patient who struggles with recognition of signals for hunger and fullness, and a patient who admits to feelings of a lack of control over food intake. The drug orlistat has also been shown to be an effective obesity medication. Orlistat works by inhibiting absorption of approximately 30 percent of dietary fat from the small intestine. In a double-blind, randomized-controlled trial of obese patients with orlistat 120 mg (three times a day) or placebo for one year in conjunction with the hypocaloric diet (600 Kcal/day deficit), Sjostrom et al. found that the orlistat group lost more body weight than the placebo group (10.2 percent versus 6.1 percent; least squared means (LSM) difference 3.9 kg, p < 0.001).42 The following group of patients has a superior response to orlistat: those with an inability to identify hidden fat in foods, those with significant restaurant eating, and those seeking negative reinforcement. Several new drugs show promise for future treatment of obesity. Axokine, a genetically engineered recombinant human variant ciliary neurotrophic factor that signals through leptinlike pathways in the hypothalamus, has been shown to bypass leptin resistance.43 Topiramate is a broad-spectrum anticonvulsant that stimulates [gamma]-aminobutyric acid activity. In a 14-week, double-blind trial comparing
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topiramate to placebo, topiramate was associated with a significant reduction in binge frequency, binge-day frequency, body-mass index, and weight.44 Zonisamide, an antiepileptic drug that has serotonergic and dopaminergic activity, has been shown to produce weight loss in randomized-controlled trials (drug versus placebo 9.2 kg versus 1.5 kg over 32 weeks).45 Glucagon-like peptide-1 (GLP-1) has been shown to be effective to stimulate insulin secretion, suppress glucagon secretion, and inhibit gastric emptying.46 Rimonabant, a Cannabinoid CB1 agonist, has been shown to be effective in weight loss in both animal models47 and early clinical trials.48 The pharmacological treatment of obesity continues to receive substantial attention from the pharmaceutical industry, and newer drugs may be marketed in the near future.
VII. CONCLUSION Controlling intake and increasing activity (dieting and exercise) are very difficult, and it is important for physicians to understand that some patients may have to do much more than others to maintain a healthy weight. There are windows of opportunity when radical behavioral changes seem to work. For example, after a diagnosis of diabetes or myocardial infarction, patients are often highly motivated to undertake behavioral changes. Unfortunately, the amount of weight loss by nonsurgical approaches rarely surpasses 15 percent from baseline weight. Table 6.2 provides some guidelines for improving adherence to dietary changes. It is important that physicians not take nonadherence to their suggestions personally and criticize patients when they don’t achieve their weight goals. After validating the difficulties that their patients face, it is important for physicians to focus on identifying obstacles and help their patients design a plan to succeed the next time.
TABLE 6.2 Practical Strategies for Improving Diet Adherence Use self-monitoring (e.g., diet records, weighing) Identify and employ alternatives to eating (e.g., exercise, hobbies) Find a partner(s) to diet with you Avoid triggers for eating (especially high-risk foods) Keep acceptable foods accessible and unacceptable foods inaccessible Keep a regular eating schedule and eat frequent small amounts rather than infrequent binges Practice responses to hosts/acquaintances that urge you to indulge or eat more Follow an eating schedule Use a shopping list and stick to the list Do not grocery shop when hungry Be involved in food preparation Eat slowly Do not feel compelled to clean your plate Indulge infrequently in small amounts After losing weight, give away or sell clothes that are too big Realize that lapses will occur and return to diet after lapses
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In fact, better adherence to diet recommendations would greatly reduce the morbidity and mortality associated with obesity and diabetes. For a number of factors, adherence to diet can be difficult and restrictive. This results in both patients and practitioners frequently abandoning diet interventions in favor of medications and even surgery, despite the many adverse effects and complications, not to mention cost, inherent to these therapies. Predictors of poor outcome include prior attempts at weight loss, poor health, psychiatric illness, and multiple life stressors.49, 50 Patients with these factors should therefore be targeted for more aggressive and supportive interventions to improve their chances of success. The future of obesity treatment involves a multidisciplinary approach that encompasses medical interventions, pharmaceutical developments, and surgical approaches in combination with broad societal changes (school-based programs, workplace programs, food industry and media involvement). Since sustained weight loss by lifestyle change is difficult to achieve, preventing weight gain should be the focus of these changes. Unfortunately, over the last three decades, childhood obesity has more than doubled for children aged 2–5 years and adolescents aged 12–19 years, and it has tripled for children 6–11 years.51 A substantial amount of research examining valid and sustainable treatment options is required.
REFERENCES 1. Allison DB, Fontaine, KR, Manson, JE, Stevens, J, and VanItallie, TB, Annual deaths attributable to obesity in the United States, JAMA, 282(16):1530–1538, 1999. 2. Reaven, GM, Banting lecture 1988. Role of insulin resistance in human disease, Diabetes, 37:1595–607, 1988. 3. Reaven, GM, Insulin resistance, compensatory hyperinsulinemia, and coronary heart disease: Syndrome X revisited, in Handbook of Physiology, Jefferson, LS and Cherrington, AD, Eds., Oxford University Press, New York, 2001, Sec. 7, The Endocrine System, Vol 2, The Endocrine Pancreas and Regulation of Metabolism, p. 1169–97. 4. Ford, ES, Giles, WH, and Dietz, WH, Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey, JAMA, 287:356–9, 2002. 5. Olefsky, J, Reaven, GM, and Farquhar, JW, Effects of weight reduction on obesity. Studies of lipid and carbohydrate metabolism in normal and hyperlipoproteinemic subjects, J. Clin. Invest., 53:64–76, 1974. 6. Ferrannini, E, Natali, A, Bell, P, Cavallo-Perin, P, Lalic, N, and Mingrone, G, Insulin resistance and hypersecretion in obesity. European Group for the Study of Insulin Resistance (EGIR), J. Clin. Invest., 100:1166–73, 1997. 7. Yip, J, Facchini, FS, and Reaven, GM, Resistance to insulin-mediated glucose disposal as a predictor of cardiovascular disease. J. Clin. Endocrinol. Metab., 83:2773–6, 1998. 8. Facchini, FS, Hua, N, Abbasi, F, and Reaven, GM, Insulin resistance as a predictor of age-related diseases, J. Clin. Endocrinol. Metab., 2001;86:3574–8, 2001. 9. Tuomilehto, J, Lindstrom, J, Eriksson, JG, et al., Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N. Engl. J. Med., 344(18):1343–1350, 2001.
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10. Knowler, WC and Nathan, DM, Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346(6):393–403, 2002. 11. Serdula, MK, Mokdad, AH, Williamson, DF, Galuska, DA, Mendlein, JM, and Heath, GW, Prevalence of Attempting Weight Loss and Strategies for Controlling Weight, JAMA, 282:1353–1358, 1999. 12. McTigue, KM, Harris, R. Hemphill, B, Lux, L, Sutton, S, Bunton, AJ, and Lohr, KN, Screening and interventions for obesity in adults: summary of the evidence for the U.S. Preventive Services Task Force, Ann. of Intern. Med., 139(11):933–49, 2003. 13. Ayyad, C and Anderson, T, Long-term efficacy of dietary treatment of obesity: a systematic review of studies published between 1931 and 1999, Obes. Rev., 1:113–119, 2000. 14. Thompson, RL, Summerbell, CD, Hooper, L, et al., Relative efficacy of differential methods of dietary advice: a systematic review, Am J Clin Nutr., 77(Suppl. 4):1052S–1057S, 2003. 15. Katan, MB, Grundy, SM, and Willett, WC, Should a low-fat, high-carbohydrate diet be recommended for everyone? Beyond low-fat diets, N. Engl. J. Med., 337(8):563–566; discussion 566–567, 1997. 16. Foster, GD, Wyatt, HR, Hill, JO, Mcguckin, BG, Brill, C, Mohammed, S, Szapary, PO, Rader, DJ, Edman, JE, Klein, S, A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348:2082–90, 2003. 17. Brownell, KD and Cohen, LR, Adherence to dietary regimens. 1: An overview of research, Behav. Med., 20(4):149–154, 1995. 18. De Castro, JM and de Castro, ES, Spontaneous meal patterns of humans: influence of the presence of other people, Am. J. Clin. Nutr. 50(2):237–247 1989. 19. DiClemente, CC and Prochaska, JO, Self-change and therapy change of smoking behavior: a comparison of processes of change in cessation and maintenance, Addict. Behav., 7(2):133–142, 1982. 20. Becker, M, The health belief model and personal health behavior, Thorofare, NJ, Stock; 1974. 21. Wallston, K and Wallston, B, Development of the multidimensional health locus of control (MHLC) scales. Health Educ. Monogr., 6:160–170, 1978. 22. Bandura, A, Self-efficacy: toward a unifying theory of behavioral change, Psychol. Rev., 84:191–215, 1977. 23. Smith DE, Marcus MD, Lewis CE, Fizgibbon M, Schreiner P, Prevalence of binge eating disorder, obesity, and depression in a biracial cohort of young adults, An. Behav. Med., 20(3):227–232, 1998. 24. Wadden, Womble, Stunkard, Anderson, Psychosocial consequences of obesity and weight loss, in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ Eds., Guilford Press, New York, 2002. 25. Powers, PS, Perez, A, Boyd, F, and Rosemurgy, A, Eating pathology before and after bariatric surgery: a prospective study, Int, J. Eat. Disord., 25:293-300, 1999. 26. Rand CS, Macgregor AM, Stunkard AJ. The night eating syndrome in the general population and among post-operative obesity surgery patients, Int. J. Eat. Disord., 22:65–69, 1997. 27. Allon, N, The stigma of overweight in everyday life, in Psychological Aspects of Obesity: A Handbook, Wolman, B, Ed., New York, Van Nostrand Reinhold, New York, 1982, p. 130–174. 28. Kaminsky, J and Gadaleta, D, A study of discrimination within the medical community as viewed by obese patients, Obes. Surg., 12(1):14–18, 2002.
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29. Schwartz, MB, Chambliss, HO, Brownell, KD, Blair, SN, and Billington, C, Weight bias among health professionals specializing in obesity, Obes. Res., 11(9):1033–1039, 2003. 30. Wing, RR, Behavioral weight control in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ, Eds., Guilford Press, New York, 2002. 31. Pate, RR, Pratt, SN, Blair, S, et al., Physical activity and public health: a recommendation from the Centers for Disease Control and Prevention and the American College of Sports Medicine, JAMA, 273:402–407, 1995. 32. between degree of obesity and in vivo insulin action in man, Am. J. Physiol., 1985:248:E286–91, 1985. 33. Usui, K, Yamanouchi, K, Asai, K, Yajima, M, Iriyama, A, Okabayashi, N, Sakakibara, H, Kusunoki, M, Kakumu, S, and Sato, Y, The effect of low intensity bicycle exercise on the insulin-induced glucose uptake in obese patients with type 2 diabetes, Diabet. Res. Clin. Pract., 41(1):57–61, 1998. 34. Perseghin, G, Price, TB, Petersen, KF, Roden, M, Cline, GW, Gerow, K, Rothman, DL, and Shulman, GI, Increased glucose transport-phosphorylation and muscle glycogen synthesis after exercise training in insulin-resistant subjects, N. Engl. J. Med., 335(18):1357–62, 1996. 35. Knowler, WC and Nathan, DM, Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346(6):393–403, 2002. 36. Jakicic, JM, Wing, RR, Butler, BA, and Robertson, RJ, Prescribing exercise in multiple short bouts versus one continuous bout: effects on adherence, cardiorespiratory fitness, and weight loss in overweight women, Int. J. Obes., 1995; 19:893–901, 1995. 37. McGuire, MT, Wing, RR, Klem, ML, Seagle, HM, and Hill, JO, Long term maintenance of weight loss: Do people who lose weight through various weight loss methods use different behaviors to maintain their weight? Int. J. Obes., 1998; 22(6):572–577, 1998. 38. Bouchard, C, Individual differences in the response to regular exercise, Int. J. Obes. Relat. Metab. Disord., 4:5–8, 1995. 39. Bouchard, CA, Tremblay, A, and Despres, JP, The response to exercise with constant energy intake in identical twins, Obes. Res., 1994; 5:400–410, 1994. 40. Apfelbaum, M, et al., Am. J. Med., 106:179, 1999. 41. Apfelbaum, M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E, Long-term maintenance of weight loss after a very low calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am. J. Med., 106(2):179–184, 1999. 42. James, WP, Astrup A, Finer N, Hilsted J, Kopelman P, Rossner S, Saris WH, Van Gaal LF, Effect of sibutramine on weight maintenance after weight loss: a randomized trial. STORM Study Group. Sibutramine Trial of Obesity Reduction and Maintenance. Lancet 356(9248):2119–2125, 2000. 43. SB, Bray, GA, Roberts, WG, Heyman, ER, Stambler, N, Heshka, S, Vicary, C, and Guler, HP, Recombinant variant of ciliary neurotrophic factor for weight loss in obese adults: a randomized, dose-ranging study, JAMA, 289(14):1826–32, 2003. 44. McElroy, SL, Arnold, LM, Shapira, NA, Keck, PE, Jr. Rosenthal, NR, Karim, MR, Kamin, M, and Hudson, JI, Topiramate in the treatment of binge eating disorder associated with obesity: a randomized, placebo-controlled trial, Am. J. Psychiat., 160(2):255–61, 2003.
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45. Gadde, KM, Franciscy, DM, Wagner, HR, 2nd, and Krishnan, KR, Zonisamide for weight loss in obese adults: a randomized controlled trial, JAMA, 289(14):1820–5, 2003. 46. Kolterman, OG, Buse, JB, Fineman, MS, Gaines, E, Heintz, S, Bicsak, TA, Taylor, K, Kim, D, Aisporna, M, Wang, Y, and Baron, AD, Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes, J. Clin. Endocrinol. Metab., 88(7):3082–9, 2003. 47. Hildebrandt, AL, Kelly-Sullivan, DM, and Black, SC, Antiobesity effects of chronic cannabinoid CB1 receptor antagonist treatment in diet-induced obese mice, Eur. J. Pharmacol., 462(1–3):125–32, 2003. 48. Black, SC, Cannabinoid receptor antagonists and obesity, Curr. Opin. Invest. Drugs, 5(4):389–94, 2004. 49. Perri, MG, McAdoo, WG, and McAllister, DA, Effects of peer support and therapist contact on long-term weight loss, J. Consult. Clin. Psychol., 55:615–617, 1987. 50. Wing, RR, Behavioral weight control, in Handbook of Obesity Treatment, Wadden, TA and Stunkard, AJ, Eds., Guilford Press, New York, 2002. 51. National Academy of Science, Preventing Childhood Obesity: Health in the Balance Fact Sheet, September 2004.
7
Bariatric Surgery for Obesity Ross L. McMahon, M.D., F.R.C.S.C., FACS
CONTENTS I. Introduction................................................................................................111 II. Definitions and Risk Factors .....................................................................112 III. Surgical Treatment of Morbid Obesity .....................................................112 A. History ...............................................................................................112 B. Current Surgical Therapies for Morbid Obesity...............................114 1. Patient Selection ..........................................................................114 2. Laparoscopic Adjustable Gastric Banding..................................115 3. Gastric Bypass.............................................................................117 4. Biliopancreatic Diversion............................................................119 IV. Laparoscopic Bariatric Surgery.................................................................120 V. Conclusion .................................................................................................121 References..............................................................................................................121
I. INTRODUCTION Obesity has become a major health problem in the United States. Nearly two-thirds of U.S. adults are overweight (BMI ≥ 25).1 This represents 129.6 million American adults. Of these, 61.3 million are obese (BMI > 30), and it is estimated that 4 million are severely obese, and 1.5 million are morbidly obese.2,3 From 1960 to 1990, the incidence of obese American adults increased from 13 percent to 35 percent.4 This rapid rise in the prevalence of obesity has occurred despite multiple public-health efforts and in the backdrop of a culture that spends $30 billion annually on commercial weight-loss products.5 Not only is obesity a significant public-health challenge, it is an enormous economic burden. Obese patients are at increased risk of multiple medical comorbidities: coronary-artery disease, hypertension, type 2 diabetes, respiratory insufficiency, venous stasis or thromboembolic disease, debilitating arthritis of weightbearing joints, and depression, as well as uterine, ovarian, colon, breast, and prostate cancer.6 The annual health-care expenditures for obesity-related diseases in the United States have increased from $39 billion in 1993 to more than $75 billion now and represent more than 5 percent of total annual health-care costs.7 111
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II. DEFINITIONS AND RISK FACTORS In 1998, the National Institutes of Health established federal guidelines for the identification, evaluation, and treatment of overweight and obese adults.8 Ideal-bodyweight (IBW) tables are based on actuarial studies performed by the Metropolitan Life Insurance Company.9 The amount a patient is overweight has been categorized based on body-mass index (BMI), which normalizes the weight with the patients height. Overweight is defined by having a BMI greater than 25 kg per m2, obesity is having a BMI greater than 30 kg per m2, severe obesity is having a BMI greater than 35 kg per m2, and morbid obesity is having a BMI greater than 40 kg per m2 or a BMI greater than 35 kg per m2 with concomitant obesity-related morbidity. A BMI of 40 kg per m2 roughly correlates with an actual weight exceeding ideal body weight by 100 pounds. Federal guidelines based on studies relating BMI to morbidity and mortality have been released. Patients with a BMI between 20 and 25 kg per m2 have the lowest mortality rate.10 As BMI increases above 25 kg per m2, mean blood pressure and total blood cholesterol increase, and mean high-density lipoprotein levels decrease.11 Women with a BMI greater than 29 kg per m2 have a significantly increased incidence of myocardial infarction.12 Obese patients have an increased risk of coronary-artery disease.13,14 Complications related to obstructive sleep apnea are twelvefold to thirtyfold higher in the morbidly obese than in the general population.15 The most significant observation is that morbidly obese patients who are 20 to 40 years of age may experience a twelvefold reduction in life expectancy in comparison with age-matched control subjects. These observations confirm the concept that obesity has become a national health crisis. Once classified, it is recommended that patients who are obese or severely obese be treated medically with caloric restriction, increased physical activity, Food and Drug Administration approved weight-loss drugs, and behavioral modification. Surgery is recommended for patients who are morbidly obese or for those who are severely obese with concomitant obesity-related diseases.
III. SURGICAL TREATMENT OF MORBID OBESITY A. HISTORY Weight loss in relation to intestinal resection was observed in the late 19th century. Trzebicky16 first noted nutritional imbalances in canines following proximal and distal small-bowel resection. Weight loss in humans after gastric or small-intestinal resection was reported by Von Eiselsberg in 1895.2 Jensenius demonstrated that after distal small-bowel resection in a canine model, there was an increased loss of fat in the stool. Kremen later demonstrated that resection of greater than 50 percent of the distal small-intestine reduced fat absorption and resulted in weight loss, whereas lesser resections of proximal small intestine resulted in normal nutritional balance. Based on this work, Kremen performed the first therapeutic bariatric procedure, an end-to-end jejunoileostomy, in 1954. In 1955, Payne and Dewind performed the first clinical trial of obesity surgery. This trial of an intestinal bypass procedure was
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abandoned due to severe metabolic disturbances, liver failure, and protein-calorie malnutrition.17,18 The procedure was subsequently modified by anastomosing the proximal jejunum to the distal ileum, with the bypassed segment of small bowel anastomosed end-to-side to the colon, known as the jejunoileal bypass. This procedure was popular in the 1960 to 1970 era, and was very effective for weight loss. However, weight loss was complicated by significant electrolyte imbalances, vitamin deficiencies, intractable diarrhea, cholelithiasis, urolithiasis, neuromyopathies, and liver failure. As many as 25 percent of these patients required reversal of the jejunoileal bypass because of these complications, and the procedure was eventually abandoned.19 Mason and Ito developed the gastric bypass procedure for weight loss in the 1960s. Their work was based on the observation by Von Eiselsberg that weight loss often followed hemigastrectomy. In their report, 24 patients who had undergone Billroth II retrocolic gastrojejunostomy to a 100 ml gastric pouch with a 2 cm gastric outlet lost an average weight of 60 pounds at 18 months' follow-up.20 Electrolyte and vitamin deficiencies were manageable with supplementation, and liver dysfunction was unusual. In order to prevent bile reflux gastritis, Griffen modified the procedure by constructing a Roux-en-Y gastrojejunostomy instead of a Billroth II anastomosis.21 Even though many variations of the original procedure have been described, gastric bypass with a Roux-en-Y gastrojejunostomy remains an effective weight-loss operation with an acceptable complication rate.22 The era of purely restrictive procedures for the treatment of obesity came in 1971, when Printen and Mason introduced restrictive gastroplasty procedures.23,24 Gastroplasties were initially performed by partitioning the proximal stomach with a stapler, leaving a small (1 cm) gastric outlet along the greater curve. The staples were expected to hold the partition and opening in place for the lifetime of the patient. This would prove to be overly optimistic. The staple line frequently disrupted over 2 to 5 years with either the small gastric outlet dilating or the partition entirely failing. The end result was the same: Many patients lost significant amounts of weight only to regain it. Stapling and other surgical technologies continued to evolve over this time period. In 1982, Mason created a 2.5 cm circular defect with an endto-end anastomosis (EEA) stapler approximately 8 to 9 cm below the angle of His and 3 cm from the lesser curve, and a polypropylene mesh collar was placed around the gastric outlet.25 The era of malabsorption returned in 1981, when Scopinaro and coworkers26 in Italy reported their initial results with biliopancreatic bypass (BPD). The BPD combines a subtotal gastrectomy with a Roux-en-Y gastroileal anastomosis and a jejunoileal anastomosis 50 cm proximal to the ileocecal valve to allow absorption of nutrients in the distal 50 cm common channel. Results reported by Scopinaro and coworkers have been excellent, with reduction in excess weight of nearly 75 percent. Complications associated with the procedure are protein malnutrition and malabsorption of vitamins; severe complications, such as liver failure, are rare, but they do occur. To reduce these complications, Marceau and associates27 in Canada modified the technique of Scopinaro and developed the biliopancreatic diversion with a duodenal switch (BPD-DS). It is constructed by performing a sleeve gastrectomy instead of subtotal gastrectomy, a Roux-en-Y duodenoileal anastomosis, and an
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ileoileal anastomosis 100 cm proximal to the ileocecal valve. Excellent results have been reported, and malabsorption complications have been less significant. Another commonly performed restrictive procedure is adjustable gastric banding (AGB). The banding devices, usually made of silicone, compartmentalize the proximal stomach into a small pouch.28 There is currently one FDA-approved device for sale in the USA, Inamed’s Lap-Band. AGB was first introduced in the 1990s.29 The adjustable band has a saline-injectable, subcutaneous reservoir that is tunneled in the subcutaneous tissue of the abdominal wall and connected to an inflatable silicone band that is wrapped around the proximal stomach. If weight loss is inadequate or symptoms of outlet obstruction arise, the silicone band can be inflated or deflated with saline, thereby changing the size of the gastric restriction. Not long after the introduction and rapid acceptance of laparoscopic cholecystectomy, surgeons began performing laparoscopic bariatric procedures. Chelala30 and Belachew31 and their colleagues reported performing laparoscopic adjustable gastric banding in 1992. Laparoscopic Roux-en-Y gastric bypass and laparoscopic verticalbanded gastroplasty were reported in 1993 by Wittgrove32 and Lonroth33 at different institutions. Initial results of laparoscopic bariatric surgery have validated its safety and feasibility.33,34 In summary, bariatric surgery evolved over the second half of the 20th century. Even though the ideal procedure has yet to be devised, surgery has emerged as the most effective treatment for sustained, significant weight loss in the morbidly obese.
B. CURRENT SURGICAL THERAPIES
FOR
MORBID OBESITY
1. Patient Selection In keeping with the National Institutes of Health Consensus Development Conference Statement on Gastrointestinal Surgery for Morbid Obesity, patients with a BMI exceeding 40 kg per m2 or 35 kg per m2 with obesity-related comorbidities are candidates for the surgical treatment of morbid obesity.10 Surgery for morbid obesity should be offered to patients who are well-informed and motivated, and who are acceptable to operative risks. Patients should be evaluated preoperatively by a multidisciplinary team of nutritionists, nurse clinicians, internists, psychologists or psychiatrists, and surgeons. Patients should be screened for common obesity-related conditions, and these conditions should be optimized. Tests to be considered are chest x-ray; electrocardiography, cardiac stress testing, and echocardiography for cardiac disorders; arterial blood-gas and pulmonary-function testing, with arterial blood gases for the hypoventilation syndrome and polysomnography for the sleep apnea syndrome; barium swallow; TS, lipid panel, HbA1c, and fasting blood sugar. The choice of procedures with risks and benefits must be clearly explained to the patient, as should be the need for long-term follow-up. The optimal operation is still a matter of much discussion. In reality, careful patient selection can result in a close match between operation and patient. This also includes the very real and not-too-infrequent denial of any surgical option for the inappropriate surgical candidate. The most commonly performed surgical procedures in the U.S. are the Lap-Band, the Roux en Y gastric bypass, and the bilopancreatic diversion.
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2. Laparoscopic Adjustable Gastric Banding The operation is performed almost exclusively laparoscopically. There are several variations in port placement and number, but five or six incisions are usually necessary. The band is introduced in its open form. The stomach is exposed, and a retrogastric tunnel is created from the lesser curve side of the inferior border of the hiatus to the angle of His with a Lap-Band passer tool. This tool is then articulated at the angle of His to create the tunnel. The Lap-Band is threaded into the eye of the tool, which is then dearticulated and brought back through the tunnel to the lesser curvature side. The band is partially closed and a sizing balloon introduced. The band is closed with the sizing balloon in place to ensure the band is not too tight. If the band is adequately free, then the balloon is deflated and removed. If the band is too tight, fat in this area needs to be removed to prevent postoperative obstruction. A retaining flap is then created anteriorly by plicating the stomach to itself over the band with three to four interrupted sutures. The tubing is then brought out of the abdominal wall and the port secured to the rectus sheath35 (Figure 7.1). Interpretation of outcome data for LAGB is fraught with difficulty. This is due to a number of factors. The results seem to have come full circle. All of the longterm data are from outside the U.S., and these data seem quite positive for the device. However, the original U.S. FDA trials are in striking contrast to the world literature. The operation has subsequently been modified to avoid problems, and the most recent reports from U.S. centers36–38 seem to be in line with the results from other world centers, such as Australia.39-41 To avoid confusing less-than-optimal techniques and to best present current knowledge and technique, the most recent U.S. reports
FIGURE 7.1 Gastric banding. A saline-injectable locking gastric band placed around the proximal stomach. The reservoir is buried subcutaneously and sutured to the anterior rectus sheath.
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TABLE 7.1 Adverse Events Following Laparoscopic Adjustable Gastric Banding (n = 445) Adverse Event
†
n (%)
Perioperative Death Malignant hyperthermia Splenectomy Stoma obstruction Device-related Tubing disconnection/leak Port infection Port migration Delayed Gastric prolapse Erosion Explanation †
† † † † † † † † † † † † † Total
† 1 (0.2%) 1 (0.2%) 1 (0.2%) 12 (2.7%) † 4 (0.9%) 5 (1%) 4 (0.9%) † 14 (3%) 1 (0.2%) 4 (0.8%) 47 (10.5%)
are the best indicators of this procedure’s true potential. For longer-term data, the Australian series seems most suited for comparison. In the U.S. series by Ren and colleagues, a total of 445 patients underwent LAGB using the Lap-Band.42 There were 341 female and 103 male individuals with an average age of 42.1 years and an average BMI of 49.6 kg/m2. Average body weight was 299.4 lb. Conversion to laparotomy was necessary in one patient (0.2 percent) because of splenic bleeding. One operation was aborted due to extreme hepatomegaly in a male patient with BMI = 43, excessive bleeding, and nonvisualization of the gastroesophageal junction. Mean length of hospital stay was 1.1 days. Adverse events occurred in 10.5 percent of patients (Table 7.1). The one death occurred in a patient who experienced sudden cardiac arrest the afternoon after surgery from a presumed arrhythmia. Acute postoperative stoma obstruction was felt to be secondary to presumed gastric-wall edema or hematoma and usually responded to conservative management. Intravenous hydration was required in seven patients. Four patients (1.1 percent) required laparoscopic revision to remove perigastric fat incorporated within the band, and one patient required laparoscopic band explantation. All postoperative stoma obstructions occurred in the first 125 operations performed by one surgeon. The procedure was modified with removal of perigastric fat to minimize the amount of fat incorporated within the band, which caused external gastric compression and, subsequently, obstruction. No acute stomal obstructions occurred thereafter. There were no known cases of thromboembolism, myocardial infarction, or intestinal sepsis. There were 13 (3 percent) reservoir port-related complications. There were five patients with port infection requiring removal of the ports. The ports were reimplanted three to six months after removal. Gastric prolapse, or band slippage, occurs when the stomach slides up
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through the band, displacing the band and causing obstruction. In this series, gastric prolapse was treated by repositioning or replacement of the Lap-Band. Band erosion occurred in one patient, and that band was removed. Two bands were explanted because of intraabdominal abscesses. There has been no evidence of esophageal dilatation. Four patients were lost to follow-up, and 99 of the 445 were available for one-year review. The average percent excess weight loss (EWL) at 12 months after Lap-Band surgery was 44.3 percent ± 17 (range 6.5–92 percent). In an earlier report, Rubinstein showed 38 percent EWL at one year after LAGB, yet achieved 54 percent EWL by three years.38 Ren and colleagues’ one-year data match that of the large series from two Australian centers, as reported by Fielding et al.41 and O’Brien39,40 Achieving successful weight loss with LAGB seems to lie with both surgical technique and patient follow-up with band adjustments. Weight loss at one year in this series is slightly less than that commonly reported for RYGB.29,32 However, over time, weight loss appears to continue in patients who have undergone a gastric band, such that three- and five-year data result in a comparable percentage of EWL.39–41. The Lap-Band is presently the safest available surgical procedure to treat morbid obesity. It seems to be, at least in the short term, as effective as other surgical alternatives. 3. Gastric Bypass This procedure is highly suited to performance through a laparoscopic approach. The open approach, however, is still used in many centers. Whether done open or laparoscopically, the steps of the procedure are the same. The operation can be divided into distinct steps: Step one, creation of the roux limb: The ligament of Treitz is identified; approximately 40 cm distal to the ligament is measured; the small bowel is divided at this position; the small-bowel mesentery is then divided; the small bowel to be bypassed, 75 cm–150 cm, depending on anatomy and amount of malabsorption, if any, desired, is then measured; the enteroenterostomy is constructed; and the defect in the mesentery closed. Step two, division of the omentum: The space between the roux limb and the transverse mesocolon — Peterson’s space — a potential space for an internal hernia, is closed. Step three, creation of the gastric pouch: The avascular window in the gastrohepatic omentum is incised and opened along the lesser curve of the stomach, and the fatty and vascular tissue divided from the gastric wall, to create a 30 ml pouch; one transverse staple firing and two to three vertical firings create the pouch; the roux limb is then anastomosed to the pouch to complete the procedure; and a drain is placed across the upper anastomosis (Figure 7.2). The long-term results of the Roux-en-Y gastric bypass on weight loss and improvement in obesity-related comorbidities have been described by a number of authors. Pories and colleagues43 have described their results over a 14-year period with a 97 percent follow-up in 608 morbidly obese patients. The mean weight loss was 49.2 percent (99.7 pounds) of excess body weight. A more striking finding in this study was the long-term control of adult-onset diabetes. Of 298 glucose-intolerant patients (146 with noninsulin-dependent diabetes mellitus and 152 with
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FIGURE 7.2 Roux-en-Y gastric bypass. A Roux limb, created by dividing the proximal jejunum 40–60 cm distal to the ligament of Treitz, is anastomosed end-to-side to a 30-ml gastric pouch. The proximal jejunal (biliopancreatic) limb is anastomosed end-to-end to the Roux limb 75–150 cm distal to the gastroenterostomy.
impaired glucose tolerance), 271 (91 percent) maintained normal fasting glucose levels, glycosylated hemoglobins, and insulin levels. Of the diabetic patients, 80 percent were off all hypoglycemic agents. Although the mechanism remains unclear, the results have been reproduced in a number of shorter-term studies. In 353 patients with hypertension, only 85 (14 percent) remained hypertensive. Other studies report significant reductions in blood pressure, triglycerides, and low-density lipoproteins, with an increase in the plasma levels of high-density lipoproteins.44 Complications of open gastric bypass include splenic injuries (0.7 percent to 2.5 percent), anastomotic leaks (1.2 percent to 5 percent), seromas or superficial wound infections (11.4 percent to 14.5 percent), deep-wound infections (3 percent to 4.4 percent), deep venous thrombosis or pulmonary embolisms (0.6 percent to 2 percent), and a 30-day mortality rate of approximately 0.4 percent.45,46 Although the leak and coagulation complications remain with the laparoscopic approach, the wound problems and splenic-injury problems have declined significantly. Late complications include gastric-outlet stenosis and obstruction (3.4 percent to 14.6 percent), marginal ulcer (0.2 percent to 13.3 percent), small-bowel obstruction (4.7 percent), incisional hernia (4.7 percent to 23.9 percent), and symptomatic gallbladder disease (10 percent to 11.4 percent).47–49 The incisional hernia rate with the laparoscopic approach is significantly reduced. Nutritional deficiencies of iron, vitamin B12, folate, calcium, and the fatsoluble vitamins A, D, and E can occur without appropriate supplementation. Currently Roux-en-Y gastric bypass is the gold standard weight-loss operation with good long-term follow-up studies.50
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4. Biliopancreatic Diversion Biliopancreatic bypass is performed either laparoscopically or through a midline incision. A subtotal gastrectomy is performed, leaving a proximal gastric remnant of 200 to 500 ml. The ileum is transected 250 cm proximal to the ileocecal valve. The distal ileal limb is brought through a retrocolic opening in the transverse mesocolon and anastomosed to the gastric pouch. The biliopancreatic or proximal limb is anastomosed end-to-side to the distal ileum, 50 cm proximal to the ileocecal valve. This results in a 50 cm common channel between the two limbs (Figure 7.3). A modification of this technique is the biliopancreatic bypass with a duodenal switch (BPD-DS).51,52 The greater curvature of the stomach is resected to create a lesser curvature gastric sleeve (sleeve gastrectomy). This reduces the gastric volume to 200 ml to 500 ml, equivalent to a subtotal gastrectomy, and maintains the integrity of the vagus nerves. The duodenum is transected 5 cm distal to the pylorus. The ileum is transected 250 cm proximal to the ileocecal valve, and the distal ileal limb is anastomosed end-to-end to the proximal duodenum. The biliopancreatic limb is anastomosed end-to-side to the distal ileum, 100 cm proximal to the ileocecal valve, resulting in a 100 cm common channel between the two limbs. There are significant reports of the outcomes after BPD and BPD-DSs from Italy and Canada, but fewer have been reported in the U.S. Scopinaro and colleagues53 at the University of Genoa, Italy, published results for 1356 patients undergoing
FIGURE 7.3 Biliopancreatic bypass with a duodenal switch. The greater curvature
of the stomach is resected to create a sleeve gastrectomy. After dividing the duodenum 5 cm distal to the pylorus, the distal alimentary (Roux) limb, created by dividing the ileum 250 cm proximal to the ileocecal valve, is anastomosed end-to-end to the proximal duodenum. The biliopancreatic limb is anastomosed end-to-side to the distal ileum 100 cm proximal to the ileocecal valve, leaving a 100-cm common channel between the biliopancreatic and the distal alimentary limb.
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BPD. Short- and long-term weight loss and weight maintenance has been excellent. Loss of excess body weight has been 74 percent and 78 percent at 2 and 14 years, respectively. Other beneficial effects include significant improvement of the hypoventilation and obstructive sleep apnea syndromes, hypertension, venous stasis disease, hypercholesterolemia, glucose intolerance, and adult-onset diabetes mellitus following the procedure. Marceau and associates51 in Canada reported results in 465 patients undergoing BPD-DS. Mean percentage excess weight loss at 51 months follow-up was 73 percent, or an average of 101.2 pounds per patient. Only 4 percent of patients with diabetes mellitus, 42 percent with hypertension, and 49 percent with obstructive sleep apnea or hypoventilation syndromes still required medical treatment for these obesity-related conditions. When Marceau51 compared the 457 patients undergoing BPD-DS to 233 previous patients undergoing BPD, revision rates were lower and calcium and iron homeostasis improved in the BPD-DS group. However, there was no significant difference in weight loss between the two groups. Gagne and colleagues have reported a comparison between open and laparoscopic BPD-DS. In their report, 54 patients, 26 laparoscopic and 28 open procedures, were retrospectively reviewed. The laparoscopic approach had improved operative time, blood loss, and hospital stay; however, none reached statistical significance. Complication rates were slightly higher in the laparoscopic group (23 percent versus 17 percent), and death rate was higher in the laparoscopic group (7.6 percent versus 3.5 percent), but again, the levels did not reach statistical significance.54 Short-term complications from BPD vary, but include abdomical abscess (1.9 percent), anastomotic leak (1.9 percent), wound infection (5.6 percent), wound dehiscence (1.9 percent), respiratory failure (1.9 percent), and pancreatitis (1.9 percent). Late complications can include marginal ulceration (12 percent), bone demineralization (6 percent) secondary to calcium and vitamin D deficiencies, protein malnutrition (15.1 percent) characterized by hypoalbuminemia, anemia, edema, asthenia, and alopecia, and vitamin B12, iron, and folate deficiencies (5 percent).53 In summary, BPD with or without a duodenal switch has demonstrated superb weight-loss results. However, its complication rate is significant. There is a high rate of protein malnutrition, and the degree to which medications are malabsorbed is still unknown.
IV. LAPAROSCOPIC BARIATRIC SURGERY Since the first Roux-en-Y gastric bypass was described by Wittgrove et al. in 1994,55 laparoscopic bariatric surgery has been a rapidly evolving field. LAGB, verticalbanded gastroplasty, biliopancreatic diversion, and Roux-en-Y gastric bypass are technically challenging operations that require advanced laparoscopic surgery skills. Yet, the safety and feasibility of these procedures in the hands of qualified surgeons have been validated.32,56–62 LAGB is a less technically demanding procedure compared with other laparoscopic procedures, and it has gained widespread adoption outside the U.S.63,64 Most centers offer the laparoscopic approach for most uncomplicated candidates.
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V. CONCLUSION Obesity is a national health problem in the U.S. Thirty percent of the current American population is obese, compared with only 13 percent in 1960, placing a tremendous economic burden on the health-care system to care for the increased number of obesity-related health problems. An additional $30 billion is spent annually on medical weight-loss programs that use caloric restriction, exercise, or behavior modification and on appetite-suppressing medications. Though clouded in a history of less-than-successful attempts, surgery has finally emerged as the only effective long-term treatment for morbid obesity. Bariatric operations allow for substantial weight loss, extended weight maintenance, and control or reversal of obesity-related comorbidities. Several surgical options exist, each with their own pros and cons. Roux-en-Y gastric bypass is the gold standard. Lap-Band shows great promise. Biliopancreatic bypass is an effective operation for morbid obesity, however, long-term studies regarding nutritional and drug malabsorption are still lacking. The laparoscopic approach is now the access method of choice. There is currently a very active effort to develop less-invasive methods of achieving weight loss. There are devices currently under investigation that provide some restriction without a formal surgical procedure. There is also significant work looking into gastric pacing/stimulation to help induce satiety and provide for weight loss. Scientists are actively measuring hundreds of hormones, cytokines, and metabolites before and during weight loss induced by surgery to try to see if there are any profiles that might predict success or failure for any given procedure. In the end, continued success of bariatric surgery will rest on the continuing refinement of the procedures themselves and also on the ability to select patients based on current knowledge, as well as novel biochemical predictors to increase the success of each procedure and to tailor the treatment to the patient. Regardless of the algorithm for selection or the procedure itself, the success of any surgical approach to morbid obesity requires a multidisciplinary team of internists, nurses, dietitians, psychologists, and surgeons to select the best candidates for this approach, to operate, and to provide long-term follow-up.
REFERENCES 1. Flegal, KM, Carroll, MD, Ogden, CL, and Johnson, CL, Prevalence and trends in obesity among US adults, 1999-2000, JAMA, 288:1723–1727, 2002. 2. Kremen, AJ, Linner, JH, and Nelson, CH, An experimental evaluation of the nutritional importance of proximal and distal small intestine. Ann. Surg., 140:439, 1954. 3. Kucamarski, RJ, Prevalence of overweight and weight gain in the United States, Am. J. Clin. Nutr. 55:495S, 1992. 4. Alverez-Cordero, R, Treatment of clinically severe obesity, a public health problem: Introduction, World J. Surg., 22:905, 1998. 5. National Institutes of Health Consensus Conference, Health implications of obesity, Ann. Intern. Med., 103:1073, 1985.
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6. Melissas, J, Chistodoulakis, M, Spyridakis, M, et al., Disorders associated with clinically severe obesity: Significant improvement after surgical weight reduction, South. Med. J., 91:1143, 1998. 7. Finkelstein, EA, Fiebelkorn, IC, and Wang, G, State-level estimates of annual medical expenditures attributable to obesity, Obes, Res., 12(1):18–24, 2004. 8. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults, WMJ, 97:20, 1998. 9. Metropolitan height and weight tables, Stat. Bull. Metrop. Life Found., 64:3, 1983. 10. National Institutes of Health Development Consensus Statement, Gastrointestinal surgery for severe obesity, Am. J. Clin. Nutr., 55:615S, 1992. 11. Eckel, RH and Krauss, RM, American Heart Association call to action: Obesity as a major risk factor for coronary heart disease, AHA Nutritional Committee, Circulation, 97:2099, 1998. 12. Manson, JE, Coldita, GA, and Stampfer, MJ, A prospective study of obesity and risk of coronary heart disease in women, N. Engl. J. Med., 322:882, 1990. 13. Hubert, HB, Feinteib, M, and McNamera, PN, Obesity as an independent risk factor for cardiovascular disease. A 26 year follow-up of participants in the Framingham heart study, Circulation, 67:968, 1983. 14. Williams, SR, Jones, E, Bell, W, et al., Body habitus and coronary artery disease in men. A review with reference to methods of body habitus assessment, Eur. Heart J., 18:376, 1997. 15. Peiser, J, Lavie, P, Ovnat, A, and Charuzi, I, Sleep apnea syndrome in the morbidly obese as an indication for weight reduction surgery, Ann. Surg., 100:112, 1984. 16. Trzebicky, R, Uber die grenzen der zulassigkeit-resection, Arch. f. Klin. Chir., 48:54, 1894. 17. Halverson, JD, Wise, L, Wazna, MF, and Ballinger, WF, Jejunoileal bypass for morbid obesity, Am. J. Med., 64:461, 1978. 18. Payne, JH and DeWind, LT, Surgical treatment of obesity, Am. J. Surg., 118:141, 1969. 19. Behrns, KE, Smith, CD, Kelly, KA, and Sarr, MG, Reoperative bariatric surgery: Lessons learned to improve patient selection and results, Ann. Surg., 218:646, 1993. 20. Mason, EE and Ito, C, Gastric bypass, Ann. Surg., 170:329, 1969. 21. Jordan, JH, Hocking, MP, Rout, WR, and Woodward, ER, Marginal ulcer following gastric bypass for morbid obesity, Am. Surg., 57:286, 1991. 22. Pories, WJ, Flickinger, EG, Mellheim, D, et al., The effectiveness of gastric bypass over gastric partition in morbid obesity, Ann. Surg., 194:389, 1982. 23. Mason, EE, Printen, KJ, Blommers, TJ, et al., Gastric bypass in morbid obesity, Am. J. Clin. Nutr., 33:395, 1980. 24. Printen, KJ and Mason, EE, Gastric surgery for relief of morbid obesity, Arch. Surg., 106:428, 1973. 25. Mason, EE, Vertical banded gastroplasty for obesity, Arch. Surg., 117:701, 1982. 26. Scopinaro, N, Gianetta, E, Civalleri, D, et al., Partial and total biliopancreatic bypass in the surgical treatment of obesity, Int. J. Obes., 5:421, 1981. 27. Marceau, P, Hould, FS, Simard, S, et al., Biliopancreatic diversion with duodenal switch, World J. Surg., 22:947, 1998. 28. Bo, O and Modalshi, O, Gastric banding, a surgical method of treating morbid obesity: preliminary report, Int. J. Obes., 7:493, 1983. 29. Kuzmak, LI, Stoma adjustable silicone gastric banding, Probl. Gen. Surg., 9:298, 1992. 30. Chelala, E, Cadiere, GB, Favretti, F, et al., Conversions and complications in 185 laparoscopic adjustable silicone gastric banding cases, Surg. Endosc., 11:268, 1997.
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31. Belachew, M, Legrand, M, Vincent, V, et al., Laparoscopic adjustable gastric banding, J. Surg., 22:955, 1998. 32. Wittgrove, AC and Clark GW, Laparoscopic gastric bypass, Roux-en-Y: Technique and results in 300 patients with 3-34 months follow-up, Scientific presentation, 6th World Congress of Endoscopic Surgery, Rome, Italy, June 3–6, 1998. 33. Lonroth, H, Dalenback, J, Haglind, E, and Lundell, L, Laparoscopic gastric bypass. Another option in bariatric surgery, Surg. Endosc., 10:636, 1996. 34. Goergen, M, Ansay, J, Azagra, JS, et al., Mason’s vertical banded gastroplasty for morbid obesity. Results of a randomized prospective trial of laparoscopic vs. open approach, Surg. Endosc., 12:601, 1998. 35. Ren, CJ and Fielding, GA, Laparoscopic adjustable gastric banding: surgical technique, J. Laparoendosc. Adv. Surg. Tech. A., 13(4):257–63, 2003. 36. Fox, SR, Fox, KM, Srikanth, MS, and Rumbaut R, The Lap-Band system in a North American population, Obes. Surg., 13(2):275–80, 2003. 37. Ren, CJ, Horgan, S, and Ponce, J, US experience with the LAP-BAND system, Am. J. Surg. 184(6B):46S–50S, 2002. 38. Rubenstein, RB, Laparoscopic adjustable gastric banding at a U.S. center with up to 3-year follow-up, Obes. Surg., 12(3):380–4, 2002. 39. O’Brien, PE and Dixon, JB, Lap-band: outcomes and results J. Laparoendosc. Adv. Surg. Tech. A., 13(4):265–70, 2003. 40. O’Brien, PE, Dixon, JB, Brown, W, Schachter, LM, Chapman, L, Burn, AJ, Dixon, ME, Scheinkestel, C, Halket, C, Sutherland, LJ, Korin, A, and Baquie, P, The laparoscopic adjustable gastric band (Lap-Band): a prospective study of medium-term effects on weight, health and quality of life, Obes. Surg., 12(5):652–60, 2002. 41. Fielding, GA, Rhodes, M, and Nathanson, LK, Laparoscopic gastric banding for morbid obesity. Surgical outcome in 335 cases, Surg. Endosc., 13(6):550–4, 1999. 42. Ren, CJ, Weiner, M, and Allen, JW, Favorable early results of gastric banding for morbid obesity: the American experience, Surg. Endosc., 18(3):543–546, 2004. 43. Pories,WJ, Swanson, MS, MacDonald, KG, et al., Who would have thought it? An operation proves to be the most effective therapy for adult-onset diabetes mellitus, Ann. Surg, 222:339, 1995. 44. Cowan, GS and Buffington, CK, Significant changes in blood pressure, glucose, and lipids with gastric bypass, World J. Surg., 22:987, 1998. 45. Pope, GD, Birkmeyer, JD, and Finlayson, SR, National trends in utilization and inhospital outcomes of bariatric surgery, J. Gastrointest. Surg., 6(6):855–60; discussion 861, 2002. 46. Sagar, PM, Surgical treatment of morbid obesity, Br. J. Surg., 82:732, 1995. 47. Griffen, WO, Jr., Young, L, and Stevenson, CC, A prospective comparison of gastric and jejunoileal bypass procedures for morbid obesity, Ann. Surg., 186:500, 1977. 48. Kellum, JM, DeMaria, EJ, and Sugarman, HJ, The surgical treatment of morbid obesity, Curr. Probl. Surg., 35:791, 1998. 49. Printen, KJ, Scott, D, and Mason, EE, Stomal ulcers after gastric bypass, Arch. Surg., 115:525, 1980. 50. Mason, EE, Tang, S, Renquist, KE, et al., for the National Bariatric Surgery Registry Contributors: A decade of change in obesity surgery, Obes. Surg., 7:189, 1997. 51. Marceau, P, Hould, FS, Simard, S, et al., Biliopancreatic diversion with duodenal switch, World J. Surg, 22:947, 1998. 52. Hess, DS and Hess, DW, Biliopancreatic diversion with a duodenal switch, Obes. Surg., 6:122, 1996.
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53. Scopinaro, N, Adami, GF, Marinari, GM, et al., Biliopancreatic diversion, World J. Surg., 22:936, 1998. 54. Won-Woo, K, Gagner, M, Kini, S, Inabet, WB, Quinn, T, Herron, D, and Pomp, A, Laparoscopic vs. open biliopancreatic diversion with duodenal switch: a comparative study, J. G.I. Surg., 7:552–557, 2003. 55. Wittgrove, AC, Clark, GW, and Tremblay, LJ, Laparoscopic gastric bypass, Rouxen-Y: preliminary report of five cases, Obes. Surg., 1994; 4:353–357. 56. Cadiere, GB, Bruyns, J, Himpens, J, and Favretti, F, Laparoscopic gastroplasty for morbid obesity, Br. J. Surg., 81:1524, 1994. 57. Chua, TY and Mendiola, RM, Laparoscopic vertical banded gastroplasty: The Milwaukee experience, Obes. Surg., 5:77, 1995. 58. Deitel, M, Laparoscopic bariatric surgery, Surg. Endosc., 11:965, 1997. 59. Gagner, M, Garcia-Ruiz, A, Arca, M, and Heniford, BT, Laparoscopic isolated gastric bypass for morbid obesity, Surg. Endosc, 13:S6, 1999. 60. Hallerback, B, Glise, H, Johansson, B, and Johnson, E, Laparoscopic surgery for morbid obesity, Eur. J. Surg., 582:128, 1998. 61. Lonroth, H and Dalenback, J, Other laparoscopic bariatric procedures, World J. Surg., 22:964, 1998. 62. Schauer, PR, Ikramuddin, S, Gourash, W, and Panzak, G, Laparoscopic Roux-en-Y gastric bypass for super-morbid obesity, Surg. Endosc., 13:A75, 1999. 63. Fried, M, Peskova, M, and Kasalicky, M, The role of laparoscopy in the treatment of morbid obesity, Obes. Surg., 8:520, 1998. 64. Garfinkel, L, Overweight and cancer, Ann. Intern. Med., 103:1034, 1985.
8
Postoperative Management of the Bariatric-Surgery Patient Jarol Boan, M.D., M.P.H.
CONTENTS I. Introduction................................................................................................125 II. Surgical Procedures ...................................................................................125 A. Roux-en-Y Gastric Bypass................................................................125 B. Lap-Band ...........................................................................................126 III. Predictors of Complications ......................................................................126 A. Phase One Complications (One to Six Weeks) ................................127 B. Phase Two Complications (Six Weeks to Two Months) ..................128 C. Phase Three Complications (2 to 12 Months)..................................130 IV. Summary ....................................................................................................132 References..............................................................................................................132
I. INTRODUCTION The prevalence of morbid obesity is increasing considerably in the U.S., and the number of bariatric procedures for weight loss has grown dramatically over the last five years. The American Society for Bariatric Surgery reported that more than 140,000 gastrointestinal surgeries for obesity were performed in 2004,1 and the numbers are increasing dramatically as more surgeons become proficient at the procedure. After the surgical follow-up care is completed, primary-care physicians interact with these patients for a multitude of medical problems. This review outlines the common problems encountered in the postoperative management of the bariatricsurgery patient.
II. SURGICAL PROCEDURES A. ROUX-EN-Y GASTRIC BYPASS Roux-en-Y gastric bypass (RYGB) is considered the gold standard for achieving a sustainable weight loss in the morbidly obese. 2 This procedure purports an average 125
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weight loss of 100 lbs after one year and has low mortality and morbidity rates for patients.3 The 30 day mortality rate is reported to be 0.5 percent–1.9 percent.4,5 The most common causes of death are pulmonary embolus, gastrojejunal anastomotic leak, respiratory failure, sepsis, and GI hemorrhage. These patients are high-risk surgical patients with multiple underlying comorbidities, and 50 percent of deaths are due to underlying comorbidities (hypertension, diabetes, sleep apnea, pulmonary embolus, cirrhosis, etc.).6 With the introduction of a laparoscopic technique for RYGB, risks associated with this surgery decreased dramatically. In a recent series of surgeries comparing open gastric bypass to laparoscopic technique, laparoscopic RYGB was associated with decreased operative mortality, wound infection, and incisional hernia.4 Unfortunately, laparoscopic gastric bypass has been associated with an increased incidence of stomal stenosis and internal hernia.7
B. LAP-BAND Lap-Band adjustable gastric-banding device was Food and Drug Administration approved in 2001.8 The Lap-Band is a silastic ring that forms a small gastric pouch and can be removed when weight loss has been achieved. The procedure is less invasive than the RYGB and has a lower postoperative mortality rate. Unfortunately, the morbidity rate is higher, and the degree of weight loss is less than that with the RYGB. In a review of 500 cases,9 10.4 percent of patients had complications requiring an abdominal reoperation. In another study, five-year follow up of patients with Lap-Band showed 10 percent of patients had the band removed and 2.4 percent were converted to a RYGB.10 The FDA has tracked complaints for this procedure. Between June 2001 and August 2002 there were 556 complaints. The majority of these were related to device malfunction, most commonly leak at the access port. In this series, only two deaths related to the procedure were reported.11 Despite its complication rate, it is a very popular procedure due to its ease of insertion and its ability to achieve weight loss.
III. PREDICTORS OF COMPLICATIONS In an analysis of the complication rate after bariatric surgery, Schwartz et al. analyzed 600 laparoscopic RYGBs and found the overall complication rate approached 26 percent.12 One of the main predictors of complications is the experience of the surgeon.13 In fact, the American Society of Bariatric Surgeons recommends that a surgeon perform 100 procedures before technical expertise is obtained. The higher the weight (body-mass index > 55 kg/m2), the more likely there will be complications. Males over 50 years of age are at increased risk of complications. The presence of hypertension and sleep apnea will increase the likelihood of complications. Interestingly, the presence of diabetes is not a predictor of complications. The presence of psychiatric illness is believed to be a predictor of complications. The data supporting this conclusion is discordant. In some series, severe psychiatric illness is associated with poor outcome, such as inadequate weight loss, chronic
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TABLE 8.1 Post-Operative Complications After Major Complications
Minor Complications
Peritonitis/leak Pulmonary embolus Respiratory failure Wound dehiscence Small bowel obstruction Cardiac arrest Intra-abdominal
Pulmonary atelectasis Wound infection Urinary tract infection Stomal stricture Marginal ulcer Hypotension
nausea and vomiting, poor compliance, and weight regain. On the other hand, weight loss after bariatric surgery is associated with an improvement in depression, selfesteem, and productivity. In some cases, patients who have a history of emotional eating combined with poor psychological insight are more likely to develop somatization. These patients are likely to have repeat visits to the physician for a variety of complaints. Screening tools for predicting which patients will have an unsatisfactory outcome after bariatric surgery are needed.
A. PHASE ONE COMPLICATIONS (ONE
TO
SIX WEEKS)
Complications following surgery are often managed by the surgeons involved. As shown in Table 8.1, postoperative complications include postoperative bleeding, staple-line leak, bowel perforation, bowel obstruction, severe wound infections, minor wound infections, pulmonary embolism, perioperative myocardial infarction (MI), pneumonia, and urinary-tract infection. The most disastrous complication associated with RYGB, a staple-line leak at the gastrojejunal anastomosis, has a reported incidence of 4.6%.7 Table 8.2 lists its clinical features. In approximately one-third of leaks, the patient requires reexploration and is taken back to the operating room. Every patient should be aware of the potential of this serious complication prior to undergoing bariatric surgery.
TABLE 8.2 Post-Operative Anastomotic Leak Reported rate Mean time to presentation Symptoms Treatment Prognosis
4.6% Within 1–2 days post-op Tachycardia, respiratory distress NPO, drainage tube, watch carefully Can progress to systemic sepsis and organ failure
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During the immediate perioperative period, obesity-related medical comorbidities change dramatically. Blood pressure often decreases to the normal range without medications, and blood-pressure monitoring is important to document during all postoperative visits. Hypotension is commonly seen, especially if there is poor fluid intake or persistent postoperative vomiting. The need for reinstituting antihypertensive medications needs to be monitored carefully. Routine antireflux medications should be discontinued, unless symptoms persist after surgery. Every patient with a diagnosis of diabetes should have frequent monitoring of blood glucose, and a sliding scale for subcutaneous insulin injections should be provided. Many diabetic patients decrease the need for insulin after bariatric surgery. In diabetic patients previously managed with oral medications, such as sulfonylureas or thiazolidinediones, there is an increased risk of hypoglycemia after bariatric surgery. The biguanides (metformin) is the safest drug in the postoperative period since it is not associated with dramatic fluctuations in blood glucose. The decreased requirement for insulin and modification of oral medications after bariatric surgery is due to several reasons. The average caloric intake ranges between 400–800 Kcal/day for the first month and is associated with rapid weight loss, and decreased insulin needs. Weight loss can be significant in the first month postoperatively, ranging from 20–40 lbs, resulting in decreased need for insulin. It has also been suggested that the anatomical changes after RYGB results in changes in insulin signaling. Discontinuation of diabetic medications should be entertained when blood glucose normalizes and after the patient is eating. Patients on antidepressants and other psychiatric medications should have these medications continued in the immediate postoperative period. Dramatic weight loss occurs in the first few months after bariatric surgery, and this can be associated with emotional liability. Emotional stability associated with continuation of antidepressants allows smooth transition after surgery, and patients should be urged to continue these medications Patients in this phase are dealing with many different changes, both physiological and psychological. The small gastric pouch only allows very small portion sizes, and they feel full and satisfied. They are not hungry, and often forget to eat. Attempts at overeating result in vomiting, and they quickly learn to control portion sizes and food reactions. The patient in this phase is dealing with significant changes in comorbidities, physiological feedback, and psychological changes associated with surgery.
B. PHASE TWO COMPLICATIONS (SIX WEEKS
TO
TWO MONTHS)
In addition to the medical monitoring of the comorbidities listed above, the postoperative care of the bariatric-surgery patient requires additional components in phase two. This phase is characterized by a distinct set of complications as the patient struggles to learn new ways of eating and becomes skilled at interpreting physiological feedback. Psychological characteristics become a predominant factor in the postoperative visits, often characterized by food and weight obsessions. The most common complication in this phase after bariatric surgery is prolonged vomiting. A diet history recording dietary intake and portion sizes is important. After
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TABLE 8.3 Stomal Stenosis/Stricture Reported rate Mean time to presentation Symptoms Treatment
2.8–7.0% 6–7 weeks Nausea, vomiting, early satiety, food intolerances, abdominal pain Endoscopic balloon dilatation, repeat dilatation required in 17% of cases
dietary indiscretions and vomiting associated with bulimia are ruled out, a stomal stricture at the gastrojejunal anastomosis should be considered. The reported prevalence of stricture ranges from 2.8 percent–7 percent.14,15 The presenting complaint is vomiting and postprandial pain in the gastric pouch (Table 8.3). A barium swallow often detects narrowing at the gastrojejunal anastomosis, and a referral to a gastroenterologist for endoscopic dilatation should be made. Marginal ulcers at the anastomosis should be searched for. A decision to insert a nasojejunal feeding tube at the time of endoscopy should be considered depending on the degree and rate of weight loss. Dumping syndrome occurs in approximately 50 percent of patients after RYGB. The same phenomenon does not appear to happen after the Lap-Band procedure. It is characterized by symptoms of nausea, shaking, diaphoresis, and diarrhea immediately after eating high-glucose containing foods. It is considered a positive outcome after RYGB, especially in sweet eaters, since it results in food aversion to sweet eating. Patients who experience these symptoms should be advised to avoid the foods that produce them. After gastric-bypass surgery, there are psychological changes associated with the change in eating patterns, and these changes can cause significant dysfunction. It is well-established that extreme weight loss results in symptoms of psychopathology. In the classic Keys’ studies in the 1950s, weight loss of 25 percent resulted in the development of lethargy, depression, and other psychopathology.16 Preoperatively, patients with morbid obesity often use food for emotional reasons, and when they experience a small gastric pouch postoperatively, they often grieve the loss of food. Displaced emotions often result in somatization with symptoms of nausea and vomiting. It is important that physicians recognize the psychological aspect of the loss of food after gastric-bypass surgery, and reassure patients that the symptoms are related to the small gastric-pouch size. Antidepressants often help to decrease the anxiety related to the grieving associated with the loss of food, although the use of antidepressants needs to be approached with an empathetic style. Nutritional deficiencies are common after bariatric surgery for two reasons: inadequate dietary intake and the surgical procedure itself. The lack of intrinsic factor results in inability to absorb vitamin B12. Intramuscular injections of 1000 μg of Vitamin B12 should be given every six months for life. Long-term nutritional deficiencies are common, especially if dietary variety is lacking and vitamin supplements are not ingested regularly. After RYGB, the lack of acid in the gastric pouch results in poor absorption of iron, and iron deficiency has been described in
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up to 15 percent of patients. It is important to emphasize the importance of a daily multivitamin, in addition to adequate intake of dietary fruits and vegetables, in order to prevent nutritional deficiencies. Clearly, a significant number of individuals go into obesity surgery with preexisting eating-disordered behavior. To maintain the weight loss that typically follows surgery, they have to change their eating patterns dramatically. General normalization of eating behavior has been reported characterized by fewer meals, less food consumed at each meal, less eating between meals, and less eating in response to strong emotions.17,19 Severe binge eating becomes virtually impossible following gastric bypass due to the severely restricted stomach. Despite this, patients with a preexisting eating disorder continue to have disordered-eating patterns.
C. PHASE THREE COMPLICATIONS (2
TO
12 MONTHS)
In the majority of patients after bariatric surgery, this phase is characterized by a significant change in eating habits, improvement in medical comorbidities, and continued weight loss. The most important change in eating habits that result from bariatric surgery is the change in portion size. Initially, the stomach can only tolerate 30 cc at one time, but over time there is a gradual increase in portion size. There are very few reports of the actual change in stomach size. At three months, patients are ingesting an average of 1500 Kcal per day in three to six meals per day. It is important in this stage to emphasize normal eating patterns and prevent development of a grazing lifestyle. With appropriate nutrition advice, patients decrease the need for frequent meals and increase the amount eaten at each meal, reaching three meals a day by six months. Patients learn to be satisfied with very small portion sizes and maintain a dietary intake appropriate for their new size by the 12th month followup visit. For a minority of patients, this phase is characterized by difficulty in adjustment to weight loss, food intolerances, self-destructive behaviors, and, occasionally, requests for a reversal of the procedure. These patients tend to be time-consuming for the treating physician. Discerning the difference between psychological symptoms and physical symptoms can be difficult in this phase. Gallstone formation is associated with rapid weight loss,20 and the reported prevalence of gallstones at six months postoperatively is 22 percent.21 Small-bowel obstruction from internal hernias after laparoscopic surgery13 can present with crampy abdominal pain, nausea, and vomiting (Table 8.4). A high index of suspicion and close consultation with the bariatric surgeon is needed. Common food intolerances associated with bariatric surgery include bread, rice, pasta, and meat. Vomiting often occurs after eating these foods, resulting in food aversions. For patients who enjoyed these foods prior to the surgery, the loss of food variety results in anger and frustration. These patients will often complain that they experience anxiety and fear when eating. They often express buyer’s remorse, may request extensive investigations for problems with the gastric pouch, and request referral to another surgeon for a reversal of the procedure. Reassurance about the ability of the pouch to tolerate a wide variety of foods with time is necessary. Often, fresh fruits and vegetables are tolerated without a problem, resulting in a significant
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TABLE 8.4 Small Bowel Obstruction Reported rate Time to presentation Symptoms Diagnosis Common causes Treatment
1.5–7.3% Early (within 1 week) Late (several months later) Crampy abdominal pain, nausea, vomiting High index of suspicion Radiological studies can be normal Internal hernia, torsion of Roux limb at transverse mesocolon, adhesions, jejunal-jejunal intussusception Laproscopic or open exploration often required
change in eating habits compared to preoperative eating habits. Some patients have continuing food intolerances, especially to red meat, and become vegetarian. Reassurance and empathy is essential to help the patient overcome food intolerances. By six months, most patients are able to tolerate most foods, and tend to eat three small meals per day. If problems continue, referral to an experienced dietitian can be helpful. Patients with a preoperative history of eating disorders (binge eating, reactive overeating, etc.) tend to manifest difficulty in adjusting to the change in eating habits more commonly. Referral to an experienced psychologist can help unmask some of the underlying emotional issues associated with food. Weight loss is rapid in the first six months, averaging 10–15 lbs per month. Average weight loss at the six-month follow-up visit is 60–80 lbs. Thereafter, the rate of weight loss tends to slow down to 5–7 lbs per month, reaching a peak at 12 months postoperatively, averaging 100–120 lbs. Despite its superiority to other methods of weight loss for the morbidly obese, surgery still carries the risk of failed weight loss or weight regain. When there is weight regain, it typically begins 18–24 months postsurgery.22–24 Delin and Watts report that although most patients do well initially, some ultimately fail to sustain their improvement.23 Continuous snacking and consuming large quantities of soft or liquid foods has been described. Some researchers attribute the weight gain to physiological factors, but others claim that inadequate coping strategies are usually at the source of patients’ inability to maintain weight loss.25 Unfortunately, a small percentage of patients become grazers after bariatric surgery and have a poor weight loss. Rapid weight loss results in many psychological changes as the body shape changes. Several studies have shown increases in self-esteem, self-confidence, assertiveness, and expressiveness.26,27 Improvements in the patients’ self-esteem and psychological state result in greater assertiveness and improvement in social interaction, sexual activity, and work performance. On the other hand, a significant number of patients discover they have underdeveloped coping mechanisms in their new persona as a thin person. These patients often require psychological therapy to deal with issues of past sexual abuse, bodyimage changes, and relationships with intimate partners.
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The most striking changes in medical symptoms after bariatric surgery are those that are most difficult to quantify. Fatigue improves with an increase in energy level. Exercise habits improve with an increase in activity of daily living, as well as recreational activity. In a majority of patients, back pain disappears. Osteoarthritis improves to a lesser degree, and is dependent on the degree of underlying bone and cartilage damage. The advantage of bariatric surgery is that the preoperative risk for an orthopedic procedure decreases, making subsequent surgery risks similar to those of lean controls. Sleep apnea tends to improve significantly, and refitting of the mask is often needed by six months postoperatively. At 12 months postop, repeat overnight somnography is suggested to document the need for continued CPAP. While weight loss improves the social lives of patients, they often have difficulty adjusting to dramatic changes in social circles. Patients previously involved in relationships with other obese persons may find that changes in their lifestyle (i.e., more activity, greater social contacts, and changes in eating behavior) become incompatible with that of presurgical relationships. Given that the capacity of the stomach is significantly reduced following restrictive surgery, social and business functions that revolve around food become awkward. Family members, friends, coworkers, and acquaintances may also react with envy or feel threatened following the patient’s rapid weight loss. The patient may feel resentment at his sudden social acceptance following weight loss. Being related to positively by people who once treated you badly because of your weight may not be a joyful experience.23 These issues are often dealt with in long-term support groups. When weight loss has stabilized, usually at the 12-month follow-up visit, the majority of patients request information about plastic surgery. Unfortunately, most insurance companies regard plastic surgery following bariatric surgery as cosmetic surgery and will not cover it. There are cases where the abdominal pannus is infected or excoriated, and documentation will be required by the insurance company for coverage. An experienced plastic surgeon will be helpful for those who wish to pursue plastic surgery.
IV. SUMMARY Morbid obesity is a complex disease with a multitude of associated diseases that require special management after bariatric surgery. The patient with a BMI > 40 kg/m2 is a unique patient. It is necessary to modify many of the standard medicalassessment techniques, and recognize the unique interaction of psychosocial issues and medical issues when caring for a patient after bariatric surgery.
REFERENCES 1. Steinbrook, R, Surgery for severe obesity, N. Engl. J. Med., 350(11):1075–9, 2004. 2. Pories, WJ, MacDonald, KG, Morgan, EJ, Sinha, MK, Dohm, GL, Swanson, MS, Barakat, HA, Khazanie, PG, Leggett-Frazier, N, Long, SD, O’Brien, KF, and Caro, JF, Surgical treatment of obesity and its effect on diabetes: 10-y follow-up, Am. J. Clin. Nutr., 55:582S–585S, 1992.
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3. DeMaria, EJ, Sugerman, HJ, Kellum, JM, et al., Results of 281 consecutive total laparoscopic Roux-en-Y gastric bypasses with a linear stapled gastrojejunostomy to treat morbid obesity, Ann. Surg., 235:640–645, 2002. 4. Podnos, YD, Jimenez, JC, Wilson, SE, Stevens, CM, and Nguyen, NT, Complications after laparoscopic gastric bypass: a review of 3464 cases, Arch. Surg., 138(9):957–61, 2003. 5. Flum DR, Dellinger EP, Impact of gastric bypass operation on survival: a population based analysis. J. Am. Coll. Surg., 199:543–551, 2004. 6. Melinek, J, Livingston, E, Cortinia, G, and Fishbein, MC, Autopsy findings following gastric bypass surgery for morbid obesity, Arch. Path. Lab. Med., 126(9):1091–1095, 2002. 7. Maggard MA, Shurgarman LR, Suttorp M, et al. Meta-Analysis: surgical treatment of obesity, Ann. Int. Med., 142:547–559, 2005. 8. Lap-Band, Adjustable gastric band system report of safety and effectiveness data, U.S. Federal Drug Agency Center for Devices and Radiological Health NDA, 2001, available at www.fda.gov/cdrh/pdf/P000008b.pdf. 9. Zinzindohoue, F, Chevallier, JM, Douard, R, Elian, N, Ferraz, JM, Blanche, JP, Berta, JL, Altman, JJ, Safran, D, and Cugnenc, PH, Laparoscopic gastric banding: a minimally invasive surgical treatment for morbid obesity: prospective study of 500 consecutive patients, Ann. Surg., 237(1):1–9, 2003. 10. Angrisani, Obes. Surg., 13, Abstr. 13, 2003. 11. Brown, SL, Obes. Surg., 13, Abstr. 14, 2003. 12. Schwartz, ML, Drew, RL, and Chazin-Caldie, M, Laparoscopic Roux-en-Y gastric bypass: preoperative determinants of prolonged operative times, conversion to open gastric bypasses, and postoperative complications, Obes. Surg., 13(5):734–738, 2003. 13. Perugini, RA, Mason, R, Czerniach, DR, Novitsky, YW, Baker, S, Litwin, DE, and Kelly, JJ, Predictors of complication and suboptimal weight loss after laparoscopic Roux-en-Y gastric bypass: a series of 188 patients, Arch. Surg., 138(5):541–545, 2003. 14. Suter, M, Giusti, V, Heraief, E, Zysset, F, and Calmes, JM, Laparoscopic Roux-enY gastric Bypass: initial 2-year experience, Surg. Endoscop., 17(4):603–609, 2003. 15. Nguyen, NT, Stevens, CM, and Wolfe, BM, Incidence and outcome of anastomotic stricture after laparoscopic gastric bypass, J. Gastroint. Surg., 7(8):997–1003, 2003. 16. Keys, A, The Biology of Human Starvation, Minneapolis, University of Minnesota Press, 1950. 17. Mills, MJ and Stunkard, AJ, Behavioral changes following surgery for obesity, Am. J. Psychiatr., 2:239–243, 1976. 18. Crisp, AJ, Kalucy, RS, and Pilkington, TR, Some psychological consequences of ileojejunal bypass surgery, Am. J. Clin. Nutr., 30:109–120, 1977. 19. Adami, GF, Meneghelli, A, and Scopinaro, N, Night eating and binge eating in obese patients, Int. J. Eat. Disord., 25:335–338, 1999. 20. Weinsier, RL, Wilson, LJ, and Lee, J, Medically safe rate of weight loss for the treatment of obesity: a guideline based on risk of gallstone formation, Am. J. Med., 98(2):115–7, 1995. 21. Villegas L, Schneider, B, Provost, D, Chang, C, Scott, D, Sims, T, Hill, L, Hynan, L, and Jones, D, Is routine cholecystectomy required during laparoscopic gastric bypass? Obes. Surg., 14(1):60–6, 2004. 22. Shamblin, JR and Shamblin, WR, Bariatric surgery should be more widely accepted, S. Med. J., 80:861–865, 1987.
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23. Hsu, LK, Benotti, PN, Roberts, SB, Saltzman, E, Shikory, S, Rolls, BJ, and Rand, W, Nonsurgical factors that influence the outcome of bariatric surgery: a review, Psychosom. Med., 60:338–346, 1998. 24. Powers, PS, Rosemurgy, A, Boyd, F, and Perez, A, Outcome of gastric restriction procedures: weight, psychiatric diagnoses, and satisfaction, Obes. Surg., 7:471–477, 1997. 25. Delin, CR and Watts, J, Success in surgical intervention for morbid obesity: is weight loss enough? Obes. Surg., 5:189–191, 1995. 26. Leon, GR, Eckert, ED, Teed, DB, and Buchwald, H, Changes in body image and other psychological factors after intestinal bypass surgery for massive obesity, J. Behav. Med., 2:39–55, 1979. 27. Solow, C, Silberfarb, P, and Swift, K, Psychosocial effects of intestinal bypass surgery for severe obesity, N. Engl. J. Med., 290:300–304, 1974.
Section II Pathophysiology and Treatment of Diabetes
Introduction As pointed out in section I, there is a very strong link between obesity and bloodglucose dysregulation, which is apparent in type 2 diabetes. The growing incidence of obesity among children and adults, in the U.S in particular, is accompanied by a commensurate increase in the prevalence type 2 diabetes in all individuals. As expected, with the various comorbidities associated with diabetes, there is also a concomitant increase in the incidence of diabetic complications. Consequently, there is an exponential rise in the health-care costs associated with the management of diabetes and its many complications. In this section, therefore, there is an appropriate overview of the rising incidence of type 2 diabetes and its various complications in many populations of the world. There is also detailed review of how the high-energy nutrient, fat, which is abundant in obesity, inhibits the utilization of carbohydrates, leading to impaired bloodglucose regulation. The interaction of nutrients and the effects on blood-glucose levels is then illustrated with extensive discussions on both the pathophysiology and treatment of type 2 diabetes in both children and adults. Furthermore, owing to the disproportionate incidence of type 2 diabetes in underrepresented ethnic minorities in the U.S, there is a special review that is focused on the issues involved in the diagnosis and treatment of diabetes in these populations. As pointed out earlier, there is a universal increase in the incidence of type 2 diabetes and its many complications. Therefore, it becomes an issue of particular concern for the Third World countries with little or no resources to address these problems. In one chapter, first, there is an adequate overview of the etiology of diabetes in developing countries, and the effect of many different factors, including culture and economic status, on the prevalence and treatment of diabetes among these populations. Second, there is a good outline of what it is going to take to avoid the looming calamity that would be the toll of diabetes and its complications in developing countries. Diabetes in pregnancy presents a particular challenge to the physician. With the rising incidence of diabetes, it is, therefore, most appropriate that a detailed overview of the strategies to manage the different forms of diabetes in pregnancy is provided in this section. The section ends with a Web-based education program for the management of diabetes, as illustrated with type 1 diabetes.
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Epidemiology, Risks, and Health-Care Expenditures for Diabetes and Its Complications William F. Kendall, Jr., M.D.
CONTENTS I . Estimated Health-Care Expenditures Associated with Diabetes ..............140 II. Prevalence of Diabetes ..............................................................................140 III. Defining Impaired Glucose Tolerance, Insulin Resistance, and Diabetes Mellitus ................................................................................142 IV. Diagnostic Criteria for Diabetes Mellitus .................................................143 V. Risk Factors ...............................................................................................145 A. Gestational Diabetes..........................................................................145 B. Posttransplantation Diabetes .............................................................145 C. Association of Obesity with Diabetes ..............................................146 D. Diet and Diabetes ..............................................................................147 E. Diabetes and Microalbuminuria........................................................147 F. Effects of Alcohol and Cigarettes .....................................................147 G. Diabetes and Physical Limitations....................................................148 H. Diabetes and Mental Health..............................................................148 VI. Diabetic Complications .............................................................................149 A. Coronary-Vascular Disease ...............................................................149 B. Peripheral Neuropathy and Peripheral Vascular Disease .................150 C. Cerebrovascular Disease ...................................................................151 D. Erectile Dysfunction..........................................................................152 E. Diabetic Nephropathy .......................................................................152 F. Retinopathy........................................................................................152 G. Dental Disease...................................................................................153 VII. Mortality ....................................................................................................153 VIII. Level of Health Care .................................................................................153 References..............................................................................................................154
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I. ESTIMATED HEALTH-CARE EXPENDITURES ASSOCIATED WITH DIABETES Diabetes mellitus has been present since antiquity. It was described in 400 B.C. as a disease of “well-fed people,” and Bose wrote in 1895 “amongst the Zemindars and Talookdars, who consider it a pride and honor to lead an indolent life, diabetes is a common disorder” (1). It is a common disease that is now estimated to affect more than 16 million Americans and more than 100 million people worldwide (2, 3). It is most prevalent in countries such as India, China, and the U.S. (4). Its direct and indirect costs account for at least 15 percent of health-care expenditure in the U.S., which totals at least $100 billion annually (2, 5, 6). The annual estimated cost in other countries is just as formidable. The estimated annual health-care costs associated with diabetes in various developed countries in 1995 (4) are shown in Table 9.1. A large portion of the costs of diabetes is associated with its complications (7). The University Group Diabetes Program, the earliest randomized clinical trial of the treatment of hyperglycemia in people with diabetes, failed to show a positive effect of glycemic control on the prevention of the development or progression of microvascular complications (8). However, the Diabetes Control and Complication Trial and the United Kingdom Prospective Diabetes Study clearly showed that strict control of blood glucose could positively affect the progression of diabetic complications (9). It has also been shown that elevated hemoglobin A1c (HbA1c), an indicator of poor glucose control, is associated with increased mortality in diabetic populations (9). The American Diabetes Association recommends a goal for HbA1c of < 7 percent, with the need for intervention when HbA1c is > 8 percent (10).
II. PREVALENCE OF DIABETES Type 1 diabetes mellitus comprises approximately 10 percent of diabetes incidence (11). Most cases of type 1 diabetes mellitus are sporadic, with only 10 percent to 15 percent of affected individuals having a first-degree relative with type 1 diabetes mellitus at the time of diagnosis (11). The risk of developing diabetes is 5 percent if a family member also has type 1 diabetes mellitus, in comparison to general population risk of 0.2 percent (11). Type 1 diabetes mellitus is characterized by Tlymphocyte mediated destruction of insulin-producing cells of the pancreatic islets of Langerhans (11). A majority of cases of type 1 diabetes mellitus result from proven beta-cell destruction and are classified as type 1a. Ten percent to 20 percent of cases are antibody negative and are classified as idiopathic (11). Type 2 diabetes mellitus comprises approximately 90 percent of diabetes (11). Prevalence among ethnic groups in the U.S. include: 2 percent to 8 percent Caucasians; 4 percent to 12 percent African Americans; 4 percent to 19 percent Mexican Americans; 14 percent to 12 percent Asian Americans; and 35 percent to 50 percent Pima Native Americans, with Arizona having the highest diabetes incidence in the world among this group (Table 9.2) (11). In comparison, a Singapore national survey showed a prevalence of 13.1 percent among Mauritian Chinese, 2.7 percent in Asian Indians in Asia, and 1.6 percent in Chinese in China (12). It is estimated that diabetes
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TABLE 9.1 The Estimated Annual Health-Care Costs Associated with Diabetes in Various Developed Countries, in 1995 Country Cost
Denmark $247 billion
Germany $145 billion
Japan $18.7 billion
United Kingdom $10.8 billion
Italy $3.78 billion
Sweden $2.0 billion
Spain $1.78 billion
Source: King, H, Aubert, RE, and Herman, WH, Diabet. Care, 21(9):1414–1431, 1998.
TABLE 9.2 Estimated Prevalence of Diabetes Mellitus Among Ethnic Groups in the U.S. Caucasians
African Americans
Mexican Americans
Asian Americans
Pima Native Americans
2%–8%
4%–12%
4%–19%
4%–12%
35%–50%
is undiagnosed in one-third of all people with diabetes (13). The lifetime risk of developing diabetes mellitus is 40 percent if there is one parent with type 2 diabetes mellitus, 80 percent to 100 percent if there are two affected parents, 35 percent if there is an affected sibling, and 70 percent to 80 percent among monozygotic twins (11). Only 5 percent to 10 percent of type 2 diabetes mellitus cases are due to slowly progressive beta-cell dysfunction (11). Approximately 10 percent to 15 percent of people diagnosed with type 2 diabetes mellitus after the age of 40 have positive islet cell cytoplasmic antibodies and GaD65 autoantibodies, which actually represent a subgroup of type 1 diabetes mellitus, also known as latent autoimmune diabetes (11). Although classically thought to primarily affect adults, type 2 diabetes mellitus also affects youths (14). In a recent analysis, prevalence was 15.9 per 1000 among 15- to 19-year-old Pima Indians, 4.5 per 1000 for all U.S. American Indians, and 2.3 per 1000 for Canadian Cree and Ojibway Indians in Manitoba (14). Thirty-three percent of all cases of diabetes mellitus among 10- to 19-year-old African Americans and Caucasians in Ohio were type 2 diabetes (14). These individuals tended to be obese, have a family history of type 2 diabetes, have acanthosis nigricans, belong to minority populations, and were more likely girls than boys (14). The Strong Heart Study looking at diabetes among American Indian tribes and communities showed age-adjusted diabetes rates to be 65 percent in men and 72 percent in women in tribes and communities in Arizona; 38 percent in men and 42 percent in women in Oklahoma; and 33 percent in men and 40 percent in women in South Dakota and North Dakota (15). Diabetes rates were positively associated with age, level of obesity, amount of Indian ancestry, and parental diabetes status
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(15). Rate of impaired glucose tolerance was 14 percent to 17 percent, which is similar to rates among the general U.S. population (15). Compared to their Caucasian counterparts, African American men are 20 percent to 50 percent more likely and African American women 100 percent more likely to have or develop diabetes (16). They are also at much higher risk for end-stage renal disease, lower-extremity amputation, and blindness (16). A cross-sectional study of three Mexican communities showed a higher prevalence in men compared to women (17). In younger adults, prevalence was 16.7 percent versus 9.5 percent in men compared to women; it was 30.8 percent versus 22.8 percent in older adults (17). Variables associated independently with diabetes in older people were gender (male sex: odds ratio [OR] = 2.1, p < 0.009); diminished carbohydrate intake (OR = 0.77, p < 0.03); central distribution of adiposity (OR = 1.9, p < 0.03); and functional disability (OR = 2.3, p < .01) (17). There seemed to be a higher prevalence of diabetes in urban versus rural populations (17). Approximately 52 percent of all persons aged ≥ 20 years with diabetes are women (18). A study looking at the socioeconomic status of women with diabetes suggests that women with diabetes were more likely to have a low socioeconomic status (18). Twenty-five percent of women with diabetes aged ≥ 25 years had lowlevel formal education, and 40 percent lived in low-income households (18). Women with diabetes (40.4 percent [95 percent confidence interval [CI] = 38.1 percent – 42.6 percent]) were twice as likely as women without diabetes (22 percent [95 percent CI = 21.5 percent – 22.5 percent]) to have an annual household income < $25,000 (18). Diabetes prevalence continues to increase quite rapidly. A 16 percent increase in prevalence was noted between 1980 and 1994, and a 33 percent increase between 1990 and 1998 (19, 20). The prevalence of diabetes seems highly correlated with the prevalence of obesity (21). On the basis of age, sex, and race, it is estimated that there will be a 225 percent projected increase in diabetes between 2000 and 2050, which means an increase from approximately 12 million to 39 million people diagnosed with diabetes in the U.S. (13). Other studies have estimated an increase ranging between 12 million to 29 million (19). Diagnosis of diabetes is expected to increase 460 percent in people 75 years of age or older, 241 percent among those 65 to 74 years old, 159 percent among those 45 to 64 years old, 125 percent among those 20 to 44 years old, and 97 percent among those 0 to 19 years old (13). Due to expected demographic changes, prevalence, and population growth, prevalence is expected to increase 149 percent among Hispanics, 118 percent among African Americans, and 104 percent among Caucasians (13).
III. DEFINING IMPAIRED GLUCOSE TOLERANCE, INSULIN RESISTANCE, AND DIABETES MELLITUS Impaired glucose tolerance (IGT), determined by the postload glucose value of the oral glucose tolerance test (OGTT), is found in individuals with moderately disturbed glucose metabolism (22). These individuals are generally hyperinsulinemic and have an increased risk of developing diabetes (22). The National Diabetes Data Group
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guidelines require at least one intermediate glucose level greater than 11.1 mmol/L for the diagnosis of IGT (22). According to current American Diabetes Association guidelines, a two-hour postload glucose ≥ 140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) is defined as impaired glucose tolerance (23). Insulin resistance, manifested by a diminished ability to keep glucose levels low with insulin levels in the normal range, precedes the onset of noninsulin-dependent diabetes mellitus. The glucose-clamp technique is the gold standard for the assessment of insulin resistance (22, 24). In individuals with insulin resistance, the glucose level is slightly raised, but remains below the diabetes range at the expense of raised insulin levels (22). Insulin resistance is thought to be a key factor in a cluster of cardiovascular risk factors (syndrome X or insulin resistance syndrome) (22). According to 1993 criteria, diabetes mellitus was diagnosed when plasma glucose exceeded 11.1 mmol/l (200 mg/dl) and classic symptoms of diabetes (polydipsia, polyuria, polyphagia, and weight loss) were present, or when the fasting plasma glucose exceeded 7.8 mmol/l (140 mg/dl) (22). If diabetes was not confirmed by these, but still suspected, an OGTT was performed (22). When a number of single glycemic measures are compared, the two-hour postload glucose level seems to be the best indicator of the presence of diabetes (22, 25, 26). The OGTT is a nonphysiologic procedure with high interperson variability (27). In a population of elderly people studied over a five-year period of time, the reliability coefficient of the diagnosis was 0.62 (27). Researchers have found that only 50 percent of OGTTs are reproducible (28). In patients that are diagnosed with impaired glucose tolerance on the first OGTT, only 40 percent to 60 percent are diagnosed with impaired glucose tolerance or diabetes on a second test (29–31). Therefore, epidemiologic studies based on a single OGTT may overestimate the prevalence of diabetes (22). More recent criteria regarding the diagnosis of diabetes include: classic symptoms of diabetes plus casual (casual defined as any time of day without regard to time since last meal) plasma glucose concentration ≥ 200 mg/dl; fasting (no caloric intake for at least eight hours) plasma glucose ≥ 126 mg/dl (7.0 mmol/l); and twohour plasma glucose ≥ 200 mg/dl during an OGTT using a glucose load containing the equivalent of 75 grams anhydrous glucose dissolved in water (23). There are two major types of diabetes: type 1 diabetes (5 percent to 10 percent of all diagnosed cases in the U.S.), which classically involves children and is primarily characterized by an absolute deficiency of insulin secretion; and type 2 diabetes (90 percent to 95 percent of all diagnosed cases), which is due to a combination of resistance to insulin action and an inadequate compensatory insulin secretory response. There are several other, less common forms of diabetes (1 percent to 5 percent of all diagnosed cases), which result from genetic conditions, surgery, drugs, malnutrition, infections, and other illnesses (23, 32).
IV. DIAGNOSTIC CRITERIA FOR DIABETES MELLITUS Prior to 1979, various criteria existed, and there was no consensus on how to diagnose diabetes (33). In 1979, the National Diabetes Data Group developed guidelines for diagnosing diabetes mellitus and impaired glucose tolerance, which were adopted
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by the American Diabetes Association in 1993 (33). According to these guidelines, diabetes was diagnosed when: 1) there was unequivocal elevation of plasma glucose (≥ 200 mg/dl [11.1 mmol/l]) and presence of classic symptoms of diabetes including polydipsia, polyuria, polyphagia, and weight loss; 2) fasting plasma glucose ≥ 140 mg/dl (7.8 mmol/l) on two occasions; 3) fasting plasma glucose less than 104 mg/dl and two OGTTs with the two-hour plasma glucose ≥ to 200 mg/dl and one intervening value ≥ 200 mg/dl after a 75-gram glucose load (33). Impaired glucose tolerance was defined by fasting plasma glucose less than 140 mg/dl and two-hour plasma ≥ 140 mg/dl, and less than 200 mg/dl with one intervening value ≥ 200 mg/dl after a 75-gram glucose load (33). The 1985 World Health Organization criteria use the fasting and two-hour values only, with fasting glucose ≥ to 140 mg/dl or two-hour glucose ≥ 200 mg/dl (33, 34). The 1997 American Diabetes Association criteria require fasting plasma glucose ≥ to 126 mg/dl (34). An International Expert Committee, established in May 1995, working under the auspices of the American Diabetes Association, published new recommendations in 2000 (23), as shown in Table 9.3. They stipulate that the diagnosis of diabetes mellitus should include one of these three criteria, namely classic symptoms of diabetes plus casual (casual defined as any time of day without regard to time since last meal) plasma glucose concentration ≥ 200 mg/dl; fasting (no caloric intake for at least eight hours) plasma glucose ≥ 126 mg/dl (7.0 mmol/l); or two-hour plasma glucose ≥ 200 mg/dl during an OGTT using a glucose load containing the equivalent of 75 grams anhydrous glucose dissolved in water (23). This expert committee defined: fasting plasma glucose < 110 mg/dl (6.1 mmol/l) as normal fasting glucose; fasting plasma glucose ≥ 110 mg/dl (6.1 mmol/l) and < 126 mg/dl (7.0 mmol/l) as impaired fasting glucose; and fasting plasma glucose > 126 mg/dl (7.0 mmol/l) as provisional diagnosis of diabetes (23). When OGTT is performed, a two-hour postload glucose < 140 mg/dl (7.8 mmol/l) is normal glucose
TABLE 9.3 American Diabetes Association 2000 Recommendations Regarding Diagnosis of Diabetes Mellitus
Diabetes Mellitus Normal fasting plasma glucose Impaired fasting plasma glucose Provisional diagnosis of diabetes mellitus
Classic Symptoms Plus Casual Plasma Glucose Concentrations ≥ 200 mg/dl (11.1 mmol/l) or Fasting Plasma Glucose ≥ 126 mg/dl (7.0 mmol/l) or 2-hour Plasma Glucose ≥ 200 mg/dl (11.1 mmol/l) during Oral Glucose Tolerance Test < 110 mg/dl (6.1 mmol/l) ≥ 110 mg/dl and < 126 mg/dl > 126 mg/dl (7.0 mmol/l)
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tolerance; a two-hour postload glucose ≥ 140 (7.8 mmol/l) and < 200 mg/dl (11.1 mmol/l) is defined as impaired glucose tolerance; and a two-hour postload glucose ≥ 200 mg/dl (11.1 mmol/l) gives a provisional diagnosis of diabetes (23). There has been much debate regarding the impact of changes in methods of diagnosing diabetes on prevalence rates and on the number of nondiagnosed cases of diabetes. It is clear, however, that the current system of diagnosis is much more organized than it was prior to 1979.
V. RISK FACTORS A. GESTATIONAL DIABETES Gestational diabetes affects 0.6 percent to 15 percent of pregnant women (35). It implies an increased risk of development of impaired glucose tolerance and diabetes (35). Most develop type 2 diabetes, with an incidence of at least 13.8 percent. The incidence of type 1 diabetes is reported to be 0.7 percent to 6.6 percent over 2–11 years. In a study looking at gestational diabetes, the cumulative risk for diabetes and abnormal glucose tolerance was 13.8 percent and 42.4 percent after 11 years versus 0.0 and 2.8 percent in women without diabetes (35). Independent, predictive factors for diabetes were prior hyperglycemia; four abnormal glucose values on the diagnostic OGTT; overt diabetes during pregnancy; two-hour blood glucose ≥ 11.7 mmol/l on the diagnostic OGTT; gestational age at diagnosis < 24 weeks; and prepregnancy body-mass index (BMI) ≥ 26.4 kg/m2 (35). Race is thought to be a risk factor for gestational diabetes (36). Recurrence rates for gestational diabetes have been reported to range from 30 percent to 35 percent in studies looking at predominantly Caucasian populations, to ≥ 50 percent in nonwhite populations (36). Factors predictive of recurrent gestational diabetes include large infant birth weight, prepregnancy weight ≥ 190 pounds, and weight gain between pregnancies (36). The effect of additional pregnancies on the risk of future diabetes is controversial, with some studies suggesting an increased risk and others showing no increase (35). The range of relative risk (RR) for developing diabetes after gestational diabetes, in the literature, is 1.8 to 20.4 (37). In a carefully designed meta-analysis of controlled follow-up studies of women with gestational diabetes, the overall RR for developing diabetes after gestational diabetes was estimated to be 6.0 (95 percent, CI 4.1–8.8), with a population attributable risk of 0.10–0.31 (10 percent to 31 percent of cases of diabetes in parous women are associated with previous diabetes) (37).
B. POSTTRANSPLANTATION DIABETES Posttransplantation diabetes (PTDM) is, as the name implies, the development of diabetes after transplantation. Steroid diabetes was first reported in renal-transplant recipients (38). Its early frequency was 40 percent to 60 percent (38). The incidence ranges from 2 percent to 50 percent, with most cases being diagnosed within three months of transplantation (39, 40). Risk factors for posttransplant diabetes include age, non-Caucasian ethnicity (risk of posttransplantation diabetes is higher in African
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American recipients than Caucasian recipients), and immunosuppression (39). Transplant recipients with posttransplant diabetes tend to be 0 to 12 years older than those without (39). Non-Caucasian patients had a twofold increased risk of posttransplant diabetes (RR 3.3, 95 percent CI 1.7–7.0) (39). There is an increased incidence of posttransplant diabetes in patients treated with glucocorticoid therapy, cyclosporine, and those treated with high doses of tacrolimus (39, 41). The mean time from transplantation to development of PTDM is 1.2 years (range from one day to 6.2 years), with most cases occurring during the first three months after transplant or after treatment for rejection (41, 42). Significant risk-factor development of PTDM included: first-degree family history of type 2 diabetes mellitus, tacrolimus use, and hyperglycemia in the two weeks immediately after transplantation (42). Patients that developed persistent PTDM had later onset disease (mean 1.9 years) compared to those with transient PTDM (0.3 years) (42). Posttransplantation diabetes is associated with impaired long-term allograft survival and function. Reported six-year actuarial graft survival in one series was 67 percent in patients with PTDM versus 93 percent in control patients (38). Another series reported a 12-year graft survival of 48 percent for patients with PTDM versus 70 percent in control patients (38, 40). Cirrhosis is commonly associated with impaired glucose metabolism. Sixty to 80 percent of people with cirrhosis develop mild glucose intolerance associated with hyperinsulinism and increased insulin resistance (43). Diabetes mellitus develops in 10 percent to 30 percent of people with cirrhosis (43). Liver transplantation does not significantly modify pretransplant diabetes (43). Diabetes after liver transplant frequently develops de novo, is transient, and seems to be related primarily to immunosuppressive drug administration (43).
C. ASSOCIATION
OF
OBESITY
WITH
DIABETES
As extensively discussed in section I of this book, obesity and weight gain clearly seem to be associated with an increased risk of diabetes, although there are some studies that don’t show the association (44–46). Each year, 300,000 U.S. adults die of causes related to obesity (44). In 2000, the prevalence of obesity was 19.8 percent among U.S. adults (65.5 percent of men and 47.6 percent of women), which was a 61 percent increase from 1991 (44, 45). Weight gain, excess BMI, waist-hip ratio, and waist circumference are major risk factors for diabetes, with the waist circumference displaying the greatest relative risk (44, 47). In a national sample of adults, for every 1-kilogram increase in measured weight, the risk of diabetes increased by 4.5 percent (44). There seems to be an association between race and modification of diabetes risk by BMI, with African Americans having an increased risk at lower BMIs (i.e., adjusted RR for African Americans; for Caucasians, it was 2.83 for men and 3.13 for women at a BMI < 20 kg/m2) when compared to Caucasians, but an equivalent risk at high BMIs (at BMI ≥ 32 kg/m2, adjusted RR decreased to 1.14 for men and 1.09 for women) (48). The cause for this difference is not fully understood. One hypothesis is that the difference could be attributed to differences in fat distribution between African Americans and Caucasians (48).
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DIABETES
Studies examining effects of total fibers or types of fiber on self-reported incidence of diabetes have shown mixed results, with some showing no association and others showing inverse associations between diabetes risk and fiber intake (49). It has been well-established that carbohydrate intake can produce different glycemic responses, although there is some controversy surrounding the validity of the glycemic index and its use as a predictor of diabetes risk (49). Several studies have shown that fat intake is associated with impaired glucose metabolism (50), as reviewed in chapter 10 of this book. Glucose levels, insulin resistance, and hyperinsulinemia have been found to correlate with fat intake, particularly saturated fatty acids (50). Increased intake of vegetables and legumes is inversely associated with the development of impaired glucose tolerance or diabetes mellitus (50). The intake of vitamin C has been inversely associated with two-hour plasma glucose levels, although not completely understood (50).
E. DIABETES
AND
MICROALBUMINURIA
Microalbuminuria has been shown to be an important risk factor for cardiovascular disease and nephropathy in patients with type 2 diabetes (51). Meta-analysis has shown that the presence of microalbuminuria doubles the risk of cardiovascular morbidity or mortality and doubles the risk of total mortality (51). In patients with diabetes, the presence of microalbuminuria confers a tenfold higher risk of developing diabetic nephropathy annually, compared to patients without microalbuminuria (51). In a large cross-sectional analysis, when compared to patients with diabetes and normoalbuminuria, patients with diabetes and microalbuminuria had a longer duration of diabetes and higher waist-to-hip ratio, systolic and diastolic blood pressure, hemoglobin A1c (HbA1c), ankle-to-arm index, and serum creatinine (51). They were more likely to have a history of retinal laser therapy, hypertension, cerebrovascular disease, peripheral vascular disease, require insulin therapy, be smokers, and have electrocardiogram criteria for left-ventricular hypertrophy (51).
F. EFFECTS
OF
ALCOHOL
AND
CIGARETTES
Data from a prospective study of 87,938 subjects indicated that low to moderate consumption of alcohol is associated with decreased risk of coronary vascular disease in men with diabetes comparable to those without diabetes (52). There are several prospective cohort studies that suggest smoking is associated with the etiology of diabetes (53). In one study, the relative risk of type 2 diabetes in women smoking ≥ 25 cigarettes per year versus women who never smoked was 1.42 (95 percent CI, 1.18–1.72) (53). It was concluded that this suggested a moderate association between smoking and subsequent development of diabetes (53). In a similar study, the relative risk of type 2 diabetes in men smoking ≥ 25 cigarettes per year versus men who never smoked was 1.94 (95 percent CI, 1.25–3.03) (53). Furthermore, cigarette smoking has been associated with insulin resistance, larger
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upper-body fat distribution (a marker of insulin resistance), and raised plasmaglucose concentration (53). It has also been associated with blunting the rise of HbA1c (53). Cigarette smoking has been shown to be a significant risk factor for death by coronary artery disease in type 2 diabetes in several studies, including the Multiple Risk Factor Intervention Trial, The Finnish Prospective Study, and the Paris Prospective Study (53). Former smokers are 1.54 times (95 percent CI, 1.49–1.58) more likely to be diagnosed with coronary artery disease (53). Cigarette smoking has also been shown to be an independent predictor for stroke (53). It also appears to heighten the development of macrovascular and microvascular complications, including nephropathy and neuropathy (53). Its association with the development of retinopathy is not well-defined (53).
G. DIABETES
AND
PHYSICAL LIMITATIONS
People with diabetes have a higher prevalence of risk factors, such as obesity and sedentary behavior, and higher prevalence of health conditions, such as vision loss, depression, and cardiovascular disease, that are associated with physical limitations (54). In a nationwide, cross-sectional analysis, people with diabetes had a higher proportion of physical limitation than people without diabetes overall (66 percent versus 29 percent, p < 0.001), for men (59 percent versus 24 percent, p < 0.001), and women (72 percent versus 34 percent, p < 0.001) (54). The difference declined with increasing age: 18–44 years (46 percent versus 18 percent), 45–64 years (63 percent versus 35 percent), 65–74 years (74 percent versus 53 percent), and ≥ 75 years (85 versus 70 percent) (54). The OR for physical limitation among adults with diabetes versus adults without diabetes was 1.9 (95 percent CI, 1.8–2.1) (54). Although this association is not clearly defined, women seem to have a greater prevalence of physical limitations than men (54). In a national survey, 32 percent of women and 15 percent of men with diabetes versus 14 percent of women and 8 percent of men without diabetes reported inability to walk one-fourth of a mile, climb stairs, or do housework (55). There were two to three increased odds of not being able to do each task and up to 3.6-fold increased risk of not being able to do all three tasks associated with diabetes (55). Women with diabetes tend to have slower walking speed, inferior lower-extremity function, decreased balance, and increased risk of falling (55).
H. DIABETES
AND
MENTAL HEALTH
National surveys have reported that mentally ill people have worse health insurance and poorer access to care than people that are not mentally ill (56). A multicenter Veterans Administration hospital study, however, found little difference in the quality of diabetes care between those that were mentally ill and those that were not (56). This finding may be unique to that setting, owing to accessibility and monitoring of the level of care that occurs in that setting, and may not be reflective of national trends outside of the VA (56).
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VI. DIABETIC COMPLICATIONS A. CORONARY-VASCULAR DISEASE In 2000, 37.2 percent of people with diabetes age 35 years or older were diagnosed with cardiovascular disease (13). Prevalence of ischemic heart disease among people with diabetes was approximately 14 times that of those without diabetes in people 18 to 44 years of age (2.7 percent versus 0.2 percent), three times more in people 45 to 64 years of age (14.3 percent versus 4.7 percent), and approximately twice more in people 65 years of age or older (13). Classical risk factors for coronary artery disease include age, male gender, hypertension, and diabetes (57). The risk of clinical or isolated subclinical ischemic heart disease is more pronounced in women than men in older individuals, although there is a lower absolute prevalence, with an increased risk noted with the presence of diabetes (58, 59). Additional factors include diet and serum cholesterol, cigarette smoking, obesity, and sedentary lifestyle (57). The Framingham Study showed that smoking, hypertension, and elevated triglycerides were significant, independent predictors of coronary-vascular disease in patients with diabetes (60). A few studies have shown LDL cholesterol to be a significant, independent predictor of cardiovascular disease (60). Premature development and accelerated progression of macrovascular atherothrombotic disease is a major factor contributing to the high morbidity and mortality rates in diabetes (2). The relationship between hyperinsulinemia and the risk of cardiovascular disease is somewhat controversial, with articles both supporting and challenging this relationship (61–66). It still remains unclear whether the relationship is causal or whether the two diseases are causally unrelated, independent manifestations of an underlying disease state (2). Diabetes is well-established as an independent risk factor for the development of coronary-artery disease (2). Once a patient with diabetes develops clinical coronary-artery disease, cardiac complications occur with increased frequency, with diabetic patients with coronary-artery disease experiencing more morbidity and mortality than nondiabetic patients with coronary artery disease (67). Longitudinal studies looking at mortality from all causes, heart disease, and ischemic heart disease have shown that adults with diabetes experience less decline in their mortality rates than adults without diabetes (68). Diabetes has been shown to increase left ventricle wall thickness and mass (69). In the setting of ischemic heart disease, diabetes is associated with twice the incidence of acute coronary syndromes and a 1.5-fold to twofold increase in the incidence of death after myocardial infarction (2). Cardiovascular disease accounts for up to 80 percent of deaths in patients with diabetes, with approximately 75 percent of these deaths occurring as a result of ischemic heart disease (2). The most common cause of death is myocardial pump failure, and the second most common cause is myocardial reinfarction (70). The clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE) study, which looked at the use of aspirin versus clopidogrel in patients with recent ischemic stroke, recent myocardial infarction (MI), or established peripheral vascular disease, showed an 8.7 percent relative risk reduction in vascular death, MI, or
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ischemic stroke with use of clopidogrel (54, 71). There was an additional 8.7 percent reduction noted in rehospitalization for ischemia or bleeding (54, 71). Postmenopausal women with diabetes have a twofold to fivefold increased risk of death from coronary-artery disease (72). Also, women who undergo simple hysterectomies and those who undergo bilateral oophorectomies have an increased risk of coronary-artery disease (72). In one study, women with diabetes who are prescribed hormonal-replacement therapy have been shown to be 40 percent less likely to suffer acute heart disease than women with diabetes who have never been prescribed hormonal-replacement therapy (72). Other studies, however, have shown no cardiovascular benefit from hormonal-replacement therapy (72). Women with insulin-treated diabetes were found to be more likely to develop coronary-artery disease than women treated with oral hypoglycemic medication or diet alone (72).
B. PERIPHERAL NEUROPATHY
AND
PERIPHERAL VASCULAR DISEASE
The health-care cost of problems related to the diabetic foot, the most common cause of hospitalization in patients with diabetes, is estimated to be more than $1 billion annually (73). In 2003, the total annual cost of diabetic peripheral neuropathy and its complications were estimated to be between $4.6 and $13.7 billion (74). In large cohort studies, prevalence rates for neuropathy have ranged from 7.5 percent at time of diagnosis of diabetes, to 50 percent 25 years after initial diagnosis (75). It is present in more than 80 percent of diabetic patients with foot lesions (73). Poor glycemic control is associated with an increased risk for neuropathy and amputation (76). In one study, a HbA1c > 13.4 was associated with 2.2 relative risk of amputation (76). In another study, a 50 mg/dl increase in the mean random glucose was associated with a 1.6 OR for amputation (76). Diabetic peripheral neuropathy predisposes to foot ulceration and lower-extremity amputation (74). The presence of peripheral neuropathy is associated with eightfold to eighteenfold higher risk of ulceration and twofold to fifteenfold higher risk of amputation (76). The incidence of self-reported foot ulcers in people with diabetes is 2.4 percent to 2.6 percent per year (76). The prevalence of foot ulcers ranges from 4 percent to 10 percent, and it is estimated in the U.S. that 15 percent of patients with diabetes will develop foot ulceration at least once during their lifetime (74, 76, 77). While vascular disease does play a role, 60 percent to 70 percent of diabetic foot ulcers are neuropathic in origin (74). It is also estimated that approximately 85 percent of all diabetic lower-extremity amputations are preceded by a nonhealing foot ulcer (76). It is estimated that 45 percent of lower-limb amputations are done on people with diabetes, with the relative probability of lower-extremity amputation reported to be as high as 27 times more likely among patients with diabetes (78, 79). The risk of diabetic ulcers and lower-extremity amputation increases twofold to fourfold with age and duration of diabetes (76). Most studies of people with type 2 diabetes have shown a 1.6 increased risk of lower-extremity ulcers and a 2.8-fold to 6.5-fold higher risk of amputation associated with male sex (76). Lack of patient education on foot care is associated with a 3.2 increased risk of amputation (76). A comprehensive review showed that in the U.S. between 1989 and 1993, the
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prevalence of amputations was 1.6 percent for people age 18–44 years, 2.4 percent for people age 45–64 years, and 3.6 percent for people ≥ 65 years old (76). A statewide analysis performed in California showed Hispanics to have proportionally more amputations associated with diabetes than African Americans or nonHispanic whites (82.7 percent versus 61.6 percent versus 56.8 percent) (80). Overall, however, the incidence of diabetes-related, lower-extremity amputations was higher in African Americans at every level of amputation (80). The level of amputation was: toe (19.9–41.02 percent); foot (3.58–12.91 percent); leg (12.25–37.07 percent); and thigh (4.29–18.73 percent) (80). A retrospective review of patients admitted to a university hospital showed that patients admitted with diabetic foot ulceration underwent less-than-adequate foot examinations, with 31.4 percent not having documentation of pedal pulses, 59.7 percent not being evaluated for presence of protective sensation, 90 percent of wounds not evaluated for involvement of underlying structures, and 32.9 percent not having foot radiographs (81). This study highlighted the need for a systematic, detailed lower-extremity examination for every patient with diabetes admitted to a hospital (81). Patients with extremity infections should also be carefully evaluated for the presence of undiagnosed diabetes mellitus (82). In a large retrospective study, 17.2 percent of all patients seen with extremity infections had previously undiagnosed diabetes mellitus, with 12.1 percent having lower-extremity infections (82). Other studies have reported a 3 percent to 7 percent incidence of newly diagnosed diabetes in people presenting with extremity infections (82).
C. CEREBROVASCULAR DISEASE People with diabetes are at increased risk for cerebrovascular events (83). The estimated relative risk for patients with diabetes was initially reported to be 2.5-fold to 3.5-fold greater in diabetic patients that were aged 45 to 74 in the Framingham study (83). It was later modified to 1.4 for diabetic men and 1.72 for diabetic women after adjusting for other known risk factors (84). Diabetes was found to be responsible for 16 percent of stroke deaths in men and 33 percent in women, in a study reviewing stroke mortality (85). In a stroke-survival study, the 30-day survival rate was 89 percent in men and 79 percent in women; one-year survival was 79 percent for men and 64 percent for women (86). There may be specific patterns of stroke associated with diabetic patients. Review of a prospective, community-based registry showed that diabetes mellitus was associated with a lower relative prevalence of intracerebral hemorrhage (OR [95 percent CI]:0.63 (0.45 to 09.9); p = 0.022), higher relative prevalence of subcortical infarction (1.34 [1.11 to 1.62]; p = 0.009), and higher relative frequency of small-vessel disease (1.78 [1.31 to 3.82]; p = 0.012) and large-artery disease (2.02 [1.31 to 2.02] p = 0.002) (87). There was, however, no significant difference in the level of moderate to severe deficit on admission (31.1 percent versus 31.6 percent; p = 0.4) and poor functional outcome at one month (14.1 percent versus 15.3 percent; p = 0.24) when comparing patients with diabetes mellitus to patients who do not have the disease (87). A European study evaluating diabetes in 937 patients revealed that patients
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with diabetes were more likely to have limb weakness (p < 0.02), dysarthria (p < 0.001), ischemic stroke (p << 0.001), and lacunar cerebral infarction (p = 0.03) (88). Handicap (Rankin scale) disability (Barthel Index) was significantly higher in patients with diabetes (p = 0.005 and p = 0.016) (88).
D. ERECTILE DYSFUNCTION Diabetes has been associated with the development of erectile dysfunction since 1798 (89). The OR of having erectile dysfunction if a man is diabetic is 1.9 to 4 times greater than in men without diabetes, and it is estimated that 25 percent to 75 percent of men with type 1 diabetes will complain of erectile dysfunction (89). There is an age association with the development of erectile dysfunction, with 15 percent of diabetic men having erectile dysfunction by age 30 and 55 percent by age 60 (89). The mechanism of diabetes-induced erectile dysfunction is multifactorial (89). Related causes include smooth-muscle dysfunction, endothelial dysfunction, and neuropathic damage (89).
E. DIABETIC NEPHROPATHY The National Health and Nutrition Examination Survey found an incidence of endstage renal disease of 0.23/100 person years, with rates of 0.29 for patients with type 1 diabetes and 0.27 for patients with type 2 diabetes (90). Factors such as African American race, gout, and hypertension more than doubled the risk of endstage renal disease (90). In a study by Klein et al., analyzing 891 patients with type 1 diabetes, the 10-year cumulative incidence of renal failure or serum creatinine > 2.0 mg/dl was 14.9 percent (90). The risk of renal failure almost doubled for every 1 percent increase in HbA1c (36). Hypertension almost tripled the risk (90).
F. RETINOPATHY Diabetes can lead to multiple eye pathologies, including retinopathy, certain lens opacities, increased intraocular pressure, rubeosis iridis, and possibly open-angle glaucoma (91). The association between diabetes and open-angle glaucoma is controversial, with several studies demonstrating an association but several other large studies failing to demonstrate any association (92). Retinopathy affects more than 300,000 people in the U.S. (90). It is the leading cause of blindness in people age 20 to 64 years old (13). It accounts for 12 percent of all new cases of blindness, with 12,000 to 24,000 new cases each year in the U.S. (13). The prevalence of diabetic retinopathy is 46 percent higher in non-Hispanic blacks and 84 percent higher in Mexican Americans compared to non-Hispanic Caucasians (93). There is evidence to suggest that retinopathy begins to develop at least seven years before type 2 diabetes is clinically diagnosed (94, 95). The Wisconsin Epidemiologic Study of Diabetic Retinopathy examined the prevalence and incidence of diabetic retinopathy (91). The pathogenesis of retinopathy is thought to begin with hyperglycemia, which leads to increased levels of protein kinase C and aldose reductase activities, nonenzymatic glycosylation, vasoactive substances, growth factors, and free radicals (90, 96). These changes cause functional changes,
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such as increased vitreous fluorometry and abnormal electrical conductance (90). They also cause anatomic changes (90). Glycemic control, as measured by glycosylated hemoglobin, and not C-peptide secretion or the type of diabetes, seems to be the most important predictor of diabetic complications, such as retinopathy (8, 96–98). Retinopathy incidence increases above a fasting plasma glucose of ≥ 126 mg/dl (96, 99). The Wisconsin Epidemiologic Study of Diabetic Retinopathy, which studied > 900 patients aged < 30 at onset of diabetes, showed 20 percent of patients at age 15 were affected by retinopathy, 60 percent at age 20, and 80 percent at age 30 (90). The risk of retinopathy increased 50 percent for every 1 percent increase in HbA1c, for every 10-mm Hg increase in systolic blood pressure, and for every three years’ diabetes duration (90). The findings in the Wisconsin Epidemiologic Study of Diabetic Retinopathy were similiar to those found in the concurrently run Diabetes Control and Complications Trial (98). A population-based cohort study showed a modest increased risk of incidence of diabetic retinopathy in patients with younger-onset diabetes and hypertension (10 years after the baseline examination) [OR, 1.27; 95 percent CI, 1.03–1.57] (100). There was no consistent association of blood pressure and retinopathy in subjects with older-onset diabetes (100).
G. DENTAL DISEASE Dental complications of diabetes mellitus include severe periodontitis and subsequent tooth loss, gingivitis, dental abscesses, xerostomia, and soft-tissue lesions of the tongue and oral mucosa, such as candidiasis (101). Routine, preventive dental care may be important in preventing and treating these complications. A large crosssectional study, however, showed that dentate adults with diabetes were less likely to see a dentist than those without diabetes (65.8 percent versus 73.1 percent, p = 0.0000) (101).
VII. MORTALITY The development of diabetes seems to predict premature mortality (102). In 2000, diabetes was listed as the sixth leading cause of death in the U.S. (13). It is estimated that approximately 17 percent of Americans age 25 years and older who die have diabetes (13). A cross-sectional study revealed mortality rates of 41.8 per 1000 for the diabetic population in comparison to 10.1 per 1000 for the nondiabetic population (102). The risk of mortality relative to the nondiabetic population decreased with age (102). The increased risk for death associated with diabetes is 3.6:1 for people age 25 to 44 years and 1.5:1 for people age 65 to 74 years (13). Males with diabetes lost an average of 7.0 years from the year of diagnosis, and females with diabetes lost an average of 7.5 years (102). Sixty-five percent of all deaths in people with diabetes in the U.S. are reported to be due to cardiovascular disease (13).
VIII. LEVEL OF HEALTH CARE In a study looking at African Americans, Hispanics, and non-Hispanic Whites, they were found to be equally likely to receive treatment for diabetes (103). However,
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African Americans were more likely to have poorly controlled diabetes (HbA1c > 8.0 percent, OR 2.23, 95 percent CI 1.26–3.94) (103). A cross-sectional study suggests that underuse of recommended preventive-care practices is common among people with diabetes (48). Among this population, 78 percent practiced self-monitoring of blood glucose, 72 percent visited a health-care provider at least once in a 12-month period, 61 percent had their blood glucose examined at least once per year, and 61 percent received a dilated eye examination (48).
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30. Riccardi, G, Vaccaro, O, Rivellese, A, Pignalosa, S, Tutino, L, and Mancini, M, Reproducibility of the new diagnostic criteria for impaired glucose tolerance, Am. J. Epidemiol., 1985. 121:422–429, 1985. 31. Eriksson, KF and Lindgarde, F, Impaired glucose tolerance in a middle-aged male urban population: a new approach for identifying high-risk cases, Diabetologia, 33:526–531, 1990. 32. Engelgau, MM, Geiss, LS, Saaddine, JB, Boyle, JP, Benjamin, SM, Gregg, EW, Tierney, EF, Rios-Burrows, N, Mokdad, AH, Ford, ES, Imperatore, G, and Venkat, N, The evolving diabetes burden in the United States, Ann. Int. Med., 140(11):945–950, 2004. 33. Davidson, MB, Peters, AL, and Schriger, DL, An alternative approach to the diagnosis of diabetes with a review of the literature,. Diabet. Care, 18(7):1065–71, 1995. 34. Bloomgarden, ZT, The European Association for the Study of Diabetes annual meeting, 1998: The U.K. Prospective diabetes study and other topics in type 2 diabetes, Diabet. Care, (6):989–995, 1999. 35. Albareda, M, Caballero, A, Badell, G, Piquer, S, Ortiz, A, de Leiva, A, and Corcoy, R, Diabetes and abnormal glucose tolerance in women with previous gestational diabetes, Diabet. Care, 2003. 26(4):1199–1205, 2003. 36. MacNeill, S, Dodds, L, Hamilton, DC, Armson, BA, Vandenhof, M, Rates and risk factors for recurrence of gestational diabetes, Diabet. Care, 24(4): 659–662, 2001. 37. Cheung, NW and Byth, K, Population health significance of gestational diabetes, Diabet. Care, 26(7):2005–2009, 2003. 38. Miles, AMV, Sumrani, N, Horowitz, R, Homel, P, Maursky, V, Markell, MS, Distant, DA, Hong, JH, Sommer, BG, and Friendman, EA, Diabetes mellitus after renal transplantation: as deleterious as non-transplant associated diabetes? Transplantation, 65(3):380–384, 1998. 39. Montori, VM, Basu, A, Erwin, PJ, Velosa, JA, Gabriel, SE, and Kudva, YC, Post transplantation diabetes: a systematic review of the literature, Diabetes, 25(3):583–592, 2002. 40. Cosio, FG, Pesavento, TE, Osei, K, Henry, ML, and Ferguson, RM, Post-transplant diabetes mellitus: increasing incidence in renal allograft recipients transplanted in recent years, Kidney Int., 59(2):732–737, 2001. 41. First, MR, Gerber, DA, Hariharan, S, Kaufman, DB, and Shapiro, R, Post transplant diabetes mellitus in kidney allograft recipients: incidence, risk factors, and management, Transplantation, 73(3):379–386, 2002. 42. Greenspan, LC, Gitelman, SE, and Leung, MA, Increased incidence in post-transplant diabetes mellitus in children: a case-control analysis, Pediatr. Nephrol., 18(12):1315–1316, 2003. 43. Navasa, M, Bustamante, J, Marroni, C, Gonzalez, E, Andreu, H, Esmatjes, E, GarciaValdecasas, JC, Grande, L, Cirer, I, Rimola, A, and Rodes, J, Diabetes mellitus after liver transplantation: prevalence and predictive factors, J. Hepatol., 25(1):64–71, 1996. 44. Mokdad, AH, Bowman, BA, Ford, ES, Vinicor, F, Marks, JS, and Koplan, JP, The continuing epidemics of obesity and diabetes in the United States, JAMA, 286(10):1195–1200, 2001. 45. Mokdad, AH, Ford, ES, Bowman, BA, Nelson, DE, Engelgau, MM, Vinicor, F, and Marks, JS, The continuing increase of diabetes in the US, Diabet. Care, 24(2):412–414, 2001.
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46. Klein, R, Klein, BE, and Moss, SE, Is obesity related to microvascular and macrovascular complications in diabetes?: the Wisconsin epidemiologic study of diabetic retinopathy, Arch. Int. Med., 157(6):650–656, 1997. 47. Folsom, AR, Kushi, LH, Anderson, KE, Mink, PJ, Olson, JE, Hong, CP, Sellers, TA, Lazovich, D, and Prineas, RJ, Associations of general and abdominal obesity with multiple health outcomes in older women: the Iowa women’s health study, Arch. Int. Med., 160(14):2117–2128, 2000. 48. Resnick, HE, Valsania, P, Halter, JB, and Lin, X, Differential effects of BMI on diabetes risk among black and white Americans, Diabet. Care, 21(11):1828–1835, 1998. 49. Stevens, J, Ahn, K, Juhaeri, P, Houston, D, Steffan, L, and Couper, D, Dietary fiber intake and glycemic index and incidence of diabetes in African-American and white adults: the ARIC study, Diabet. Care, 25(10):1715–1721, 2002. 50. Feskens, EJ, Virtanen, SM, Rasanen, L, Tuomilehto, J, Stengard, J, Pekkanen, J, Nissinen, A, and Kromhout, D, Dietary factors determining diabetes and impaired glucose tolerance: a 20-year follow-up of the Finnish and Dutch cohorts of the seven countries study, Diabet. Care, 18(8):1104–1112, 1995. 51. Gerstein, HC, Mann, JFE, Pogue, J, Dinneen, SF, Halle, JP, Hoogwerf, B, Joyce, C, Rashkow, A, Young, J, Zinman, B, and Yusuf, S, Prevalence and determinants of microalbuminuria in high-risk diabetic and nondiabetic patients in the heart outcomes prevention evaluation study, Diabet. Care, 23(2):B35–B39, 2000. 52. Ajani, UA, Gaziano, JM, Lotufo, PA, Liu, S, Hennekens, CH, Buring, JE, and Manson, JE, Alcohol consumption and risk of coronary heart disease by diabetes status, Circulation, 102(5):500–505, 2000. 53. Haire-Joshu, D, Glasgow, RE, and Tibbs, TL, Smoking and diabetes, Diabet. Care, 22(11):1887–1898, 1999. 54. Ryerson, B, Tierney, EF, Thompson, TJ, Engelgau, MM, Wang, J, Gregg, EW, and Geiss, LS, Excess physical limitations among adults with diabetes in the U.S. population, 1997-1999, Diabet. Care, 26(1):206–10, 2003. 55. Gregg, EW, Beckles, GLA, Williamson, DF, Leveille, SG, Langlois, JA, Engelgau, MM, and Narayan, KMV, Diabetes and physical disability among older U.S. adults, Diabet. Care, 23(9):1272–1277, 2000. 56. Desai, MM, Rosenheck, RA, Druss, BG, and Perlin, JB, Mental disorders and quality of diabetes care in the Veterans Health Administration, Am. J. Psychiat., 159(9):1584–1590, 2002. 57. Javier, NF, Cardiovascular disease and risk factor epidemiology: a look back at the epidemic of the 20th century, Am. J. Pub. Health, 89(3):292–294, 1999. 58. Barzilay, JI, Spiekerman, CF, Kuller, LH, Burke, GL, Biittner, V, Gottdiener, JS, Brancati, FL, Orchard, TJ, O’Leary, DH, and Savage, PJ, Prevalence of clinical and isolated subclinical cardiovascular disease in older adults with glucose disorders: the cardiovascular health study, Diabet. Care, 24(7):1233–1239, 2001. 59. Lundberg, V, Stegmayr, B, Asplund, K, Eliasson, M, and Huhtassaari, F, Diabetes as a risk factor for myocardial infarction: population and gender perspectives, J. Int. Med., 241(6):485–492, 1997. 60. Howard, BV, Robbins, DC, Sievers, ML, Lee, ET, Rhoades, D, Devereux, RB, Cowan, LD, Gray, RS, Welty, TK, Go, OT, and Howard, WJ, LDL cholesterol as a strong predictor of coronary heart disease in diabetic individuals with insulin resistance and low LDL: the Strong Heart Study, Arteriosclero., Thromb. Vasc. Biol., 20(3):830–835, 2000.
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61. Ducimetiere, P, Eschwege, E, Papoz, L, et. al., Relationship of plasma insulin levels to the incidence of myocardial infarction and coronary heart disease mortality in a middle-aged population, Diabetologia, 19:205–210, 1980. 62. Despres, JP, Lamarche, B, Mauriege, P, et al., Hyperinsulinemia as an independent risk factor for ischemic heart disease, N. Engl. J. Med., 334:952–957, 1996. 63. Pyorala, M, Miettinen, H, Laakso, M, et. al., Hyperinsulinemia predicts coronary heart disease risk in healthy middle-aged men: the 22-year follow-up results of the Helsinki policemen study, Circulation, 98:398–404, 1998. 64. Welin, L, Erikson, H, Larrson, B, et. al., Hyperinsulinemia is not a major coronary risk factor in elderly men: the study of men born in 1913, Diabetologia, 35:766–770, 1992. 65. Ferrara, A, Barrett-Connor, EL, and Edelstein, SL, Hyperinsulinemia does not increase the risk of fatal cardiovascular disease in elderly men or women without diabetes: the Rancho Bernardo study, 1984-1991, Am. J. Epidemiol., 140:857–869, 1994. 66. Ruige, B, Assendelft, WJJ, Dekker, JM, et, al. Insulin and risk of cardiovascular disease: a meta analysis, Circulation, 97:996–1001, 1998. 67. Grundy, SM, Balady, GJ, Criqui, MH, Fletcher, G, Greenland, P, Hiratzka, LF, Houston-Miller, N, Kris-Etherton, P, Krumholz, HM, LaRosa, J, Ockene, IS, Pearson, TA, Reed, J, Washington, R, and Smith, SC, Jr., Primary prevention of coronary heart disease: guidance from Framingham: a statement for healthcare professionals from the AHA task force on risk reduction, Circulation, 97(18):1876–1887, 1998. 68. Gu, K, Cowie, CC, and Harris, MI, Diabetes and decline in heart disease mortality in US adults, JAMA, 281(14):1291–1297, 1999. 69. Devereux, RB, Roman, MJ, Paranicas, M, O’Grady, MJ, Lee, ET, Welty, TK, Fabsitz, RR, Robbins, D, Rhoades, ER, and Howard, BV, Impact of diabetes on cardiac structure and function: the Strong Heart Study, Circulation, 101(19):2271–2276, 2000. 70. Malmberg, K and McGuire, DK, Diabetes and acute myocardial infarction: the role of insulin therapy, Am. Heart J., 138(5, Part 1):381–386, 1999. 71. Bhatt, DL, Marso, SP, Hirsch, AT, Ringleb, PA, Hacke, W, and Topol, EJ, Amplified benefit of clopidogrel versus aspirin in patients with diabetes mellitus. Am. J. Cardiol., 90(6):625–628, 2002. 72. Lawrenson, RA, Leydon, GM, Newson, RB, and Feher, MD, Coronary heart disease in women with diabetes: positive association with past hysterectomy and possible benefits of hormone replacement therapy, Diabetes, 22(5):856–857, 1999. 73. Akbari, CM and LoGerfo, FW, Diabetes and peripheral vascular disease. J. Vasc. Surg., 30(2):373–384, 1999. 74. Gordois, A, Scuffham, P, Shearer, A, Oglesby, A, and Tobian, JA, The health care costs of diabetic peripheral neuropathy in the U.S., Diabet. Care, 2003. 26(6):1790–1795, 2003. 75. Currie, CJ, Morgan, CL, and Peters, JR, The epidemiology and cost of inpatient care for peripheral vascular disease, infection, neuropathy, and ulceration in diabetes, Diabet. Care, 21(1):42–48, 1998. 76. Mayfield, JA, Reiber, GE, Sanders, LJ, Janisse, D, and Pogach, LM, Preventive foot care in people with diabetes, Diabet. Care, 21(12):2161–2177, 1998. 77. Palubo, PJ and Melton, LJ, Peripheral vascular disease and diabetes, in Diabetes in America, NIH Publishing, chap. 15, p. 1–21, 1985.
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78. Apelquist, J, Ragnarson-Tennvall, G, Larrson, J, and Perrson, U, Long-term costs for foot ulcers in diabetic patients in a multidisciplinary setting, Foot Ankle Int., 16:388–394, 1995. 79. Nabarro, JDN, Diabetes in the United Kingdom: some facts and figures, Diabet. Med., 5:816–822, 1988. 80. Lavery, LA, Ashry, HR, van Houtum, W, Pugh, JA, Harkless, LB, and Basu, S, Variation in the incidence and proportion of diabetes-related amputations in minorities, Diabet. Care, 19(1):48–52, 1996. 81. Edelson, GW, Armstrong, DG, Lavery, LA, and Caicco, G, The acutely infected diabetic foot is not adequately evaluated in an inpatient setting, Arch. Int. Med., 156(20):2373–2378, 1996. 82. Cohen, GD, Schnall, SB, and Holtom, P, New onset diabetes mellitus in patients presenting with extremity infections, Clin. Orthoped. Rel. Res., 1 9403: 45–48, 2002. 83. Kannel, WB and McGee, DL, Diabetes and cardiovascular disease: the Framingham Study, JAMA, 241:2035–2038, 1979. 84. Wolf, PA, D’Agostino, RB, Belanger, AJ, and Kannel, WB, Probability of stroke: a risk profile from the Framingham Study, Stroke, 22:312–318, 1991. 85. Tuomilehto, J, Rasetnyte, D, Jousilahti, P, Sarti, C, and Vartiainen, E, Diabetes mellitus as a risk factor for death from stroke: prospective study of the middle-aged Finnish population, Stroke, 27:210–215, 1996. 86. Brown, RD, Jr., Whisnant, JP, Sicks, JD, O’Fallon, WM, and Wiebers, DO, Stroke incidence, prevalence and survival: secular trends in Rochester, Minnesota, through 1989, Stroke, 27:373–380, 1996. 87. Karapanayiotides, T, Piechowski-Jozwiak, B, Van Melle, G, Bogousslavsky, J, and Devuyst, G, Stroke patterns, etiology, and prognosis in patients with diabetes mellitus, Neurology, 62(9):1558–1562, 2004. 88. Megherbi, SE, Milan, C, Minier, D, Couvreur, G, Osseby, GV, Tilling, K, Di Carlo, A, Inzitari, D, Wolfe, CDA, Moreau, T, and Giroud, M, Association between diabetes and stroke subtype on survival and functional outcome 3 months after stroke: data from the European BIOMED stroke project, Stroke, 34(3):688–694, 2003. 89. Costabile, RA, Optimizing treatment for diabetes mellitus induced erectile dysfunction. J. Urol., 170(2):S35–S39, 2003. 90. Bloomgarden, ZT, American Diabetes Association annual meeting, 1998: nephropathy and retinopathy. Diabet. Care, 22(4):640–644, 1999. 91. Klein, BEK, Klein, RM, and Scot, E, Incidence of self reported glaucoma in people with diabetes mellitus, Br. J. Ophthalmol., 81(9):743–747, 1997. 92. Ellis, JD, Evans, JMM, Ruta, DA, Baines, PS, Leese, G, MacDonald, TM, and Morris, AD, Glaucoma incidence in an unselected cohort of diabetic patients: is diabetes mellitus a risk factor for glaucoma, Br. J. Ophthalmol., 84(11):1218–1224, 2000. 93. Harris, MI, Klein, R, Cowie, CC, Rowland, M, and Byrd-Holt, DD, Is the risk of diabetic retinopathy greater in non-Hispanic blacks and Mexican-Americans than in non-Hispanic whites with type 2 diabetes?: a U.S. population study, Diabet. Care, 21(8):1230–1235, 1998. 94. Leiter, LA, Barr, A, Belanger, A, Lubin, S, Ross, SA, Tildesley, HD, and Fontaine, N, Diabetes screening in Canada (DIASCAN) study: prevalence of undiagnosed diabetes and glucose intolerance in family physician offices, Diabet. Care, 24(6):1038–1043, 2001. 95. Rajala, U, Laakso, M, Qiao, Q, and Keinanen-Kiukaanniemi, S, Prevalence of retinopathy in people with diabetes, impaired glucose tolerance, and normal glucose testing, Diabet. Care, 21(10):1664–1669, 1998.
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96. Stolk, RP, Vingerling, JR, de Jong, PTVM, Dielemans, I, Hofman, A, Lamberts, SWJ, Pols, HAP, and Grobbee, DE, Retinopathy, glucose, and insulin in an elderly population: the Rotterdam study, Diabetes, 44 (91):11–15, 1995. 97. Klein, R, Klein, BEK, and Moss, SE, The Wisconsin epidemiologic study of diabetic retinopathy: XVI. The relationship of c-peptide to the incidence and progression of diabetic retinopathy, Diabetes, 44(7):796–801, 1995. 98. Klein, R and Moss, S, A comparison of the study populations in the diabetes control and complications trial and the Wisconsin epidemiologic study of diabetic retinopathy, Arch. Int. Med., 155(7):745–754, 1995. 99. Expert Committee on Diagnosis and Classification of Diabetes Mellitus, Follow-up report on the diagnosis of diabetes mellitus, Diabet. Care, 26(11):3160–3167, 2003. 100. Klein, BEK, Klein, R, Moss, SE, and Palta, M, A cohort study of the relationship of diabetic retinopathy to blood pressure, Arch. Ophthalmol., 113(5):601–606, 1995. 101. Tomar, SL and Lester, A, Dental and other health care visits among U.S. adults with diabetes, Diabet. Care, 23(10):1505–1510, 2000. 102. Morgan, CL, Currie, CJ, and Peters, JR, Relationship between diabetes and mortality: a population study using record linkage, Diabet. Care, 23(8):1103–1107, 2000. 103. Bonds, DE, Zacarro, DJ, Karter, AJ, Selby, JV, Saad, M, and Goff, DC, Jr., Ethnic and racial differences in diabetes care: the insulin resistance atherosclerosis study, Diabet. Care, 26(4):1040–1046, 2003.
10
Nutrient Interactions and Glucose Homeostasis Emmanuel C. Opara, Ph.D.
CONTENTS I. II. III. IV.
Introduction................................................................................................161 Characteristics of Energy Generation from Nutrients ..............................162 Blood-Glucose Regulation.........................................................................162 Interrelationships of Nutrient Metabolism and the Effect on Glucose Homeostasis.................................................................................163 V. Design of Treatment for Type 2 Diabetes Based on Nutrient Interactions ..................................................................................165 A. Limiting Availability of Fatty Acids .................................................166 B. Inhibition of Fatty-Acid Oxidation ...................................................167 C. Inhibition of Gluconeogenesis ..........................................................168 D. Uncoupling of Energy During Fatty-Acid Oxidation.......................169 E. Nutritionally Based Therapeutic Approach ......................................170 VI. Conclusion .................................................................................................172 References..............................................................................................................173
I. INTRODUCTION The purpose of this chapter is to present an overview of the metabolism of the key nutrients, glucose, fatty acids, and amino acids in the body and how the processes therein involved affect glucose homeostasis. We will pay particular attention to the interplay of the metabolism of fatty acids and glucose, which are the major fuel sources in the postabsorptive state. We will then explore how knowledge of the interrelationships of the metabolism of these nutrients can be used to design effective treatment strategies for type 2 diabetes. The discussion will be focused on human studies, but results from animal experiments will also be discussed where human data are either limited or not available.
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II. CHARACTERISTICS OF ENERGY GENERATION FROM NUTRIENTS The key peripheral tissues whose metabolic activities affect glucose homeostasis are the liver, muscle, adipose tissue, and kidney. These tissues play different roles in blood-glucose regulation in the fed and resting postabsorptive states, as well as during extended periods of fasting (1). Depending on the nutrient and the nutritional status, nutrients are processed primarily to provide the body’s energy needs and to replenish or augment body stores of glycogen and fat. In the fed state, excess amino acids not utilized for proteins synthesis are preferentially catabolized over glucose and fat for energy, because there are no significant storage sites for amino acids and proteins, while an accumulation of nitrogen products results in toxicity in the body. During fasting, the adipose tissue, muscle, liver, and kidneys work in different capacities to supply, convert, or conserve metabolic fuel for the body (1). In the resting, postabsorptive state, blood-glucose homeostasis is achieved by balanced contributions from glycogenolysis by the liver and lipolysis by the adipose tissue. If fasting is continued, proteolysis in the muscle ensues to supply glycogenic amino acids for gluconeogenesis in the liver and kidneys (1, 2). In periods of starvation, defined as three or more days of fasting, the body strives to conserve protein and to obtain greater supplies of its energy needs from alternative metabolic fuels, primarily fatty acids and ketone bodies. Under these circumstances, the ability of the kidneys to preserve ketone bodies prevents the loss of this valuable energy source, and the delicate interplay among these key tissues in the regulation of energy needs permits survival for extended periods of caloric deprivation (1).
III. BLOOD-GLUCOSE REGULATION Blood-glucose regulation is achieved by an intricate balance among many factors, including nutritional status, endocrine and neural mechanisms, and physical activity. However, for the purpose of this discussion, we will just focus on the different biochemical processes of glucose utilization and synthesis in the tissues, which maintain normal blood glucose. In the fed state, blood glucose is kept normal by increased utilization of glucose and storage as glycogen. Glucose produced by the catabolism of amino acids not used for protein synthesis is also stored as glycogen. Fatty acids not resynthesized into triglycerides for storage as lipids are oxidized and, by so doing, generate substrates also used for de novo glucose synthesis (gluconeogenesis) and storage as glycogen. In the postabsorptive state, normal blood glucose is maintained by a combination of gluconeogenesis and glycogenolysis. During short-term fasting, blood glucose is primarily maintained by hepatic glycogen breakdown. With extended periods of fasting, fatty-acid oxidation and amino-acid catabolism become predominant sources of energy, and through these processes, substrates are generated for gluconeogenesis. As noted earlier, glucose is a major fuel that also occupies a central position in the metabolism of other nutrients in the body. It is a precursor molecule that is capable of providing many metabolic intermediates for various biosynthetic reactions (3). Hence, the metabolism of glucose is normally regulated by a well-coordinated
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system among the different tissues in the body. For instance, in the muscle, glycolytic degradation of glucose produces ATP, and the rate of glycolysis increases as the muscle contracts more intensely, thereby demanding more ATP. On the other hand, as previously noted, the liver and the kidneys serve to keep a constant level of glucose in the blood by producing and exporting glucose when the tissues demand it, while the liver takes up and stores glucose when it is available in excess (3). The turnover of muscle protein occurs slowly with little or no diurnal changes in the size of the protein pool in response to feeding and fasting (4). There are 20 standard amino acids in proteins, with variations in their carbon skeletons. Consequently, there are many different catabolic pathways for the degradation of amino acids for energy production. Altogether, the energy from these pathways accounts for only 10 percent to 15 percent of the body’s energy production (3). Although much of the catabolism of amino acids takes place in the liver, six amino acids, namely leucine, isoleucine, valine, asparagine, aspartate, and glutamate, are metabolized in the resting muscle (4). However, the three branched-chain amino acids, leucine, isoleucine, and valine, are only oxidized as metabolic fuels in the muscle, adipose tissue, kidney, and brain. These extra-hepatic tissues have a single aminotransferase that is not present in the liver and acts on all three branched-chain amino acids to produce the corresponding keto-acids (3). The overwhelming majority of amino acids are glucogenic. Hence, their carbon skeleton generates intermediates of tricaboxylic acid (TCA) cycle that are used for de novo glucose synthesis.
IV. INTERRELATIONSHIPS OF NUTRIENT METABOLISM AND THE EFFECT ON GLUCOSE HOMEOSTASIS Competition between nutrients as sources of metabolic fuel has been known for more than eight decades. However, quantitatively, the most important interaction is between glucose and fatty acids (5). As already mentioned above, if there is a perturbation of the energy-supply system in the body, such as an abundance of fatty acids, a competition ensues between glucose and fatty acids as sources of metabolic fuel. This phenomenon came to be significantly recognized when Randle and colleagues proposed the glucose–fatty-acid cycle to explain the metabolic interactions between glucose and fatty acids and their role in insulin sensitivity and diabetes (5). Essentially, the Randle hypothesis states that the metabolic relationship between glucose and fatty acids is reciprocal and not dependent (5–7). More recently, to explain this reciprocal relationship, Randle has proposed that oversupply of glucose would promote glucose oxidation and glucose and lipid storage while inhibiting fatty-acid oxidation. On the other hand, an abundance of free fatty acids would promote fatty-acid oxidation and storage while inhibiting glucose oxidation, and may possibly enhance glucose storage if glycogen reserves are incomplete (5). According to the original Randle hypothesis, an increase in fatty-acid availability results in increased fatty-acid oxidation with concomitant inhibition of glucose oxidation. Various mechanisms are involved in the inhibition of glucose oxidation during increased fatty-acid supply and oxidation, as illustrated in Figure 10.1. The
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Glucose HK
Glucose-6-P
Fructose-6-P PFK
Fructose 1,6-BP
Citrate
Glyceraldehyde-3-P
Pyruvate PDH Acetyl CoA + Oxaoloacetate + Acetyl CoA
Fatty acid oxidation
Fatty acid levels + Glycerol
Gluconeogenesis
FIGURE 10.1 Illustration of the original Randle hypothesis. Oversupply of lipids will lead to increased fatty-acid oxidation, the products of which include increased levels of acetyl CoA, which inhibits pyruvate dehydrogenase (PDH), and citrate, which inhibits phosphofructose kinase. Simultaneously, other products of fatty-acid oxidation, such as glycerol, are converted to glucose in a pathway that generates an abundance of Glucose-6-P (G-6-P), which inhibits hexokinase, and further impairs glucose utilization.
accumulation of acetyl-CoA would result in the inhibition of pyruvate dehydrogenase (PDH), while the abundance of citrate would inhibit phosphofructokinase (PFK), and excess levels of glucose-6-phosphate (G-6-P) would inhibit the activity of hexokinase (HK) (7, 8). There has also been an accumulation of evidence to show that increases in the glycolytic flux during glucose metabolism may decrease fatty-acid oxidation. It has been proposed that the potential sites of fatty-acid metabolism affected include the transport of fatty acid into the sarcoplasma, lipolysis of intramuscular triacylglycerol by hormone-sensitive lipase, and transport of fatty acids across the mitochondrial membrane (7). One scenario among the possible mechanisms of regulation of fattyacid metabolism is an increase in malonyl-CoA concentration, which is formed from acetyl-CoA in a reaction catalyzed by acetyl-CoA carboxylase (ACC). Increased
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levels of malonyl-CoA will inhibit carnitine palmitoyl transferase 1 (CPT1) (9). Indeed, using muscle biopsies obtained from obese subjects for lipid analysis and reverse transcription-competitive polymerase chain reaction, it has been shown that down-regulation of ACC2 mRNA, induced by lowering plasma-insulin levels caused improvement in insulin sensitivity (10). Another possibility is increased levels of acetyl moiety that will result in acetylation of the carnitine pool decreasing the free carnitine concentration and thereby reducing fatty-acid transport into the mitochondria. It has also been suggested in some studies that CPT1 may be inhibited by small reductions in pH that may occur during glycolysis (7). Moreover, it has been shown that long-chain acyl-CoAs accumulate in the muscle during chronic glucose infusion, an observation that is consistent with malonyl-CoA-induced inhibition of fatty-acid oxidation. This phenomenon, by which glucose oxidation yield products that may regulate fatty-acid oxidation, has been referred to by some investigators as the reverse glucose–fatty-acid cycle (11, 12), in distinction from the original Randle hypothesis, which proposed that products of fatty-acid oxidation affect glucose metabolism. Studies performed after the original Randle hypothesis was proposed have identified other mechanisms by which oversupply of fatty acids would affect glucose utilization. First, it has been shown that with adequate insulinization, increased fattyacid levels effectively compete with glucose for uptake into peripheral tissues, regardless of the presence of hyperglycemia (13). Second, it has been reported that increased fatty-acid oxidation may inhibit glucose storage (14). Third, it has been suggested that the metabolic interactions between free fatty acid and glucose also involve impaired suppression of hepatic glucose output (HGP) by insulin (15). In addition, in a situation of enhanced lipolysis, increased levels of glycerol would promote gluconeogenesis (16). Furthermore, it has been shown that lipid-derived molecules, including diacylglycerol and ceramide, can inhibit glucose disposal by interfering with more than one pathway of the insulin-signal transduction system, depending on the prevailing species of fatty acids. These pathways include alteration of insulin action via chronic activation of protein kinase C (PKC) isoenzymes by long-chain acyl-CoA (17, 18). Putting together available information from the literature on the various mechanisms by which oversupply of lipids may impair glucose utilization and result in increased blood glucose, glucose–fatty-acid cycle today can be summarized by the various pathways shown in Figure 10.2.
V. DESIGN OF TREATMENT FOR TYPE 2 DIABETES BASED ON NUTRIENT INTERACTIONS It is perhaps apparent by now that increased lipid availability can impair glucose utilization through many different mechanisms and result in the hyperglycemia of type 2 diabetes. Consequently, there are as many different approaches that can be used to design effective treatment strategies for the disease on the basis of the competition of nutrients as substrates for metabolic reactions. These strategies include limiting the availability of lipids as metabolic fuels; inhibition of fatty-acid uptake and oxidation; inhibition of gluconeogenesis; and uncoupling the energy obtained during fatty-acid oxidation with concomitant manipulation of the fatty-acid
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Glucose diposal and storage
Fatty acid oxidation
Gluconeogenesis
Fatty Acids
Glucose
Lipolysis
+ Glycerol
Hyperglycemia
FIGURE 10.2 Summary of pathways of the glucose–fatty-acid cycle. Increased fatty-acid utilization generates intermediate substrates that impair glucose utilization while enhancing de novo glucose synthesis and storage, resulting in blood-glucose overload or hyperglycemia.
oxidation gene transcription factors peroxisome proliferator activated receptors (PPARs) (19–23).
A. LIMITING AVAILABILITY
OF
FATTY ACIDS
As pointed out earlier, fatty-acid oxidation affects glycemic control not only by decreasing peripheral glucose utilization, but also by enhancing gluconeogenesis. Hence, inhibition of lipolysis is an effective strategy to reduce the availability of free fatty acids for oxidation and thus enhance glucose oxidation and decrease blood-glucose levels (19, 21). One of the early attempts to use antilipolytic agent to limit fatty-acid availability and treat type 2 diabetes was made with nicotinic acid. It was found that its inhibitory effect on lipolysis was accompanied by a stimulation of the glucose disposal. It was, however, disappointing to see that although nicotinic acid initially reduced free fatty-acid levels in type 2 diabetes, it was followed by a rebound in free fatty-acid levels that was associated with hyperglycemia and glucosuria (19). Subsequently, an analogue of nicotinic acid, acipimox, was developed, which was more potent and had less of the rebound effect than nicotinic acid (19). To date, acipimox remains an active research interest in the treatment of type 2 diabetes. In a recent experimental study with obese Zucker rats, oral administration of 150 mg/kg of acipimox significantly reduced plasma free fatty-acid (FFA), glucose, and insulin levels, and thus improved glucose tolerance while reducing insulin response (24). Clinical trials with acipimox have also yielded positive effects in the management of type 2 diabetes. In an early double-blind, placebo-controlled trial, hepatic-glucose output (HGO) and fuel use assessed by indirect calorimetry were measured in the basal state and during the last 30 minutes of a hyperglycemic clamp in obese, type 2 diabetics three times thrice during 12 hours. It was found that this protocol of prolonged suppression of lipolysis caused a reduction of fasting blood glucose
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and HGO while increasing peripheral hepatic sensitivity to insulin in the study subjects (25). The data from this early study were consistent with those from another overnight placebo-controlled study with acipimox (26). In the later study, 250 mg acipimox was administered three times in 12 hours to four different groups of individuals, namely lean control subjects, obese, nondiabetic individuals, obese subjects with impaired glucose tolerance, and patients with type 2 diabetes. It was found that lowering plasma FFA levels reduced insulin resistance/hyperinsulinemia and improved oral glucose tolerance in all groups of the study subjects (26). The observations from these studies of short-term use of acipimox have been confirmed in a randomized, double-blind, placebo-controlled study in which 25 individuals with type 2 diabetes were given 250 mg four times daily, and another 25 received a placebo for one week. The study showed that the treatment with acipimox lowered plasma FFA levels and improved acuteinsulin response and insulin-mediated glucose uptake (27). However, in one of the earlier studies, acipimox gave mixed results on suppression of plasma FFA levels and had no effect on hepatic-glucose production (28). The reason for this discrepant observation with acipimox is not clear.
B. INHIBITION
OF
FATTY-ACID OXIDATION
One strategy that has received significant attention is the use of fatty-acid oxidation inhibitors in the management of type 2 diabetes. As can be predicted from the glucose–fatty-acid cycle, the rationale in the use of this approach is that inhibiting fatty-acid oxidation would enhance peripheral tissue glucose utilization while inhibiting gluconeogenesis. Hence, there has been significant interest in the development of drugs to inhibit fatty-acid oxidation and improve glycemic control in individuals afflicted with type 2 diabetes. Long-chain fatty acids are converted to fatty acylCoA esters in the outer mitochondrial membrane and require carnitine to get across the inner mitochondrial membrane for oxidation in the mitochondrial matrix. The rate-limiting enzyme that catalyzes the transesterification of the fatty acyl group from Co-A to carnitine is carnitine acyltransferase 1, the predominant form being the carnitine palmitoyl transferase 1 (CPT-1). It is therefore not surprising that the first generation of fatty-acid oxidation inhibitors developed as therapeutic agents for type 2 diabetes were inhibitors of the CPT-1 enzyme (19, 21). CPT-1 inhibitors, such as etomoxir and tetradecylglycidic acid (TDGA), have the ability to decrease blood-glucose levels. However, enthusiasm for the use of this class of inhibitors of fatty-acid oxidation waned because of observations that they induced cardiac hypertrophy in rodents treated with the drugs. The next generation of CPT-1 inhibitors developed were drugs, such as SDZ and CPI 975, whose action on the liver-specific enzyme is reversible and might therefore be less toxic to the heart. Also, some monoamine oxidase inhibitors have been shown to inhibit the acylcarnitine translocase/CPT-2 enzyme and cause reductions in blood-glucose levels (21). Further studies are required to assess both the long-term efficacy and safety of these newer compounds in human subjects.
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GLUCONEOGENESIS
As discussed earlier, one consequence of the catabolism of amino acids and fatty acids is the generation of metabolic substrates that are used for de novo glucose synthesis. It has been shown that hepatic insulin resistance in type 2 diabetes causes overproduction of glucose. Therefore, direct inhibition of gluconeogenesis by blocking a key enzyme in glucose synthesis, pyruvate carboxylase, or by limiting the availability of gluconeogenic substrates, is an attractive target for drug development. However, direct inhibition of pyruvate carboxylase is prone to unwanted side effects, because the enzyme has dual functions in both gluconeogenesis and in the TCA cycle. The alternative approach of using indirect inhibitors of pyruvate carboxylase that act by sequestering acetyl-CoA, thereby making it unavailable for the action of the enzyme, has shown promising results in experimental studies with animals (21). Another class of oral antidiabetic drugs, which are derivatives of acetic acid that reduce blood glucose and lipid levels without stimulating insulin secretion, has been developed. One member of this class of drugs being investigated is dichoroacetate (DCA), which inhibits hepatic glucose synthesis and stimulates glucose disposal by peripheral tissues (21, 29). A major effect of DCA is stimulation of the action of PDH, the rate-limiting enzyme in aerobic glucose oxidation, resulting in increased peripheral catabolism of alanine and lactate, thereby disrupting the Cori and alanine cycles and reducing availability of substrates for gluconeogenesis (29). Metformin hydrochloride, a biguanide, is currently the only clinically available antidiabetic oral agent whose mechanism of action involves suppression of hepaticglucose release through inhibition of gluconeogenesis and glycogenolysis, albeit other metabolic parameters may also be affected (21, 30, 31). For instance, it has been shown that metformin enhances insulin sensitivity at the muscle by promoting glucose transport and glycogen synthesis. It may also enhance peripheral glucose utilization by suppression of FFA release and oxidation (21). Body-weight reduction, as well as significant decreases in plasma levels of LDL cholesterol, triglycerides, and FFA, have also been reported in patients treated with metformin (21, 31). Based on these metabolic actions of metformin treatment, its use has actually been recommended as a possible strategy to prevent type 2 diabetes in individuals at high risk for developing the disease (32). Novel pharmacologic actions of metformin have recently been described. In one study, it has been shown that the drug, in combination with a dipeptidyl peptidase IV (DPPIV) inhibitor, caused reductions in food intake and body weight while enhancing the release of GLP-1, an incretin hormone that stimulates insulin secretion and also appears to reduce appetite (33). In another study, it was shown that metformin caused a significant decrease in mitochondrial permeability and aerobic respiration (34). However, the clinical significance of this latter in vitro observation remains to be determined. As with any drug, the safety of metformin use has been a subject of investigation. An earlier biguanide, phenformin hydrochloride, was withdrawn from clinical use because it was associated with lactic acidosis in some patients treated with the drug. Thus far, it does not appear that lactic acidosis is a significant side effect in the treatment of uncomplicated type 2 diabetes (35, 36), albeit it could become a rare
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but life-threatening problem when used to treat patients with renal failure (37). A few cases of hypoglycemia have been reported in a combination therapy of metformin and nateglinide (38).
D. UNCOUPLING
OF
ENERGY DURING FATTY-ACID OXIDATION
A new concept in drug development for type 2 diabetes has emerged with the introduction of therapeutic agents that may enhance lipolysis while promoting fattyacid oxidation in a futile cycle that does not yield metabolic energy, and thus decrease circulating FFA levels while stimulating peripheral-tissue glucose utilization (20, 24). One class of these new therapeutic agents is beta-3 agonists, which activate beta3-adrenergic receptors. An example of the beta-3 agonists currently under investigation is trecadrine, which has been reported to induce lipolysis in adipocytes, with increased oxygen consumption in white adipose tissue, while FFA levels decreased because of their utilization in nonenergy-generating tissue, such as the brown adipose tissue (39). It has also been shown that another beta-3 agonist, CL-316243, may indirectly stimulate glucose uptake in the muscle of type 2 diabetic rats by stimulating the brown adipose tissue to increase uncoupling protein content and fatty-acid oxidation, thus progressively decreasing the levels of circulating FFA (24). The next class of agents involved in this approach of uncoupled oxidation of fatty acids is the PPARs. This is a group of three nuclear receptor isoforms encoded by different genes, PPAR-α, PPAR-δ, and PPAR-γ. Each of these isoforms appears to be expressed in a specific tissue because of its binding to a specific consensus DNA sequence of the peroxisome-proliferator response elements (PPREs) (22, 23, 40–42). PPAR-α is highly expressed in the liver and relatively expressed in the heart, kidney, skeletal muscle, intestinal mucosa, and brown adipose tissue (23, 42). It is the most characterized of the three PPAR subtypes and has been shown to play a prominent role in the regulation of nutrient metabolism, including fatty-acid oxidation, gluconeogenesis, and amino-acid metabolism (22, 23, 40, 42). PPAR-δ is expressed ubiquitously and has been shown to be effective in the treatment of dyslipidemia and cardiovascular disease (22). PPAR-γ is mainly expressed in the brown adipose tissue where it stimulates adipogenesis and lipogenesis (22, 42). Clinically, PPAR-α and PPAR-γ agonists have been used to treat hypertriglyceridemia and insulin resistance. Thiazolidinediones are PPAR-γ agonists, which enhance insulin sensitivity mainly at the skeletal muscle and adipose tissue, with some effect at the liver where they increase insulin-stimulated glucose disposal (21). These drugs increase triglyceride uptake into the adipose tissue, thereby reducing circulating FFA levels. One member of the PPAR-γ agonists group of drugs that had been previously used clinically is troglitazone. In one study, a randomized placebocontrolled trial was performed with troglitazone to determine its effect on wholebody insulin sensitivity, pancreatic β-cell function, and glucose tolerance in Latino women with impaired glucose tolerance and a history of gestational diabetes (43). After baseline oral glucose tolerance (OGTT) and intravenous glucose tolerance (IVGTT) tests, each of three groups (14/group) of subjects was assigned to receive one of three treatments, a placebo, 200 mg troglitazone, or 400 mg troglitazone daily for 12 weeks. It was found that insulin sensitivity assessed by the minimal model
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analysis of IVGTT results changed by only 4 percent in the placebo group but was increased by 40 percent and 88 percent above basal in the groups treated with 200 mg and 400 mg troglitazone, respectively. Troglitazone treatment was also associated with a dose-dependent reduction in the total insulin output during the glucosetolerance tests (43). Another PPAR-γ agonist that is still clinically available is pioglitazone, whose potency has been compared with that of troglitazone with reference to its effects as inhibitors of fatty oxidation, esterfication, and gluconeogenesis (44). It was concluded that at similar concentration, troglitazone was more effective than pioglitazone in inhibiting fatty-acid oxidation and gluconeogenesis, and that the inhibition of gluconeogenesis by troglitazone may be the result of its inhibition of fatty-acid oxidation (44). Unfortunately, troglitazone has been withdrawn from clinical use because of its hepatotoxicity, leaving pioglitazone and rosiglitazone as the only two thiazolidinediones currently available for clinical use (21). The PPAR-α agonist group of drugs include those synthetic, therapeutic agents that are molecular targets for fibrates, such as gemfibrozil, bezafibrate, clofibrate, and fenfofibrate, which are used to treat dyslipidemia and cardiovascular disease. PPAR-α promotes fatty-acid transport across cell membranes and converts them into a metabolic form that precedes their subsequent metabolism. These drugs are gaining popularity in combination treatment with the statins (23).
E. NUTRITIONALLY BASED THERAPEUTIC APPROACH A nutritional therapy for type 2 diabetes based on nutrient competition as metabolic substrates is an approach that has been examined in studies performed by our group and others. In a series of studies, it had been shown that fatty acids stimulate insulin secretion through a mechanism involving fatty-acid oxidation (45–49), while the amino acid L-glutamine inhibits insulin secretion (50). It had also been previously shown that L-glutamine inhibits fatty-acid oxidation by islets, because it is a preferred fuel source for these cells (51). We subsequently showed that addition of Lglutamine to a fatty acid perifusate inhibited fatty-acid oxidation and prevented fatty acid-induced desensitization of islet response to glucose stimulation (52). Based on these in vitro observations, we hypothesized that L-glutamine supplementation during high-fat feeding would prevent insulin resistance characterized by hyperinsulinemia and hyperglycemia, as seen in C57BL/6J (B/6J) mice. In the B/6J mice, highfat feeding causes obesity associated with type 2 diabetes (53, 54). In our L-glutamine supplementation studies, the effect of L-alanine on glucose dysregulation induced by high-fat feeding was also examined. Each of four groups of 10 age- and weight-matched male B/6J was raised on one of four diets: 1) low fat, low sucrose (LL); 2) high fat, low sucrose alone (HL); 3) high fat, low sucrose supplemented with L-glutamine; and 4) high fat, low sucrose supplemented with Lalanine. Food intake, body weight, and plasma-glucose and insulin levels were monitored over time. We found no difference in food intake per unit body weight between the groups after the first two weeks of feeding. However, the mean body weight of the LL group measured at 16 weeks was significantly lower than that of the HL group, as shown in Figure 10.3. Although supplementation with each of the
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45 40 35 Body wt, g
a
a a b
30
b
b
25
c
c
b
b b c
c
c
HL HL + Gln HL + Ala LL
20 15 10
a
a
0
2
4
6
8
10
12
14
16
Week
FIGURE 10.3 Body weights of B/6J mice fed a low-fat diet or a high-fat diet with or without supplemental Gln or Ala. Values are means ± SEM, n = 10. The error bars were so small that they are invisible in most data points. Means at a particular time point with different letters are significantly different, p < 0.05. Abbreviations used: HL, high fat, low sucrose; HL + Gln, high fat, low sucrose with L-glutamine supplementation; HL + Ala, high fat, low sucrose with L-alanine supplementation; LL, low fat, low sucrose. Reprinted with permission from Figure 2 of reference 55.
amino acids caused 10 percent reduction in body weight compared with HL feeding, only L-glutamine supplementation resulted in persistent reductions in plasma-glucose and insulin levels during the 5.5-month duration of study. We also found that when L-glutamine was added to the HL diet of obese hyperglycemic and hyperinsulinemic animals for two months, body-weight gain, shown in Figure 10.4, as well as hyperglycemia and hyperinsulinemia, were all significantly attenuated (55). In another study, we also found that L-glutamine supplementation prevents impaired glucose regulation associated with hyperlipidemia induced by intravenous lipid administration (56). These observations have been confirmed in a study by other investigators who found that parenteral glutamine supplementation augmented whole-body insulin stimulation of whole-body glucose utilization, thus suggesting improved insulin sensitivity (57). It is of interest that glycogen synthesis is stimulated by L-glutamine (58–61), which, as previously noted, inhibits fatty-acid oxidation (51) and lipolysis (62, 63) while stimulating lipogenesis (64). The enhancement of glycogen synthesis by glutamine would imply an increase in gluconeogenic fluxes that is associated with increased rate of nonoxidative glucose clearance (65) that may result in near-normal blood-glucose levels during high-fat feeding, as seen in our studies. The clinical applicability of this nutritionally based therapeutic approach remains to be evaluated, albeit the clinical implication of our observations using this approach is discussed in the chapter in this book by Drs. Lien and Feinglos.
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120 Relative Body Weight g/100ginitial weight
HL
a
HL to HL+Gln
115 110 105
b 100 95 90 0
2
6
9
13
16
20
23
27
30
37
44
58
Days After Diet Change
FIGURE 10.4 Effect of supplemental glutamine on relative body weight in heavy,
hyperglycemic adult mice switched from the high-fat (HL) to the HL + Gln diet. The gap in the x-axis denotes an alteration in the scale because of the different intervals of determination. Two groups of mice (n = 10/group) were fed the HL diet for four months before one group was switched to the HL + Gln diet for two months, during which time the other continued being fed the HL diet. Different letters indicate significant differences between groups. Values are mean ± SEM, n = 10. Reprinted with permission from Figure 5 of reference 55.
VI. CONCLUSION It is quite clear that the processing of nutrients is intertwined through intermediary metabolism in the body. Consequently, it is imperative that there is a natural competition among the key nutrients, carbohydrate, fatty acids, and amino acids as sources of biological energy. Which nutrient becomes a primary source of energy is regulated by the nutritional status (fed or fasted state) with the concomitant hormonal balance. The convergence of the metabolism of nutrients in the tricarboxylic-acid cycle has very obvious implications in the utilization of each nutrient as substrates for the generation of expendable energy or the synthesis of macromolecules as storage forms of energy or for tissue maintenance. Depending upon the nutritional status, various studies have shown that the predominant energy-yielding sources are glucose and fatty acids, which compete with each other as sources of metabolic energy. There is overwhelming evidence to show that the converging metabolism of these two nutrients in the glucose–fattyacid cycle plays a predominant role in the pathogenesis of type 2 diabetes, albeit some studies have challenged the view that this cycle contributes to insulin resistance (66, 67). However, based on the hypothesis of the glucose–fatty-acid cycle, it is possible to design effective therapeutic strategies for type 2 diabetes mellitus. These strategies for drug development could involve inhibitions of fatty-acid oxidation and gluconeogenesis, manipulation of the enzymatic processes involved in nutrient processing, molecular targets for metabolic engineering, or a simple nutritional
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approach. A significant number of effective therapeutic agents have been developed, but there is still enormous potential for drug development for diabetes treatment on the basis of metabolic interactions of nutrients. This review that has summarized these nutrient interactions thus provides a valid scientific basis for effective strategies in designing new therapeutic agents for type 2 diabetes.
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Type 2 Diabetes in Childhood: Diagnosis, Pathogenesis, Prevention, and Treatment Michael Freemark, M.D.
CONTENTS I. Introduction................................................................................................178 II. Diagnosis of Type 2 Diabetes in Children................................................178 III Risk Factors and the Pathogenesis of Insulin Resistance and Type 2 Diabetes .........................................................................................180 IV. The Roles of Dietary Nutrients and Exercise in the Pathogenesis of Type 2 Diabetes.....................................................................................184 A. Diet ....................................................................................................184 B. Exercise .............................................................................................185 V. Complications of Type 2 Diabetes ............................................................186 A. Presenting Manifestations and Acute Complications .......................186 B. Hypertension, Atherogenesis, and Cardiovascular Disease in Obesity and Type 2 Diabetes ............................................................187 VI. Prevention of Type 2 Diabetes in High-Risk Subjects .............................189 A. Lifestyle Intervention ........................................................................189 B. Pharmacotherapy in Diabetes Prevention .........................................190 1. Drugs that Limit Nutrient Absorption ........................................190 2. Insulin Suppressors and Sensitizers............................................191 3. Other Pharmacologic Approaches...............................................195 4. Recommendations Regarding Pharmacotherapy in Diabetes Prevention.....................................................................196 VII. Pharmacologic Treatment of Type 2 Diabetes..........................................197 VIII. A Multifaceted Approach to Prevention of Complications ......................197 References..............................................................................................................198
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I. INTRODUCTION The 1985 edition of a major textbook of pediatrics described two forms of childhood diabetes mellitus: the autoimmune form of juvenile (now called type 1) diabetes, and a monogenic form of diabetes called maturity onset diabetes of the young (MODY). There was no mention of adult onset or noninsulin dependent type 2 diabetes; the condition was thought to affect only mature adults. During the past 20 years, the pediatric community has witnessed a worldwide surge in the prevalence of type 2 diabetes among children, adolescents, and young adults. The causes of this mini-epidemic are manifold, encompassing genetic, environmental, and nutritional factors, as well as changes in lifestyle that modulate energy expenditure. The objectives of this chapter are: (a) to discuss controversies related to the diagnosis of type 2 diabetes in childhood; (b) to delineate factors that play important roles in disease pathogenesis; (c) to describe potential complications that may arise in the short and long terms; and (d) to outline approaches to disease prevention and treatment.
II. DIAGNOSIS OF TYPE 2 DIABETES IN CHILDREN Many children and adolescents with type 2 diabetes are asymptomatic at the time of diagnosis and for long periods of time thereafter. Consequently, the condition is defined by measures of blood glucose that lie above the normal range. With increasing recognition of the long-term risks of mild elevations of blood-glucose concentrations in adults, the definition of diabetes has changed during the past generation. The diagnosis is established if fasting blood-glucose concentrations exceed 125 mg% and if postprandial or postdextrose challenge glucose concentrations exceed 200 mg%. Isolated fasting hyperglycemia must be confirmed on a subsequent day, while postprandial or postchallenge hyperglycemia must be accompanied by diabetic symptoms, such as polyuria or polydipsia. The transient hyperglycemia caused by acute stress, illness, pancreatitis, or certain medications (e.g., glucocorticoids, thiazides) must be excluded. Initially, it seemed that differentiation of type 2 diabetes from type 1 diabetes and MODY would be straightforward. Children with type 1 diabetes often presented emergently at an early age with ketoacidosis, and the great majority had evidence of islet autoimmunity, with seropositivity to pancreatic islet cells and islet antigens, including glutamic acid decarboxylase (GAD65), tyrosine phosphatase IA-2, and insulin. In contrast, adults with type 2 diabetes had a more protracted course, mild symptomatology, and no evidence of islet autoimmunity. Children and adults with MODY were also mildly symptomatic but had a strong family history of early-onset disease. Recent studies and clinical experience, however, have clouded the picture. For example, many children with type 1 diabetes have mild hyperglycemia and limited symptoms for weeks to months prior to diagnosis, and most now present without ketoacidosis. Although progressive beta-cell failure is a constant feature of the illness, the initial plasma C-peptide concentrations may fall within the normal range (though below those which might be expected given the coexisting hyperglycemia), and endogenous insulin production may persist for months and, in some cases, years after diagnosis. Like many patients with type 2 diabetes, some children and
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TABLE 11.1 Risk Factors for the Development of Type 2 Diabetes Mellitus in Pediatric Patients SGA, small for gestational age; IDM, infant of diabetic mother; LGA, large for gestational age; PCOS, polycystic ovary syndrome; GH, growth hormone. Genetic Background and Genetic Disorders Positive family history High risk ethnic group Girls > boys Genetic syndromes Prader Willi, Klinefelter’s, Alstrom Defects in insulin signaling (e.g., leprechaunism) Lipodystrophies Mitochondrial disorders (e.g., Friedrich’s ataxia, myotonic dystrophy) Prenatal/Perinatal Growth and Weight Gain SGA/early malnutrition with rapid catch up weight gain IDM/LGA Postnatal Weight Gain/Obesity (Especially Abdominal) Hormonal Disorders Ovarian hyperandrogenism and PCOS Cushing’s syndrome GH excess Hyperprolactinemia Medications Glucocorticoids Atypical antipsychotics Tricyclic antidepressants Lithium Anticonvulsants (e.g., valproate, carbamazepine, vigabatrin, gabapentin) Lifestyle Diet: high in saturated fat, high glycemic load low in fiber, Vitamin D, calcium and magnesium Energy expenditure: sedentary
adolescents with type 1 diabetes are obese, and a minority (particularly Asians) may fail to show evidence of islet autoimmunity [1]. Previous assumptions notwithstanding, the development of ketoacidosis (DKA) does not confirm that the patient has type 1 diabetes. DKA may occur at presentation in children and adolescents later found to have type 2 diabetes. In the experience of the author, those with severe acidosis (arterial pH < 7.1) and less-severe hyperglycemia are more likely to have type 1 diabetes, while those with severe hyperglycemia (blood glucose > 1000 mg%) and mild acidosis are more likely to have type 2 diabetes. Age of onset may be helpful but is not diagnostic; type 2 diabetes can occur as early as 3 years of age but presents more commonly after age 10 years. Type 1 diabetes can develop at any age but is far more likely than type 2 diabetes in children under the age of 8 years.
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Most confusing is the evidence of islet autoimmunity in a significant percentage of children and adolescents with type 2 diabetes. Like children with type 1 diabetes, children and adolescents with type 2 diabetes may be seropositive for antibodies to the 65 kDa form of glutamic acid decarboxylase (GAD65), to insulinoma-associated protein-2 (IA-2), to insulin, and to islet cells in cryostat sections of human pancreas. A recent investigation [2] of 156 racially-diverse patients with new-onset diabetes mellitus demonstrated seropositivity to at least one islet antigen in 74 percent of children whose subsequent clinical course suggested type 2 diabetes. Nevertheless, seropositivity to three or more islet antigens was detected in 41 percent to 46 percent of children with type 1 diabetes but only 11 percent of children with type 2 diabetes. The diabetes-related HLA types DR-3 and DR-4 were found in 89 percent of children with type 1 diabetes, 67 percent of children with type 2 diabetes, and 44 percent of the general nondiabetic population. Thus, the differentiation of type 2 diabetes from type 1 diabetes can be challenging and is in some cases impossible at the present time. Certain historical and clinical findings may, however, be informative. First, children and adolescents with type 2 diabetes are very likely to have first- and second-degree family members with adultonset type 2 diabetes. Second, peripubertal children and adolescents with type 2 diabetes, in contrast to children with type 1 diabetes or MODY, commonly have acanthosis nigricans, a marker of insulin resistance. Nevertheless, acanthosis is less common in Asians with type 2 diabetes. Third, fasting C-peptide concentrations in children with type 2 diabetes, in contrast to those in children with type 1 diabetes or MODY, commonly (but not always) exceed 1 ng/ml by one year after diagnosis. Finally, adolescent girls with hirsutism, anovulatory menses, or the polycystic ovary syndrome (PCOS) are more likely to have type 2 diabetes than type 1 diabetes. Nevertheless, poor glycemic control may cause menstrual irregularity in any form of diabetes, and mild hirsutism is common in obese adolescents, even those with type 1 diabetes.
III. RISK FACTORS AND THE PATHOGENESIS OF INSULIN RESISTANCE AND TYPE 2 DIABETES Type 2 diabetes is the endpoint of a process of metabolic decompensation in which genetic background, environmental determinants, and changes in body composition conspire to induce abnormalities in insulin production and action. Although some studies suggest that hypersecretion of insulin may induce obesity and secondarily limit peripheral insulin action, the preponderance of evidence suggests that insulin resistance is a primary event in the evolution of the disease. The resistance to insulin action is accompanied by hyperinsulinemia and (extrapolating from animal studies) an increase in islet size and beta-cell mass. Progression from insulin resistance to impaired fasting glucose (IFG) and impaired glucose tolerance (IGT or prediabetes) is associated with dysregulation of basal insulin secretion, loss of first-phase glucosedependent insulin secretion, and altered insulin processing, revealed as an increase in the circulating ratio of proinsulin to insulin [3]. The phenotype of longstanding type 2 diabetes is characterized by a decline in total insulin production, relative or absolute hypoinsulinemia, a reduction in beta-cell mass, and deposition of amyloid
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in the pancreatic islets. Thus, type 2 diabetes reflects a progressive loss of beta-cell function superimposed upon a loss of insulin sensitivity. The risk of developing type 2 diabetes is molded on a crucible of genetic inheritance and modulated by developmental and nutritional factors and energy expenditure (Table 11.1). The disease occurs more commonly among African Americans, Hispanic Americans, Native Americans, Pacific Islanders, and (possibly) Asian Americans than among those of Caucasian background and is far more prevalent among subjects with a family history of the disease [4]. The higher concordance rate among monozygotic than among dizygotic twins supports the strong influence of (thus far poorly defined) genetic factors. The prevalence of type 2 diabetes increases with age, but risk is modified by events that transpire before birth: The disease occurs more frequently in those born to diabetic mothers and those born small for gestational age (SGA), particularly if there is rapid catch-up growth in early childhood [5–7]. The heightened risk of type 2 diabetes in children born SGA may reflect reductions in skeletal-muscle insulin sensitivity and diminished pancreatic beta-cell mass. Breast-feeding of newborn infants appears to reduce diabetes risk, at least among Native American children [8]. Rates of type 2 diabetes are higher in girls (1.7-fold) than boys. The prevalence of impaired glucose tolerance and type 2 diabetes in teenage girls with ovarian hyperandrogenism or PCOS approximate 35 percent and 6 percent, respectively; by virtue of a heightened risk of PCOS in adolescence, prepubertal girls with adrenarche also appear to be vulnerable [9]. However, the most important modifiable risk factor for type 2 diabetes is obesity. The critical role of obesity in the development of type 2 diabetes in adults was established in the Nurses Health Study [10]; among nearly 17,000 adult women followed prospectively for 16 years, the risk of developing type 2 diabetes was nearly fortyfold higher among those with the highest body mass index (BMI) than in those with lowest BMI; in contrast, smoking, intake of saturated fats, and a sedentary lifestyle increased diabetes risk by 1.8-fold to 2.4-fold. Obesity plays a similarly important role in the pathogenesis of type 2 diabetes in children; with the exception of some teenage girls with PCOS, the overwhelming majority of pediatric patients with type 2 diabetes are obese. Insulin sensitivity in prepubertal and pubertal children correlates inversely with BMI and percent body fat [9, 11, 12], and severe obesity in prepubertal American children and adolescents is commonly associated with IGT (21 percent to 25 percent) and in some cases (4 percent of teenagers) with unsuspected type 2 diabetes [11, 12]. BMI in childhood (age 7–13 years) correlates with the clustering of obesity, hypertension, hyperinsulinemia, and dyslipidemia in adulthood (age 22–25 years), and obesity and hyperinsulinemia in Pima and African American children predict the development of type 2 diabetes in adolescence and adulthood [13–19]. Finally, obesity is a common feature of genetic and hormonal conditions associated with IGT and type 2 diabetes such as the Prader-Willi syndrome. Still, factors other than the simple accumulation of body fat modulate the risk of glucose intolerance. For example, the distribution of body fat appears to be of critical importance. Accumulation of upper body (visceral [intraperitoneal] and
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Visceral/abdominal obesity
Type 2 diabetes
FFA, cytokines
Liver TG VLDL Glu utilization Glu output
Skeletal muscle TG Glu disposal
IFG, IGT
Beta cells Insulin secretion
Glucose
FIGURE 11.1 The pathogenesis of glucose intolerance in obese subjects. FFA, free fatty acids; TG, triglycerides; glu, glucose; IFG, impaired fasting glucose; IGT, impaired glucose tolerance.
abdominal subcutaneous) fat is associated with insulin resistance. In contrast, insulin sensitivity correlates less well with stores of femoral and gluteal subcutaneous fat. The mechanisms by which abdominal fat deposition induces insulin resistance and glucose intolerance have begun to emerge (Figure 11.1) [20–22]. In human adults and experimental animals, the accumulation of abdominal fat is accompanied by adipose tissue resistance to insulin action and heightened sensitivity to catecholamines. Adipose tissue uptake of glucose and FFA is reduced, rates of lipolysis are increased, and triglyceride (TG) clearance is impaired because of down-regulation of lipoprotein lipase. The resistance to insulin appears to be mediated by changes in the expression of adipocyte cytokines. Tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and resistin are overexpressed in adipose tissue of obese subjects, while adiponectin expression is reduced. TNF alpha and resistin inhibit insulinmediated glucose and FFA uptake and TG synthesis in fat and, like the catecholamines, induce lipolysis and the release of FFA from adipose stores. The lipolytic effects are potentiated by IL-6, which inhibits lipoprotein lipase and TG deposition in adipose tissue. Interestingly, IL-6 and TNF alpha reduce expression of adiponectin in cultured preadipocytes, explaining, in part, the down-regulation of adiponectin in obesity. Plasma adiponectin concentrations are inversely related to BMI, waist circumference, and abdominal-fat mass and are higher in females than in males. Adiponectin levels correlate with insulin sensitivity in children as well as adults, and targeted deletion of adiponectin causes diet-dependent resistance to insulin action in skeletal muscle and liver. Rates of FFA flux in patients with upper-body abdominal obesity exceed those in lower-body obese and lean subjects. FFA derived from visceral fat are transported through the portal vein directly to the liver and used for TG synthesis; portal flux
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of FFA increases in proportion to the mass of visceral fat. FFA from abdominal subcutaneous fat gain access to the liver via the systemic circulation and are taken up by nonhepatic tissues, including skeletal muscle, pancreatic beta cells, and the heart. Storage of surplus fuel in peripheral tissues is facilitated by a resistance to, or a relative deficiency of, leptin, which normally stimulates tissue fatty-acid oxidation and inhibits lipogenesis [22]. The accumulation of TG in liver (hepatic steatosis) may induce hepatic inflammation (steatohepatitis) and a rise in serum transaminases. In rare cases, children with steatohepatitis can develop progressive liver damage, including cirrhosis [23]. Hepatic TG deposition impedes insulin uptake and clearance, contributing to circulating hyperinsulinemia, and limits insulin action. Direct effects of TNF alpha, IL-6, and resistin, and reductions in plasma adiponection concentrations, may exacerbate hepatic insulin resistance. The resulting increase in hepatic glucose production, likely mediated by induction of gluconeogenesis, contributes to mild increases in fasting blood-glucose concentrations and stimulates pancreatic insulin secretion. Hepatic production of TG is also increased; this exacerbates the rise in circulating TG levels caused by adipose tissue insulin resistance. Exchange of very low density lipoprotein-triglyceride (VLDL-TG) for cholesterol esters in high-density lipoproteins (HDL) increases HDL clearance and thereby reduces plasma HDL levels. Enrichment of LDL particles with excess TG facilitates their hydrolysis (by hepatic lipase) to small, dense LDL. Small, dense LDL particles are highly atherogenic and predispose to coronary-artery disease in adults. The elevations in plasma FFAs, TG, and circulating adipocytokines in the setting of leptin resistance have profound effects on insulin action in skeletal muscle. Analysis of muscle biopsies from insulin-resistant adults shows reductions in tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS)1, decreased IRS-1-associated PI-3 kinase activity, and impaired threonine- and serine-phosphorylation of protein kinase B (Akt). The defects in insulin signaling are thought to be induced by intramyocellular accumulation of TG or other lipid species, including long-chain fatty acyl-CoA, diacylglycerol, ceramide, or beta hydroxybutyrate [24]. The myocellular lipid accumulation may reflect in part an inherited defect in mitochondrial oxidative phosphorylation [21]; insulin resistance may, in some cases, be detected even in lean siblings of obese patients with insulin resistance or PCOS. Inhibition of Akt phosphorylation impairs skeletal muscle glucose uptake by reducing glucose transporter 4 (GLUT-4) expression, translocation, and activity [20–21]. The result is a progressive decrease in insulin-stimulated, nonoxidative glucose disposal. Insulin resistance in an obese child or adult does not guarantee progression to frank glucose intolerance; indeed, most obese, insulin-resistant subjects never develop type 2 diabetes. The development of glucose intolerance requires beta-cell dysfunction and loss of glucose-dependent insulin secretion. Some evidence suggests that beta-cell dysfunction may be a familial or genetic trait that predisposes individuals to type 2 diabetes. Other findings suggest that FFA, cytokines, and glucose may promote beta-cell dysfunction in genetically predisposed subjects [20, 21]. Acute elevations of FFA increase β-cell insulin secretion, and the rise in FFA during fasting may sustain basal insulin production and preserve the normal insulin secretory response to glucose. Prolonged administration of FFA, on the other hand,
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impairs insulin secretion in rodents, but the response to chronic lipids in humans is more variable; in some studies, insulin secretion is maintained or even increased. However, long-term administration of lipids to obese, insulin-resistant adults reduces insulin secretion, though plasma insulin concentrations are increased because insulin clearance is impaired. The response to chronic lipid administration may be conditioned by genetic factors and the prevailing metabolic milieu: In insulin-resistant adult men and women with a strong family history of type 2 diabetes, a four-day infusion of TG emulsion reduced first- and second-phase insulin secretion and hepatic insulin clearance and increased hepatic glucose production. In contrast, chronic lipid administration increased insulin secretion and had no effect on insulin clearance or hepatic glucose production in normal age- and BMI-matched controls [25]. Thus, chronic elevations in FFA likely contribute to beta-cell failure in obese, insulin-resistant subjects predisposed to developing type 2 diabetes. The mechanisms by which lipids induce toxic effects (lipotoxicity) on beta cells remain unclear. FFA and inflammatory cytokines, such as TNF alpha and IL-1 (possibly from macrophages within pancreatic islets), may enhance production of nitric oxide and reactive-oxygen species, which activate beta-cell apoptosis and inhibit glucose-stimulated insulin secretion [26]. Resistance to leptin action may contribute to lipotoxicity, because leptin reduces islet expression of nitric oxide synthetase and maintains expression of islet antiapoptotic genes, including Bcl-2 [22]. In concert with excess glucose, FFA may also impair glucose-stimulated insulin secretion by altering the mitochondrial metabolism of pyruvate. Moreover, hyperglycemia, like hyperlipidemia, increases beta-cell production of reactive-oxygen species and the expression of IL-1 and uncoupling protein-2 [26]. Nutrient- and cytokine-dependent loss of beta-cell mass and function in an insulin-resistant subject lead inexorably to glucose intolerance and ultimately to type 2 diabetes. The relative roles of visceral and subcutaneous fat in the pathogenesis of insulin resistance may vary along racial and ethnic lines. When matched for BMI and total body fat, African American children have less visceral fat than Caucasian children but have lower insulin sensitivity, higher insulin secretion, lower insulin clearance, and higher glucose-disposition index (the product of insulin sensitivity and firstphase insulin secretion) [27, 28]. Yet, the incidence of type 2 diabetes in African American children and adolescents greatly exceeds that in Caucasians. It is currently unclear if the differences in fat distribution and diabetes prevalence reflect genetic variations or environmental influences such as diet, physical activity, or stress [28].
IV. THE ROLES OF DIETARY NUTRIENTS AND EXERCISE IN THE PATHOGENESIS OF TYPE 2 DIABETES A. DIET The role of dietary macronutrients in the pathogenesis of obesity, insulin resistance, and type 2 diabetes is highly controversial. Diets high in saturated fat are typically caloric-rich; many, but not all, studies in adults and children demonstrate that such diets predispose to weight gain, insulin resistance, and hyperinsulinemia [28].
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Conversely, intake of polyunsaturated and monounsaturated fat and long-chain omega-3 fatty acids is associated with improved insulin sensitivity or glucose tolerance. Diets low in saturated fats reduce total energy intake, improve insulin sensitivity, and, in combination with exercise, can reduce significantly the risks of type 2 diabetes and cardiovascular disease in adults with impaired glucose tolerance [29–32]. Yet, recent investigations have shown that obese men and women lost more weight and had more significant reductions in plasma TG concentrations on lowcarbohydrate diets than on conventional low-fat diets [33, 34]. A review of adult studies [35] suggests that the efficacy of low-carbohydrate diets may be related to decreased caloric intake rather than to reduction in carbohydrate intake, per se. Moreover, the effect of a low-carbohydrate diet may diminish with time. Limited evidence suggests that the nature or quality of ingested carbohydrate may modulate weight gain in childhood. The insulin secretory response to foods containing rapidly absorbed, concentrated carbohydrates (high glycemic index) exceeds the response to foods containing protein, fat, and fiber; the postprandial hyperinsulinemia may facilitate weight gain and reduce resting-energy expenditure. The rapid rise and subsequent fall in blood glucose following ingestion of sucrose may precipitate hunger [36], while fructose is lipogenic and delays the oxidation of fatty acids, facilitating fat storage [37]. Studies of the effects of glycemic index on weight gain in children are inconclusive. Still, a 19-month study [38] of Massachusetts school children found a positive correlation between BMI and the consumption of sugar-sweetened drinks, and a modified low-glycemic diet (45 percent to 50 percent carbohydrate, 30 percent to 35 percent fat) reduced BMI Z score and fat mass in a pilot study of seven obese adolescents [39]. Anecdotal evidence suggests that simple elimination of concentrated soft drinks from the diet can reduce caloric intake in some obese adolescents by as much as 500–1000 Kcal/d and thereby facilitate weight reduction. Other macronutrients, vitamins, and trace elements may contribute to diabetes risk. For example, intake of fiber (particularly whole grains and cereal) correlates inversely with the risks of type 2 diabetes and cardiovascular disease [40]. Insoluble and soluble fiber may limit fat absorption and thereby improve glucose tolerance. The intake of magnesium (from whole grains, nuts, and green, leafy vegetables) and dairy products containing vitamin D and calcium may also correlate inversely with diabetes risk in young adults [41, 42].
B. EXERCISE A sedentary lifestyle increases the risk of diabetes, while exercise, in combination with caloric and fat restriction, reduces the rate of progression to diabetes in adults with IGT [29–32]. The mechanisms by which exercise improves insulin sensitivity and glucose tolerance are complex, involving metabolic adaptations in adipose tissue, liver, and skeletal muscle (Figure 11.2) [43]. Exercise has beneficial effects on fat storage and distribution, with losses of visceral-fat depots exceeding those of subcutaneous fat stores. Lean body mass increases, thereby augmenting resting-energy expenditure. A reduction in abdominal-fat mass increases adipose-tissue sensitivity
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Adipose Visceral fat Abdominal SQ fat
Liver
Skeletal muscle
Glucose uptake Glucose output Glycogen synthesis
Lean body mass (REE) Glut 4 expression Glucose uptake Mitochondrial size Mitochondrial enzyme activity FA oxidation Peak VO2 (aerobic activity)
Decreased FFA and TG, increased HDL, increased insulin sensitivity, and improved glucose tolerance Reduced risks of type 2 diabetes and cardiovascular disease
FIGURE 11.2 The beneficial effects of exercise training on carbohydrate and lipid metabolism. SQ, subcutaneous; REE, resting energy expenditure; Glut, glucose transporter.
to insulin; this explains, in part, the reductions in fasting and postprandial free fatty acid, LDL, and TG concentrations and the increase in plasma HDL levels in adults who adhere to a rigorous diet-and-exercise regimen. The effect of exercise on plasma TG is mediated through induction of lipoprotein lipase and reduction in TG production. Exercise increases hepatic glucose uptake and glycogen synthesis and decreases hepatic glucose production, thereby reducing fasting glucose and insulin concentrations. In skeletal muscle, exercise stimulates insulin-dependent glucose uptake and thereby reduces postprandial glucose levels; this action is mediated by increases in muscle GLUT-4 synthesis and induction of GLUT-4 translocation from intracellular pools to the plasma membrane [43]. The induction of GLUT-4 activity may be mediated, in turn, by an increase in cellular levels of adenosine monophosphate (AMP)activated protein kinase (AMPK) [44]. Activation of AMPK after an acute bout of exercise promotes increased cycling of existing GLUT-4 transporters in skeletal muscle, as well as enhanced expression of hexokinase II and mitochondrial enzymes. Several studies suggest that insulin action is related to the oxidative capacity of skeletal muscle. Insulin-resistant individuals (including those with type 2 diabetes) have reduced activities of muscle-oxidative enzymes; aerobic-exercise training increases muscle-oxidative enzyme activity and improves insulin sensitivity by 26 percent to 46 percent. The effect of exercise on oxidative-enzyme activity may reflect, in part, an increase in mitochondrial size [45]. Interestingly, weight loss alone may improve insulin sensitivity, but may not alter fasting rates of lipid oxidation. In contrast, weight loss coupled with exercise increases fat oxidation.
V. COMPLICATIONS OF TYPE 2 DIABETES A. PRESENTING MANIFESTATIONS
AND
ACUTE COMPLICATIONS
As noted previously, children with type 2 diabetes may be asymptomatic when first identified. On the other hand, many have longstanding polyuria and polydipsia, and some have lost weight prior to diagnosis. Presenting manifestations may include
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vaginal candidiasis, superficial bacterial and urinary-tract infections, cervical adenitis, or Bartholin gland abscess. Mild ketoacidosis occurs in 30 percent to 40 percent of African American and Hispanic American children with type 2 diabetes; less commonly, the child presents with nonketotic hyperosmolarity associated with severe hyperglycemia. Obese diabetic children commonly develop fatty liver, which may progress to cirrhosis. Other complications in obese children may include cholecystits, pancreatitis, and pseudotumor cerebri. Many patients have a history of asthma or sleep apnea, which results from upper-airway obstruction (possibly from fat deposition in pharyngeal tissues) and decreased residual lung volume (caused by increased intraabdominal pressure). Menstrual irregularity and mild hirsutism are common in adolescent girls, many of whom may have PCOS. Microalbuminuria may be detected within a short time after diagnosis, particularly in obese, hypertensive adolescents. Some patients have a form of focal glomerulosclerosis.
B. HYPERTENSION, ATHEROGENESIS, AND CARDIOVASCULAR DISEASE IN OBESITY AND TYPE 2 DIABETES The development of insulin resistance and type 2 diabetes have ominous implications for long-term cardiovascular health. Microvascular complications, including neuropathy, retinopathy, and microalbuminuria, all occur with increased frequency in adults with IGT as well as diabetes, and rates of myocardial infarction and stroke are increased twofold to fivefold [46–49]. Obesity, insulin resistance, and type 2 diabetes in childhood predispose to vascular complications in later life. Severe obesity in 9- to 11-year-old children is associated with increased stiffness of the carotid arteries, and obesity in adolescence predisposes to increased carotid intima-media thickness (CIMT) in young adulthood. Weight loss after adolescence may reduce adult CIMT [50]. Even normotensive young people (age 9–12 years) with less-severe obesity (BMI 25±3) may show evidence of brachial-artery endothelial dysfunction and increased CIMT [51]. Among 93 subjects in the Bogalusa Heart Study who underwent autopsy at age 2–39 years, the prevalence of fatty streaks and fibrous plaques in the aorta and coronary arteries increased with age and correlated positively with standard deviation (z) scores for BMI, serum TGs, cholesterol, and blood pressure [52]. The combination of multiple risk factors increased exponentially the extent of arterial intimal surface involvement. Postmortem analysis of more than 3000 subjects who died of natural causes at 15–34 years of age [53] showed that obesity and impaired glucose tolerance were associated with progression of atheromatous lesions in adolescents and young adults. In young men, BMI and abdominal-fat mass correlated with the number and size of fatty streaks and raised lesions in the right and left anterior descending coronary arteries. In both women and men, the extent of fatty streaks correlated with glycohemoglobin concentrations. Severe glucose intolerance likely accelerates the progression of vascular disease; a Canadian study [54] of 52 young adults (age 18–33 years) who developed type 2 diabetes before age 17 showed one with a toe amputation (1.9 percent) and five on dialysis (9.6 percent); two of the latter had died (3.8 percent), and one was blind (1.9 percent).
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Insulin resistance Hyperinsulinemia
Hyperglycemia Dyslipidemia
NOS inhibition PARP activation Cytokines Growth factors Prothrombotic factors
Na, water reabsorption SNS activation
Hypertension Endothelial dysfunction Vasoconstriction Vascular insufficiency Atherogenesis
FIGURE 11.3 The pathogenesis of vascular disease in patients with insulin resistance. NOS, nitric oxide synthase; PARP, poly(ADPribose) polymerase; SNS, sympathetic nervous system.
The pathogenesis of vascular disease involves a complex web of hormones, growth factors, vasoactive agents, cytokines, oxygen radicals, and cellular-adhesion molecules (Figure 11.3) [46, 55, 56]. Under normal conditions, insulin stimulates vasodilatation through induction of nitric oxide synthase (NOS) and generation of NO in vascular endothelial cells. In obesity and other states associated with insulin resistance, the production of NO is disrupted, leading to vasoconstriction and tissue ischemia. Hyperglycemia contributes to endothelial dysfunction and vascular insufficiency through production of superoxide radicals; reactive-oxygen species cause direct endothelial damage and deplete endothelial NO, reducing vascular reactivity. Oxygen radicals also activate poly(ADP ribose) polymerase (PARP), which inhibits glyceraldehyde phosphate dehydrogenase activity and thereby promotes the formation of polyols, glucosamine, and advanced glycation end products and the activation of protein kinase C [57]. These end products promote the development of microvascular and macrovascular disease. Glucose-dependent expression of growth factors (such as VEGF, EGF, and IGF-1) and cytokines (IL-1, IL-6, and TNF alpha) and a reduction in plasma adiponectin concentrations aggravate these effects by stimulating migration and proliferation of smooth-muscle cells and increasing leukocyte adhesion to endothelial surfaces. Reduction in NO availability enhances platelet aggregation and limits fibrinolysis, promoting the progression of atheromatous clots. Increases in the concentrations of the prothrombotic plasminogen activator-1, which is also overexpressed by adipose tissue in obesity, may contribute to fibrin deposition on luminal walls, and production of endothelin-1 in terminal blood vessels is increased, promoting vasoconstriction [56]. These effects are exacerbated by dyslipidemia and hypertension; increases in blood pressure may reflect insulin-dependent increases in sodium, and water reabsorption and activation of the sympathetic nervous system [58]. Reductions in tissue perfusion limit insulin-mediated glucose disposal and may increase circulating glucose concentrations, creating a vicious cycle.
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VI. PREVENTION OF TYPE 2 DIABETES IN HIGH-RISK SUBJECTS A. LIFESTYLE INTERVENTION The first objective in preventing type 2 diabetes is to assess in detail the family history. Particular attention should be focused on those with first- or second-degree family members with type 2 diabetes, hypertension, or early onset cardiovascular disease or stroke. In such cases, early intervention to prevent metabolic complications is essential. Given the risks of adult type 2 diabetes and cardiovascular disease among infants born to diabetic mothers and children born SGA, it is best for a prospective mother to be healthy and lean even before she gets pregnant and to remain healthy and well-nourished during pregnancy. If at all possible, her newborn baby should be breast-fed. The older child should be introduced to healthy meals containing lean meats, chicken and fish, low-fat dairy products, whole grains, green, leafy vegetables, and nuts. Sugary drinks, such as soda, juice, or sweet tea, should be discarded in favor of milk and water, and the intake of fried foods, white bread, pasta, gravy, potatoes, and rice should be limited. In obese subjects, moderate reductions in body-fat mass can reduce the risks of type 2 diabetes and cardiovascular complications if weight loss is accompanied by negative energy balance. Mild caloric restriction is safe for obese children and can be effective when families are motivated and encouraged to change longstanding feeding behaviors. Significant reductions in weight are unusual and often transient unless caloric restriction is accompanied by increased energy expenditure. Nevertheless, even relatively small reductions (5 percent to 10 percent) in BMI z score may increase insulin sensitivity, enhance glucose tolerance, improve measures of cardiovascular health, and reduce the risk of progression to type 2 diabetes [59]. Diets severely restricted in calories produce more dramatic weight loss but cannot be sustained under free-living conditions. Very low-calorie, low-protein diets are potentially dangerous and may precipitate recurrent and futile cycles of dieting and binge eating. The child should be encouraged to remain active, and prolonged sedentary activities (television, computer games) should be discouraged. Family and communal pursuits, such as walking, hiking, bike riding, and ball play, are best for young people. The exercise should be fun and participatory. More intensive and directed exercise may be useful in the setting of obesity. A randomized, modified crossover study [60] of 79 obese children (age 7–11 years) demonstrated that four months of exercise training (40 minutes of activity five days a week) decreased fasting insulin (10 percent) and TG concentrations (17 percent) and reduced percent body fat (5 percent) even in the absence of dietary intervention. The effects on plasma insulin and body fat were reversed when training was discontinued. An eight-week trial of cycle ergometry and resistance training in obese adolescents reduced abdominal (7 percent) and trunk (3.7 percent) fat mass and normalized flow-mediated dilation of the brachial artery [61]. Exercise exerts beneficial effects on general cardiovascular health and, in combination of a low-saturated-fat diet, may reverse hepatic steatosis.
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The capacity for voluntary exercise declines as BMI rises. It is therefore critical to begin regular exercise before the child becomes morbidly obese and functionally immobile. Benefits from lifestyle intervention are most likely to be reaped when diet-andexercise programs are coordinated with individual and family counseling and behavior modification. School-based programs, supported by community groups and by state and federal agencies, may assist families and reduce the child’s sense of isolation, frustration, and guilt.
B. PHARMACOTHERAPY
IN
DIABETES PREVENTION
Unfortunately, the long-term success of lifestyle intervention has been disappointing; rates of obesity and insulin resistance in children and adults continue to increase despite widespread recognition of the dangers of dietary indiscretion and a sedentary existence. This may reflect, in part, the resistance of complex feeding and activity behaviors to change, as well as the power of social and economic forces that shape lifestyles in the modern, industrialized world. Metabolic and hormonal adaptations to initial weight loss may also create barriers to long-term success; for example, reductions in food intake and body weight decrease the circulating concentrations of tri-iodothyronine (T3) and leptin and increase circulating concentrations of ghrelin. The fall in T3 and leptin levels limits energy expenditure and sympathetic nervous-system activity, and may facilitate rebound food intake. Hunger may be intensified by the rise in plasma ghrelin, which stimulates food intake [62]. Food restriction also causes a secondary resistance to growth hormone (GH) action and an increase in insulin sensitivity that may reduce the rates of lipolysis and fat breakdown [63, 64]. The obstacles to success with lifestyle intervention have stimulated interest in pharmacologic approaches to diabetes prevention in obese children. Studies of pharmacoprevention have focused on drugs that limit nutrient absorption and on agents that reduce insulin production through enhanced insulin action. Only a few investigations have been performed in children, though initial findings are consistent with those in adults. 1. Drugs that Limit Nutrient Absorption Orlistat inhibits pancreatic lipase and thereby increases fecal losses of TG. Orlistat reduces body weight and total and LDL cholesterol levels, and reduces the risk of type 2 diabetes in adults with impaired glucose tolerance. In obese adolescents, the combination of orlistat with lifestyle intervention reduced weight (–4.4 ± 4.6 kg), BMI, total-cholesterol, LDL, fasting-insulin, and fasting-glucose concentrations, and increased insulin sensitivity during a three-month trial period [65]. There was considerable variability in response to the drug. Variable reductions in body weight (–12.7 to +2.5 kg) and fat mass were also noted in a study of 11 morbidly obese children age 7–12 years. Side effects are tolerable as long as subjects reduce fat intake, but vitamin A, D, and E levels may decline despite multivitamin supplementation. High study-dropout rates (25 percent or more) suggest that long-term fat
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restriction is problematic in teenagers; dietary noncompliance results in flatulence and diarrhea that ultimately prove unacceptable. Acarbose, an alpha glucosidase inhibitor, may reduce progression to type 2 diabetes by limiting gastrointestinal absorption of carbohydrate. The STOP-NIDDM trial [66] demonstrated a 25 percent to 36 percent reduction in type 2 diabetes in obese adults (mean age 55 years, mean BMI 31) with impaired glucose tolerance. Postprandial glucose and insulin concentrations were reduced and weight declined slightly in patients treated with acarbose (100 mg tid) for a mean of 3.3 years. In addition, the rate of development of cardiovascular events (coronary heart disease, cardiovascular death, congestive heart failure, stroke, and peripheral vascular disease) was only onehalf that in the placebo group. However, the drop-out rate in the acarbose group was 24 percent, and the gastrointestinal side effects of the medication, which include flatulence and diarrhea, limit its acceptability in children and adolescents. 2. Insulin Suppressors and Sensitizers The synthesis and storage of TG in adipose tissue is stimulated by insulin. Thus, increases in nutrient-dependent insulin production and fasting hyperinsulinemia may contribute to fat storage and limit fat mobilization. By reducing fasting or postprandial insulin concentrations, certain pharmacologic agents may prove beneficial in the treatment of obese children and adults. a. Metformin Metformin is a bisubstituted, short-chain hydrophilic guanidine derivative that works through activation of AMP protein kinase [67]. Its major site of action is the liver: The drug increases hepatic glucose uptake, decreases gluconeogenesis, and reduces hepatic glucose production (Figure 11.4) [68, 69]. Metformin increases
Metformin
TZDs
Hepatic glucose uptake
Increased
Variable increase
HGP
Decreased
Variable decrease
Adipose glucose uptake
Variable/negligible
Increased (SQ > Visc)
Lipolysis, FFA, and TG
Variable/negligible
Decreased
Fat stores
Decreased SQ > Visc
Decreased Visc, Incr SQ
Adiponectin
No effect
Increased In
Skeletal mm glu uptake
No effect
Increased In
Total insulin sensitivity
Variable
Increased
Food intake
Decreased
No effect
Body weight
Mild decrease
Mild-mod increase
Glucose tolerance
Improved
Improved
FIGURE 11.4 Metabolic effects of metformin and the thiazolidinediones (TZDs). HGP, hepatic glucose production; FFA, free fatty acids; TG, triglycerides; glu, glucose; SQ, subcutaneous; Visc, visceral.
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insulin-receptor binding, but has variable and often only minor effects on peripheral insulin sensitivity; there is no effect on skeletal-muscle glucose uptake or plasmaadiponectin concentrations [68, 69]. Major benefits of the drug include decreased food intake, weight loss, decreased fat stores (subcutaneous > visceral), and improved lipid profiles. The drug also reduces liver enzymes in patients with hepatic steatosis [70]. Of even greater importance, long-term studies suggest that metformin reduces cardiovascular morbidity and mortality in diabetic adults [71]. In obese adults with normal glucose tolerance, and in obese women with PCOS, treatment with metformin reduced daily food intake, body weight, body fat, and plasma-leptin concentrations, and downward trends were noted in LDL and total plasma cholesterol [72–74]. In normal-weight (BMI ≤ 25), postmenarchal, young (13.6–22 years old) women with ovarian hyperandrogenism, hyperinsulinemia, and normal glucose tolerance, metformin increased insulin sensitivity and reduced plasma insulin, TG, and testosterone levels and the ratio of LDL to HDL. The addition of flutamide, an androgen antagonist, potentiated the effects of metformin on TG, LDL/HDL, and adrenal-androgen concentrations and markedly reduced hirsutism scores. The combination of metformin and flutamide reduced abdominal and total body-fat mass and increased lean body mass despite reductions in plasma GH and IGF-1 levels [75–77]. There have been two randomized, double-blind, placebo-controlled studies of metformin in obese adolescents with insulin resistance, normal glucose tolerance, and a positive family history of type 2 diabetes. In the first trial (n = 29), metformin reduced BMI Z score (3.6 percent relative to placebo controls), plasma leptin, and fasting glucose (–9.8 mg%) and insulin (–12 uU/ml), even in the absence of dietary intervention [78]. Since increases in BMI and fasting glucose and insulin concentrations predict the development of type 2 diabetes in target populations [79], these findings suggested that metformin might prove useful in preventing glucose intolerance in high-risk adolescents. In the second trial (n = 24), the combination of a low-calorie diet (1500–1800 kcal/day for girls and boys, respectively) and metformin reduced weight by 6.5 percent; diet alone caused a 3.8 percent weight loss [80]. Patients treated with metformin had greater decline in body fat (–6 percent versus –2.7 percent in the placebo group), a decrease in plasma leptin levels, a 50 percent decrease in plasma insulin concentrations, and increased insulin sensitivity as determined by fasting and two-hour glucose and insulin levels. Plasma cholesterol and TG levels also declined by 22 percent and 39 percent, respectively. These findings suggested that metformin and diet may act synergistically to limit weight gain and increase glucose tolerance in obese, insulin-resistant adolescents. The recently completed Diabetes Prevention Program [32] established the efficacy of metformin in delaying or preventing the onset of type 2 diabetes in adults (age ≥ 25 years) with IGT. The 3,234 subjects were randomly assigned to one of three interventions. These included: a placebo group that received standard lifestyle recommendations; a metformin-treated group (850–1700 mg/d) that received standard lifestyle recommendations; and a group that received an intensive program of lifestyle modification. A fourth, troglitazone-treated group was disbanded after the
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placebo metformin type2 diabetes (cases/100 persons-yr)
lifestyle 15 10 * 5
* **
*
*
*
0 overall
age 25-44
BMI > 34.9
* Differed significantly from placebo ** Differed significantly from metformin or placebo
FIGURE 11.5 Effects of metformin and intensive lifestyle intervention on rates of type 2 diabetes in adults with IGT. Data adapted from Knowler et al., Diabetes Prevention Program, N. Eng. J. Med., 346, 393, 2002. With permission.
development of severe hepatotoxicity in a small number of subjects. The experimental groups were studied for 1.8–4.6 years. Daily energy and fat intake decreased only in the group randomized to intensive lifestyle modification. Nevertheless, patients in the metformin group also lost weight, though not as much as those in the intensive-lifestyle group. In both groups, weight loss was most significant in the first 6–12 months of the study. The changes in body weight were accompanied by reductions in the rates of progression from IGT to type 2 diabetes. The three-year cumulative incidence of diabetes was 28.9 percent in the placebo group, 21.7 percent in the metformin-treated group, and 14.4 percent in the intensive-lifestyle group. Overall, therefore, intensive-lifestyle intervention was more effective than metformin. However, metformin was as effective as lifestyle change in subjects with BMI exceeding 34.9 and in those with highest fasting-glucose concentrations (Figure 11.5); these subgroups are at greatest risk for progression to type 2 diabetes. Metformin was also as effective as a lifestyle intervention in younger adults aged 25–44 years. On the other hand, treatment effects did not vary according to gender, race, or ethnic group. In addition to reducing the risk of development of type 2 diabetes, intensive-lifestyle intervention and metformin also had favorable, albeit small effects on blood pressure and serum lipids. Metformin was well-tolerated by the majority of subjects, though many patients had transient abdominal discomfort which can be prevented by taking the medication with food. There were no instances of hepatic dysfunction or lactic acidosis; nevertheless, the drug should not be administered to patients with underlying cardiac, hepatic, renal, or gastrointestinal disease. The major effects of lifestyle intervention and metformin were exerted within the first 12–18 months of the study. After the first year, fasting blood-glucose concentrations, HbA1c concentrations, and rates of diabetes increased in both the intensive-lifestyle and metformin groups, and the slopes of the intervention and
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treatment curves after the first year appeared to parallel the slope of the placebo group. This finding suggests that the interventions may delay, rather than truly prevent, the development of type 2 diabetes. Nevertheless, studies performed in nondiabetic subjects one to two weeks after the trial’s conclusion showed that the protective effect of metformin persisted in three-fourths of the drug-treated subjects even after discontinuation of medication. The duration of this protective effect is unknown; prolonged treatment with metformin might be necessary to reduce the rate of progression to diabetes in high-risk subjects. b. Thiazolidinediones The thiazolidinediones (TZDs) regulate lipid and carbohydrate metabolism through binding to peroxisome proliferator-activated receptor (PPAR)-γ. When activated by TZDs, PPAR-γ heterodimerizes with the retinoid X receptor and binds to the promoters of target genes, including lipoprotein lipase, fatty-acid transport protein, acetyl-CoA-synthase, and aP2 [81]. The major effects of the TZDs are exerted in adipose tissue and skeletal muscle (Figure 11.4) [19, 86]. The drugs induce the differentiation of small, insulin-sensitive adipocytes, increase adipose tissue insulinreceptor number, adiponectin expression, and glucose uptake, and reduce expression of TNF alpha and, in mice, resistin. Rates of lipolysis and FFA release are reduced, TG clearance is enhanced, and hepatic VLDL synthesis decreases. Circulating TG levels decline during treatment with pioglitazone and, to a lesser extent, with rosiglitazone. With adipogenic and antilipolytic actions, the TZDs increase total body-fat mass and body weight; however, the ratio of lower body/subcutaneous (SQ) fat to upper-body/visceral fat may rise [82]. TZDs potentiate the effects of insulin on skeletal-muscle glucose uptake through induction of glucose transporters (GLUTs) 1 and 4 [83]. These actions require the presence of insulin and may be mediated by activation of phosphatidylinositol (PI) 3-kinase. Glucose tolerance improves in type 2 diabetic patients treated with TZDs; plasma insulin concentrations decline, while plasma adiponectin levels rise. The rise in adiponectin, in concert with direct effects of the TZDs on the vascular endothelium, reduces carotid intimal medial thickness and increases arterial distensibility. TZDs also reduce plasma C-reactive protein concentrations in diabetic patients and the percentage of small dense LDL levels in diabetic and nondiabetic hypertensive adults [81–83]. In theory, these changes reduce the risk of development and progression of atheromatous lesions. A few studies have examined the effects of the TZDs on glucose tolerance, lipid profiles, and other cardiovascular risk factors in nondiabetic adults and in women with PCOS. No such investigations have been performed in children or adolescents. In obese, non-diabetic subjects [84], troglitazone decreased insulin resistance and improved glucose tolerance. Rates of glucose disposal and the insulin-sensitivity index increased while glycemic responses to oral glucose declined. The mean fasting insulin concentrations decreased by 48 percent, and the plasma insulin responses to oral glucose and mixed meals decreased by 40 percent and 41 percent, respectively. Other studies showed that TZDs reduced blood pressure in nondiabetic obese adults. In women with PCOS, a three-month trial of troglitazone reduced fasting glucose and insulin concentrations and improved, but did not normalize, whole-body insulin
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sensitivity. Troglitazone also improved endothelial function as measured by leg blood flow. The results of these studies indicate that the TZDs increase insulin sensitivity, improve glucose tolerance, and reduce cardiovascular risk in insulin-resistant adults and in women with PCOS. That the TZDs, like metformin, can reduce the risk of type 2 diabetes in target populations was established in the TRIPOD study [85], a randomized, placebo-controlled, double-blind investigation of women with IGT. The experimental group consisted of Latino women with a history of gestational diabetes and IGT at the time of initiation of the study. During the 30-month investigation, annual diabetes incidence rates were 12.1 percent in the placebo group and 5.4 percent in the troglitazone group. Those with an increase in whole-body insulin sensitivity following initiation of troglitazone were most likely to benefit. Interestingly, protection from diabetes persisted for at least three to eight months after the drug was discontinued. This finding suggested that troglitazone may have altered the natural progression of diabetes and not simply masked progression through a pharmacologic action. As with metformin, the duration of this protective action is currently unknown. Unfortunately, troglitazone was removed from the commercial market because the drug caused fatal hepatic failure in a small number of subjects. Nonlethal hepatotoxicity has also been reported with other currently available TZDs, though at a far lower frequency than with troglitazone. Hepatic dysfunction must be excluded before TZD therapy is initiated, and liver function tests should be measured monthly for the first six months of treatment, every two months for the remainder of the first year, and at regular intervals thereafter. Other potential complications of TZD therapy include edema and anemia, so the drug should not be administered to patients with underlying cardiac disease. 3. Other Pharmacologic Approaches Pharmacologic agents currently in use indirectly target the complications of insulin resistance. Animal studies suggest that approaches that directly target metabolic signaling and cytokine production may prove useful in the prevention of type 2 diabetes and cardiovascular disease. An appealing therapeutic candidate is the adipocytokine adiponectin. Adiponectin levels decline in obesity and other states accompanied by insulin resistance but rise following treatment with thiazolidinediones. Administration of recombinant adiponectin to obese mice reduces blood-glucose and insulin concentrations, increases insulin sensitivity and hepatic fatty-acid oxidation, reduces hepatic fattyacid synthesis, reverses hepatic steatosis, and decreases body weight [86]. Targeting of oxygen radicals and PARP also shows promise. Activation of PARP by glucose-induced oxidative stress inhibits glyceraldehyde phosphate dehydrogenase activity and may thereby promote the formation of polyols, glucosamine, and advanced glycation end products and the activation of protein kinase C [87]. These metabolites mediate glucose-dependent endothelial dysfunction. In animal models of diabetes, the pharmacological inhibition of PARP improves endothelial function.
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It is likely that future investigations will identify new targets and pharmacotherapeutic agents that will prevent long-term complications in high-risk patients. 4. Recommendations Regarding Pharmacotherapy in Diabetes Prevention In the opinion of the author, pharmacologic therapy should be considered for severely resistant or glucose-intolerant (IFG or IGT) children or adolescents who fail to respond to a 6- to 12-month trial of lifestyle intervention despite a good-faith effort. Good-faith effort means that the patient has attempted to follow a low-saturatedfat/low-calorie diet recommended by a dietary counselor and has increased his or her energy expenditure through regular exercise. Unsuccessful means that the elevations of fasting or postprandial glucose persist or worsen despite lifestyle intervention. The decision to initiate drug therapy relieves neither the child nor the physician of the commitment to long-term lifestyle change; thus, diet-and-exercise regimens should be maintained, even if they had not proven effective in the absence of medication. Given its proven efficacy in treating insulin-resistant, as well as diabetic, adolescents, adults, and women with PCOS, its track record of safety in men and women, and its ability to limit weight gain, the author considers metformin the drug of choice for treating the obese child with severe insulin resistance, IFG, or IGT. Though lactic acidosis is extraordinarily rare in pediatric patients, metformin should not be administered to children with underlying cardiac, hepatic, renal, or gastrointestinal disease. Obese subjects with mild elevations in hepatic enzymes (less than threefold higher than established norms) may receive the drug; indeed, some studies suggest that metformin may be useful in treatment of hepatic steatosis. Concurrent use of a multivitamin seems reasonable, because metformin increases urinary excretion of vitamins B1 and B6. Given the lack of studies of TZDs in insulin-resistant children or adolescents, their potential, albeit rare, for severe hepatic complications, and their tendency to cause weight gain, the author would limit the use of TZDs to adolescents who fail to respond to, or cannot tolerate, metformin. Since the danger of hepatic dysfunction with combined therapy in pediatric patients is unknown, the TZDs should not be used in conjunction with metformin in nondiabetic children pending demonstration in long-term studies that the drug combination is safe. TZDs are contraindicated in patients with preexisting hepatic or cardiac disease. Orlistat, acarbose, and other inhibitors of nutrient absorption are not tolerated by many adolescents, but may be useful in highly motivated subjects. It is not possible at this time to provide firm or uniform guidelines regarding the duration of pharmacologic intervention. A trial off medication may be warranted if glucose tolerance is normalized, particularly if there has been a decline in BMI z score. If IGT persists despite compliance with the medical/pharmacologic regimen, it may be necessary to intensify lifestyle intervention and to increase the dose of medication. If glucose tolerance declines or the patient develops overt diabetes, it may be necessary to add insulin or another pharmacologic agent to the therapeutic regimen.
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VII. PHARMACOLOGIC TREATMENT OF TYPE 2 DIABETES Some have argued that the pharmacologic treatment of type 2 diabetes in children and adolescents should be similar to that of type 2 diabetes in adults. However, differences in disease presentation and course argue for a distinct approach to treatment of childhood type 2 diabetes. Many adults with type 2 diabetes are diagnosed after a prolonged course characterized by mild or moderate symptomatology. At the time of diagnosis, many have beta-cell failure, insulin deficiency, and established vascular complications. In contrast, most children and adolescents with type 2 diabetes are identified before beta-cell function is exhausted. In such cases, it is essential to rapidly normalize blood-glucose concentrations and correct dyslipidemia in order to prevent beta-cell glucotoxicity and lipotoxicity; in theory, this should prolong beta-cell lifespan, enhance glycemic stability, and limit long-term complications. Rapid normalization of blood-glucose concentrations generally requires insulin administration, particularly if there is ketosis at diagnosis. Once near-normoglycemia is established, it is useful to begin metformin, increasing the dose gradually until maximal tolerated levels are achieved. The dose of insulin can then be reduced, facilitating weight loss in combination with lifestyle intervention. This author maintains low-level insulin therapy indefinitely if plasma C-peptide concentrations are marginal or low. Insulin corrects the insulin deficiency observed in patients with long-standing disease and can prevent the ketosis that may recur in some children and adolescents with type 2 diabetes. Clinical studies in adults suggest that blood-glucose control in type 2 diabetes may be facilitated by the addition of amylin at mealtimes [89]. Amylin is a betacell hormone that reduces postprandial hyperglucagonemia, slows gastric emptying, and reduces food intake. Amylin may reduce postprandial glucose excursions and limit weight gain, but the hormone increases the risk of severe hypoglycemia, nausea, and headache. Metformin is not tolerated in a minority of subjects. In such cases, a thiazolidinedione may prove useful. However, thiazolidinediones are not approved for use in children and may cause weight gain, edema, and hepatic dysfunction. Ongoing studies will assess the benefits and risks of TZDs and combination therapy (metformin plus TZD) in children with type 2 diabetes. Sulfonylureas are mainstays of therapy in adults with type 2 diabetes. Their use as primary agents for treatment of type 2 diabetic children is currently under investigation. However, sulfonylureas increase the risk of weight gain and severe hypoglycemia; in the opinion of the author, the preferred hypoglycemic agent in (particularly obese) children is insulin itself.
VIII. A MULTIFACETED APPROACH TO PREVENTION OF COMPLICATIONS The major causes of death in adults with type 2 diabetes are myocardial infarction and stroke. Although cardiovascular risk in patients with type 2 diabetes varies with
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glycemic control, other factors play equal or more important roles. These include obesity, hypertension, smoking, dyslipidemia, ethnic background, and family history. In theory, aggressive lifestyle intervention in children and adolescents should include abolition of smoking and reduction in the intake of caffeine, which may raise blood pressure and postprandial glucose concentrations. Pharmacologic therapy may be necessary to reduce blood pressure, control microalbuminuria, and treat dyslipidemia. A multifaceted approach that combined dietary counseling, statins, angiotensin-converting enzyme inhibitors, and low-dose aspirin reduced by 50 percent to 60 percent the long-term (eight-year) risks of nephropathy, retinopathy, autonomic neuropathy, and cardiovascular end points (myocardial disease, stroke, and amputation) in diabetic adults with microalbuminuria [90]. Such an approach may be necessary in the management of obese, insulin-resistant, and glucose-intolerant adolescents, who are commonly hypertensive and hyperlipidemic. The age and intensity of intervention may depend upon the family history of cardiovascular disease, as well as the severity of problems in the individual teenager under the physician’s care.
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41. Pereira, MA, Jacobs, DR, Van Horn, L, Slattery, ML, Kartashov, AI, and Ludwig, DS, Dairy consumption, obesity and the insulin resistance syndrome in young adults: the CARDIA Study, JAMA, 287, 2081, 2002. 42. Rodriguez-Moran, M and Guerrero-Romero, F, Oral magnesium supplementation improves insulin sensitivity and metabolic control in type 2 diabetic subjects: a randomized double-blind controlled trial, Diabet. Care, 26, 1147, 2003. 43. Spriet, LL and Watt, MJ, Regulatory mechanisms in the interaction between carbohydrate and lipid oxidation during exercise, Acta. Physiol. Scand., 178, 443, 2003. 44. McGee, SL, Howlett, KF, Starkie, RL, Cameron-Smith, D, Kemp, BE, and Hargreaves, M, Exercise increases nuclear AMPK in human skeletal muscle, Diabetes 52, 926, 2003. 45. Santoro, C, Cosmas, A, Forman, D, Morghan, A, Bairos, L, Levesque, S, Roubenoff, R, Hennessey, J, Lamont, L, and Manfredi, T, Exercise training alters skeletal muscle mitochondrial morphometry in heart failure patients, J. Cardiovasc. Risk, 9, 377, 2002. 46. Singleton, JR, Smith, AG, Russell, JW, and Feldman, EL, Microvascular complications of impaired glucose tolerance, Diabetes, 52, 2867, 2003. 47. Kuller, LH, Velentgas, P, Barzilay, J, Beauchamp, NJ, O’Leary, DH, and Savage, PJ, Diabetes mellitus: subclinical cardiovascular disease and risk of incident cardiovascular disease and all-cause mortality, Arterioscler. Thromb. Vasc. Biol., 20, 823, 2000. 48. Haffner, SM, Lehto, S, Ronnemaa, T, Pyorala, K, and Laasko, M, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, N. Engl. J. Med., 339, 229, 1998. 49. Bonora, E, Kiechl, S, Willeit, J, Oberhollenzer, F, Egger, G, Bonadonna, RO, and Muggeo, M, Carotid atherosclerosis and coronary heart disease in the metabolic syndrome: prospective data from the Bruneck Study, Diabet. Care, 26, 1251, 2003. 50. Oren, A, Vos, LE, Uiterwaal, CSPM, Gorissen, WHM, Grobbee, DE, and Bots, ML, Change in body mass index from adolescence to young adulthood and increased carotid intima-media thickness at 28 year of age: The Atherosclerosis Risk in Young Adults study, Int. J. Obes., 27, 1383, 2003. 51. Woo, KS, Chook, P, Yu, CW, Sung, RYT, Qiao, M, Leung, SSF, Lam, CWK, Metreweli, C, and Celermajer, DS, Overweight in children is associated with arterial endothelial dysfunction and intima-media thickening, Int. J. Obes., 28, 852, 2004. 52. Berenson, GS, Srinivasan, SR, Bao, W, Newman, WP III, Tracy, RE, and Wattigney, WA, Association between multiple cardiovascular risk factors and atherosclerosis in children and young adults, N. Engl. J. Med., 338, 1650, 1998. 53. McGill, HC, Jr., McMahan, CA, Herderick, EE, Zieske, AW, Malcom, GT, Tracy, RE, and Strong, JP, Pathological Determinants of Atherosclerosis in Youth (PDAY) Research Group. Obesity accelerates the progression of coronary atherosclerosis in young men, Circulation, 105, 2712, 2002. 54. Dean, H and Flett, B, Natural history of type 2 diabetes diagnosed in childhood: long term follow up in young adult years. Presented at 62nd Scientific Sessions, San Francisco, June 2002. 55. Vincent, MA, Montagnani, M, and Quon, MJ, Molecular and physiologic actions of insulin related to production of nitric oxide in vascular endothelium, Curr. Diab. Rep., 3, 279, 2003. 56. Deedwania, PC, Mechanisms of endothelial dysfunction in the metabolic syndrome, Curr. Diab. Rep., 3, 289, 2003.
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57. Du, XL, Matsumura, T, Edelstein, D, Rossetti, L, Zsengeller, Z, Szabo, C, and Brownlee, M, Inhibition of GAPDH activity by poly (ADPribose) polymerase activates three major pathways of hyperglycemic damage in endothelial cells, J. Clin. Invest., 112, 1049, 2003. 58. Montani, JP, Antic, V, Yang, Z, and Dulloo, A, Pathways from obesity to hypertension: from the perspective of a vicious triangle, Int. J. Obes., 26, s28, 2002. 59. Long SD, O’Brien K, MacDonald KG, Leggett-Frazier N, Swanson MS, Pories WJ, and Caro JF. Weight loss in severely obese subjects prevents the progression of impaired glucose tolerance to type 2 diabetes. A longitudinal interventional study. Diabetes Care, 17, 372, 1994. 60. Ferguson, MA, Gutin, B, Le, NA, Karp, W, Litaker, M, Humphries, M, Okuyama, T, Riggs, S, and Owens, S, Effects of exercise training and its cessation on components of the insulin resistance syndrome in obese children, Int. J. Obes., 22, 889, 1999. 61. Watts, K, Beye, P, Siafarikas, A, Davis, EA, Jones, TW, O’Driscoll, G, and Green, DJ, Exercise training normalizes vascular dysfunction and improves central adiposity in obese adolescents, J. Amer. Coll. Cardiol., 2004, in press. A parallel study in obese pre-teens is in press in the J. of Pediatr. 62. Inui, A, Asakawa, A, Bowers, CY, Mantovani, G, Laviano, A, Meguid, MM, and Fujimiya, M, Ghrelin, appetite, and gastric motility: the emerging role of the stomach as an endocrine organ, FASEB J., 18, 439, 2004. 63. Douyon, L and Schteingart, DE, Effect of obesity and starvation on thyroid hormone, growth hormone and cortisol secretion, Endocrinol. Metab. Clin. North. Am., 31, 173, 2002. 64. Kratzsch, J, Dehme, B, Pulzer, F, Keller, E, Englaro, P, Blum, WF, and Wabitsch, M, Increased serum GHBP levels in obese pubertal children and adolescents: relationship to body composition, leptin and indicators of metabolic disturbances, Int. J. Obes., 21, 1130, 1997. 65. Norgren, S, Danielsson, P, Jurold, R, Lotborn, M, and Marcus, C, Orlistat treatment in obese prepubertal children: a pilot study, Acta. Paediatr., 92, 666, 2003. 66. Chiasson, JL, Josse, RG, Gomis, R, Hanefeld, M, Karasik, A, and Laakso, M, STOPNIDDM Trial Research Group, Acarbose treatment and the risk of cardiovascular disease and hypertension in patients with impaired glucose tolerance: the STOPNIDDM trial, JAMA, 290(4), 486, 2003. 67. Zhou, G, Myers, R, Li, Y, Chen, Y, Shen, X, Fenyk-Melody, J, Wu, M, Ventre, J, Doebber, T, Fujii, N, Musi, N, Hirshman, MF, Goodyear, LJ, and Moller, DE, Role of AMP-activated protein kinase in mechanism of metformin action, J. Clin. Invest., 108, 1167, 2001. 68. Hallsten, K, Virtanen, KA, Lonnqvist, F, Sipila, H, Oksanen, A, Viljanen, T, Ronnemaa, T, Viikari, J, Knuuti, J, and Nuutila, P, Rosiglitazone but not Metformin enhances insulin-and exercise-stimulated skeletal muscle glucose uptake in patients with newly diagnosed type 2 diabetes, Diabetes, 51, 3479, 2002. 69. Virtanen, KA, Hallsten, K, Parkkola, R, Janatuinen, T, Lonnqvist, F, Viljanen, T, Ronnemaa, T, Knuuti, J, Huupponen, R, Lonnroth, P, and Nuutila, P, Differential effects of rosiglitazone and metformin on adipose tissue distribution and glucose uptake in type 2 diabetic subjects, Diabetes, 52, 283, 2003. 70. Schwimmer, JBMM, Deutsch, R, and Lavine, JE, Metformin as a treatment for nondiabetic NASH, J. Pediatr. Gastroenterol., 37, 342, 2003. 71. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), UK Prospective Diabetes Study (UKPDS) Group, Lancet, 352, 854, 1998.
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72. Paolisso, G, Amato, L, Eccellente, R, Gambardella, M, Tagliamonte, MR, Varricchio, G, Carrella, C, Giugliano, D, and D’Onofrio, F, Effect of metformin on food intake in obese subjects, Eur. J. Clin. Invest., 28(6), 441, 1998. 73. Glueck, CJ, Fontaine, RN, Wang, P, Subbiah, MTR, Weber, K, Illig, E, Streicher, P, Sieve-Smith, L, Tracy, TM, Lang, JE, and McCullough, P, Metformin reduces weight, centripetal obesity, insulin, leptin, and low-density lipoprotein cholesterol in nondiabetic, morbidly obese subjects with body mass index greater than 30, Metabolism, 50, 856, 2001. 74. Pasquali, R, Gambineri, A, Biscotti, D, Vicennati, V, Gagliardi, L, Colitta, D, Fiorini, S, Cognigni, GE, Filicori, M, and Morselli-Labate, AM, Effect of long-term treatment with metformin added to hypocaloric diet on body composition, fat distribution, and androgen and insulin levels in abdominally obese women with and without the polycystic ovary syndrome, J. Clin. Endocrinol. Metab., 85, 2767, 2000. 75. Ibanez, L, Valls, C, Potau N, Marcos MV, and deZegher F, Sensitization to insulin in adolescent girls to normalize hirsutism, hyperandrogenism, oligomenorrhea, dyslipidmeia and hyperinsulinism after precocious pubarche, J. Clin. Endocrinol. Metab., 85, 3526, 2000. 76. Ibanez, L, Valls, C, Ferrer, A, Ong, K, Dunger, DB, and DeZegher, F, Additive effects of insulin-sensitizing and anti-androgen treatment in young, nonobese women with hyperinsulinism, hyperandrogenism, dyslipidemia, and anovulation, J. Clin. Endocrinol. Metab., 87, 2870, 2002. 77. Ibanez, L, Ong, K, Ferrer, A, Amin, R, Dunger, D, and deZegher, F, Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism, J. Clin. Endocrinol. Metab., 88:2600, 2003. 78. Freemark, M and Bursey, D, The effects of metformin on body mass index and glucose tolerance in obese adolescents with fasting hyperinsulinemia and a family history of type 2 diabetes, Pediatrics, 107(4), e55, 2001. 79. Freemark, M, Pharmacologic approaches to the prevention of type 2 diabetes in high risk pediatric patients, J. Clin. Endocrinol. Metab., 88, 3, 2003. 80. Kay, JP, Alemzadeh, R, Langley, G, D’Angelo, L, Smith, P, and Holshouser, S, Beneficial effects of metformin in normoglycemic morbidly obese adolescents, Metabolism, 50, 1457, 2001. 81. Spiegelman, BM, PPAR-gamma: Adipogenic regulator and thiazolidinedione receptor, Diabetes, 47, 507, 1998. 82. Gurnell, M, Savage, DB, Chatterjee, KK, and O’Rahilly, S, The metabolic syndrome: PPAR gamma and its therapeutic modulation, J. Clin. Endocrinol. Metab., 88, 2412, 2003. 83. Hauner, H, The mode of action of thiazolidinediones, Diabet. Metab. Res. Rev., 18, Suppl. 2, S10, 2002. 84. Nolan, JJ, Ludvik, B, Beerdsen, P, Joyce, M, and Olefsky, J, Improvement in glucose tolerance and insulin resistance in obese subjects treated with troglitazone, N. Engl. J. Med., 331, 1188, 1994. 85. Buchanan, TA, Xiang, AH, Peters, RK, Kjos, SL, Marroquin, A, Goico, J, Ochoa, C, Tan, S, Berkowitz, K, Hodis, HN, and Azen, SP, Preservation of pancreatic (beta)cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women, Diabetes, 51, 2796, 2002. 86. Berg, AH, Combs TP, Du, X, Brownlee M, and Scherer, PE, The adipocyte-secreted protein Acrp30 enhances hepatic insulin action, Nat. Med., 7, 947, 2001.
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87. Soriano, FG, Pacher, P, Mabley, J, Liaudet, L, and Szabo, C, Rapid reversal of the diabetic endothelial dysfunction by pharmacological inhibition of poly (ADPribose) polymerase, Circ. Res., 89, 684, 2001. 88. Artz, E and Freemark, M. The pathogenesis of insulin resistance in children: metabolic complications and the roles of diet, exercise and pharmacotherapy in the prevention of type 2 diabetes, J. Pediatr. Endocronol. Metab., 3, 296, 2004. 89. Hollander, PA, Levy, P, Fineman, MS, Maggs, DG, Shen, LZ, Strobel, SA, Weyer, C, and Kolterman, OC, Pramlintide as an adjunct to insulin therapy improves longterm glycemic and weight control in patients with type 2 diabetes, Diabet. Care, 26, 784, 2003. 90. Gaede, P, Vedel, P, Larsen, N, Jensen, GV, Parving, HH, and Pedersen, O, Multifactorial intervention and cardiovascular disease in patients with type 2 diabetes. N. Engl. J. Med., 348, 383, 2003.
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Management of ObesityAssociated Type 2 Diabetes Lillian F. Lien, M.D., and Mark N. Feinglos, M.D., C.M.
CONTENTS I. Pathophysiology: Dietary Effects on Subjects at Risk for the Development of Obesity-Induced Diabetes Mellitus Type 2 ...................206 A. Animal Studies ..................................................................................206 B. Human Studies – Dietary Fat............................................................208 C. Human Studies – Dietary Carbohydrate...........................................209 II. Nutritional Management of Patients with Obesity-Associated DM 2: Macronutrient Composition...........................................................210 A. Low-Fat Diets....................................................................................210 B. Modified Fat/High-Monounsaturated Fatty Acid (MUFA) Diets ...................................................................................212 C. Low-Carbohydrate Diets ...................................................................213 D. High-Protein Diets.............................................................................218 III. Pharmacologic Management Options: From Diet with Exercise to Oral Agents to Insulin ............................................................220 A. Oral Hypoglycemic Agents...............................................................220 1. Biguanides ...................................................................................220 2. Sulfonylureas ...............................................................................221 3. Thiazolidinediones ......................................................................222 4. Other Oral Hypoglycemic Agents ..............................................222 B. Insulin Therapy..................................................................................222 IV. Conclusion .................................................................................................223 References..............................................................................................................223
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I. PATHOPHYSIOLOGY: DIETARY EFFECTS ON SUBJECTS AT RISK FOR THE DEVELOPMENT OF OBESITY-INDUCED DIABETES MELLITUS TYPE 2 A. ANIMAL STUDIES The impact of dietary factors on metabolism in general and glycemia in particular is well-established in animal models [1–4]. For example, Surwit et al. in 1988 noted that the obese (C57BL/6J ob/ob) mouse only develops significant hyperglycemia in the presence of stress [5]. Initially, the background strain (C57BL/6J) was used as a normal control animal. However, when data using both the C57BL/6J animal and another strain (AJ) were compared, it became clear that the former mouse strain was always mildly hyperglycemic and hyperinsulinemic compared to the latter. This raised the possibility that the ob/ob mutation was an obesity mutation exacerbating the genetic predilection to hyperglycemia already present in the background strain. Thus, Surwit and Feinglos developed a nutritional experiment to explore the effect of a high-fat, high-calorie diet on the development of obesity and hyperglycemia in these mice. This would serve as a model of the development of type 2 diabetes induced by diet in human populations with a similar genetic predisposition. Both A/J and C57BL/6J mice were studied. For each strain, 10 mice were fed a control diet of ad libitum water and Purina Rodent Chow, whereas 10 mice were fed a highfat, high-simple-carbohydrate diet ad libitum. (For more detailed nutrient composition of the diets, see Table 12.1.) The control diet and the high-fat, high-simplecarbohydrate diet were administered for six months. Both strains of mice developed obesity after 16 weeks, but the C57BL/6J mice were significantly more obese. Furthermore, the diet-induced obesity led to moderate glucose intolerance and insulin resistance in the A/J mice, but obesity in the C57BL/6J mice led to clear-cut diabetes with markedly increased fasting glucose and insulin levels; (glucose 248 ± 8 mg/dL versus 162 ± 6 mg/dL in C57BL/6J mice versus A/J mice, respectively). The authors concluded that, on this diabetogenic diet, C57BL/6J mice appear to
TABLE 12.1 Nutrient Composition of Mice Diets in Surwit et al. Nutrient
High-fat, High-simple Carbohydrate Diet
Protein Fat Fiber Ash Moisture Carbohydrate
20.5 percent 35.8 percent 0.4 percent 3.6 percent 3.1 percent 36.8 percent (mostly disaccharides)
Source: Surwit, RS, et al., Diabetes, 37, 1163, 1988.
Control Diet (Purina Rodent Chow and Water) 23 percent 4.5 percent 6.0 percent 8.0 percent – 56 percent complex carbohydrate
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TABLE 12.2 Plasma Insulin Levels in Bray et al. — Sham-Operated Animals Sham-Operation Rats Fatty Lean
High-Fat Diet
Control Stock Diet
344.1 ± 53.0 μU/mL 99.6 ± 18.7 μU/mL
300.3 ± 38.7 μU/mL 54.6 ± 6.5 μU/mL
Source: Bray, G, Stern, JS, and Castonguay, TW, Am. J. Physiol., 262, E32, 1992. With permission.
develop diabetes in a manner that is analogous to most cases of human type 2 diabetes in predisposed individuals [5]. Several subsequent studies addressed factors that could attenuate the progression to insulin resistance in the diet-induced diabetes mouse model. Bray et al. studied Zucker lean (Fa/?) and obese fatty (fa/fa) rats, which were placed on a control stock diet or a high-fat diet. At 10 weeks of age, the rats were either adrenalectomized or received a sham operation [6]. The dietary interventions began at 15 weeks of age. Among the many parameters analyzed in the study were plasma insulin concentrations in the rats at 32 weeks of age. Results showed that diet affected the insulin levels in the sham-operated rats: Insulin levels were higher in the rats fed a highfat diet than in those fed the control diet (Table 12.2). This difference was not statistically significant in the fatty rats but was significant in the lean rats. Furthermore, adrenalectomy drastically reduced insulin levels and eliminated the dietary effects. Insulin levels were almost identical in adrenalectomized fatty rats fed a highfat diet versus fatty rats fed the control diet, and this was the case with adrenalectomized lean rats as well (Table 12.3). After studying the effects of adrenalectomy on other parameters, such as body composition and lipoprotein lipase activity in the rats, the authors concluded that “adrenalectomy ameliorates but does not cure the (genetic and dietary obesity) syndrome” [6]. Nonetheless, the authors concluded that
TABLE 12.3 Plasma Insulin Levels in Bray et al. — Adrenalectomized Animals Adrenalectomized Rats Fatty Lean
High-Fat Diet
Control Stock Diet
97.5 ± 14.2 μU/mL 26.1 ± 3.3 μU/mL
99.5 ±128.0 μU/mL 25.2 ± 1.9 μU/mL
Source: Bray, G, Stern, JS, and Castonguay, TW, Am. J. Physiol., 262, E32, 1992. With permission.
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high-fat feeding to animals with obesity (whether caused by hypothalamic injury or by genetic defects) does accelerate the further development of obesity. Opara et al. also investigated methods of ameliorating diet-induced obesity and diabetes in animal models by analyzing the effects of amino-acid supplementation during high-fat feeding. The authors studied C57BL/6J mice on 4 diets: 1) a low-fat, low-sucrose diet (LL); 2) a high-fat, low-sucrose diet (HL); 3) a high-fat, low-sucrose diet supplemented with L-glutamine (HL + Gl); and 4) a high-fat, low-sucrose diet supplemented with L-alanine (HL + Ala) [7]. For each dietary regimen, 10 age- and weight-matched male mice were maintained on the diet for 5.5 months. As expected, the mice that received a high-fat diet were significantly heavier than those who received a low-fat diet. Yet, at eight weeks, it was noted that the HL + Gln and HL + Ala mice had gained significantly less weight than the HL mice. With regard to glucose metabolism, it was found that HL mice had higher plasma glucose levels than LL mice, as expected, and this difference persisted for more than five months. However, both alanine and glutamine supplementation of the high-fat diet were effective in reducing plasma glucose concentrations for the first three months, and glutamine supplementation helped maintain normoglycemia for more than five months. Hyperinsulinemia was also attenuated by amino-acid supplementation. Thus, the authors concluded that the supplementation of a high-fat diet with glutamine reduces body weight and attenuates hyperglycemia and hyperinsulinemia [7]. These findings in mice are particularly intriguing given the recent interest in high-protein diets in human studies (see the Nutrition Management section – High Protein Diets).
B. HUMAN STUDIES – DIETARY FAT Numerous studies have attempted to address the impact of dietary patterns on the development of type 2 diabetes in humans, but these studies are very heterogeneous in design and are thus difficult to compare. In 2001, Hu et al. performed a literature search of metabolic studies examining dietary intake and hyperglycemia. With regard to the effect of dietary fat, they noted that the impact of fatty acids on the development of insulin resistance could arise from mechanisms independent of obesity, such as direct effects of fatty acids on insulin-receptor binding, ion permeability, and cell signaling [8]. In their review of the literature, Hu et al. found that human studies were far less consistent than animal studies in demonstrating adverse effects of high-fat diets on insulin sensitivity, but they cited a number of weaknesses of some of the early studies, including diets administered in nonrandomized order and studies of very short duration (less than one month). Among the major studies investigating totalfat intake and insulin sensitivity was the Insulin Resistance and Atherosclerosis (IRAS) study. IRAS was a large, cross-sectional investigation of insulin sensitivity (assessed using intravenous glucose tolerance test [IVGTT] data subjected to minimal model analysis) in more than 1000 subjects. In multivariate analyses adjusting for variables, such as BMI, the study could not demonstrate a statistically significant association between dietary-fat intake and insulin sensitivity [8, 9]. Alternatively, there have been other studies demonstrating positive associations between total fat and diabetes development (i.e., the San Luis Valley Diabetes Study [10]) and
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especially between saturated fat and hyperglycemia (i.e., the Netherlands Zutphen Study [11]). At the time, Hu et al. reached a tentative conclusion that total dietaryfat intake may not be predictive of the risk of developing human type 2 diabetes. However, they noted that available data did suggest a possible beneficial effect of polyunsaturated fat and a possible adverse effect of saturated fat, although the data on types of dietary fat were not consistent [8]. In addition, they pointed out that analyses of monounsaturated fat may have been confounded by its usual correlation with saturated-fat intake in the typical Western diet. Subsequently, Hu et al. collaborated in further investigations of the influence of dietary fat on risk of type 2 diabetes. In the Nurses’ Health Study, Hu et al. followed 84,941 women from 1980 to 1996 who, at baseline, were free of diagnosed cardiovascular disease, diabetes, and cancer [12]. Information about the macronutrient composition of the diet and lifestyle of the subjects was collected over 16 years of follow-up. The authors found that lack of exercise, smoking, and a poor diet significantly increased the risk of diabetes even after adjustment for BMI. Specifically, trans-fat intake was quantified (in terms of ascending quintiles of intake), as was the ratio of polyunsaturated-to-saturated fat intake. As the ratio of polyunsaturatedto-saturated fat increased, the relative risk of type 2 diabetes decreased significantly. From the first to fifth quintile of trans-fat intake, the relative risk trended upward significantly, thus implying a positive association of trans-fat, and an inverse association of polyunsaturated fat with risk of type 2 diabetes in women [12]. Similarly, Van Dam et al. studied dietary-fat intake and risk of type 2 diabetes in men [13]. Men who, at baseline, were free of diagnosed diabetes, cardiovascular disease, and cancer were followed in the Health Professionals Follow-Up study (n = 42,504) for 12 years, during which 1321 incident cases of type 2 diabetes were documented. The authors found that both total- and saturated-fat intake were associated with a significantly increased risk of developing type 2 diabetes. The relative risk (and 95 percent confidence Interval [CI]) for extreme quintiles was 1.27 (1.04–1.55) for total fat and 1.34 (1.09–1.66) for saturated fat, although, on additional adjustment for BMI, the associations lost statistical significance. However, in an accompanying editorial, Marshall and Bessesen pointed out that, although adjusting for BMI eliminated the effect, that fact does not imply that dietary fat is not important at all; they emphasized that any dietary factor that leads to weight gain will likely lead to the development of diabetes as well [14]. In addition, they cited the major, randomizedcontrolled trials that have shown that lifestyle change, including dietary modifications, can reduce the risk of type 2 diabetes (i.e., Finnish Diabetes Prevention Study [15], Diabetes Prevention Program [16]). Thus, although debate continues as to the extent with which dietary fat contributes to the development of obesity-associated diabetes, it is clear that attention to not only total fat intake, but also fat subtypes, is warranted in human nutrition analyses.
C. HUMAN STUDIES – DIETARY CARBOHYDRATE With regard to the issue of dietary carbohydrate and risk of development of diabetes, Hu et al. proposed in 2001 that the traditional notions of simple versus complex carbohydrates are not that helpful in predicting the risk of type 2 diabetes [8]. Rather,
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the authors addressed use of the concepts of glycemic index (GI) and glycemic Load (GL). The GI of a particular ingested carbohydrate refers to its effect on plasma glucose, i.e., how much 50 grams of the particular carbohydrate causes the plasma glucose (area under the curve) concentration to increase, as compared with 50 grams of a reference carbohydrate, such as white bread or glucose [8, 17]. The GL is an attempt to account for both the glycemic effect and quantity of carbohydrate simultaneously (i.e., GL = product of the GI and the carbohydrate content) [8, 18]. Although some studies showed lower plasma insulin levels, fructosamine, and urinary C-peptide concentrations in response to low-GI versus high-GI diets, and others showed a higher incidence of diabetes in association with higher GL, not all data have been consistent [8]. Thus, the significance of GI and GL on progression to diabetes continues to be a subject of debate. The utility of the GI and GL concepts in dietary patterns of patients already diagnosed with impaired glucose tolerance or frank diabetes will be discussed further in the Nutrition Management section. A recent investigation into the epidemic of type 2 diabetes and its potential relationship to increased carbohydrate consumption received an ecologic analysis by Gross et al. [19]. The authors performed an ecologic-correlation study of per capita nutrient consumption in the U.S. during the 20th century and of the prevalence of type 2 diabetes. In multivariate analyses, corn syrup was positively associated with type 2 diabetes prevalence, whereas fiber was negatively associated, and protein and fat associations were not statistically significant. The authors note that corn syrup is a form of refined carbohydrate and that the refining process has changed the composition and quality of carbohydrates. They believe that the risk of type 2 diabetes could be reduced by replacement of refined carbohydrates with low-GI carbohydrate sources, as well as high-fiber, whole-grain foods [19]. However, the authors readily acknowledge the difficulty in accounting for confounding factors, such as obesity and physical activity, and note that further studies would aid in establishing cause-and-effect with regard to refined carbohydrate consumption.
II. NUTRITIONAL MANAGEMENT OF PATIENTS WITH OBESITY-ASSOCIATED DM 2: MACRONUTRIENT COMPOSITION A. LOW-FAT DIETS For many years, the general public and the scientific community have suggested dietary choices for patients with diabetes based on the concept that lowering fat intake is crucial to achieving health benefits. The origin of this impression derives in large part from the abundant animal and human data noted above, which lead to the conclusion that high-fat dietary regimens can induce obesity and diabetes in atrisk subjects. Additionally, the low-fat recommendation recognizes the importance of lowering serum LDL cholesterol levels to help prevent coronary disease, an issue of particular importance to the diabetic population. The American Diabetes Association (ADA) technical review of nutrition principles describes the data in support of limiting saturated-fat intake in terms of corresponding reductions in plasma total cholesterol, LDL cholesterol, and triglycerides. However, the review also notes that
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“studies in diabetic subjects demonstrating the effects of specific percentages of saturated fatty acids … and specific amounts of dietary cholesterol … are not available. Therefore, the goal for patients with diabetes remains the same as for the general population: to reduce saturated-fat intake to < 10 percent of energy intake” [20]. It is important to note that, in the older literature, the reduction in dietary fat was often assumed to be predominantly replaced by a corresponding increase in dietary carbohydrate intake. Thus, questions about the effects of this dietary modification in the overtly diabetic population have arisen and generated a fair amount of controversy. In 1973, Brunzell et al. studied 15 subjects with untreated fasting hyperglycemia (defined as fasting plasma glucose [PG] over 115mg/dL) [21]. Two diets were administered to all patients for 7 to 10 days each: a basal diet with 40 percent fat, 45 percent carbohydrate, and 15 percent protein, or a fat-free, high-carbohydrate diet with 0 percent fat, 85 percent carbohydrate, and 15 percent protein. All patients were hospitalized in a metabolic ward and received five equal feedings at 8 a.m., 11 a.m., 2 p.m., 5 p.m., and 8 p.m. The authors estimated the calories required to maintain body weight in relation to the degree of obesity. Specifically, they stated that a mean of 32 calories/kg was given for all subjects with a mean ideal body weight of 130 percent. FPGs were measured three times per week, and daily, 24hour urine-glucose levels were measured over the dietary period. These values were used to calculate mean glucose values for each dietary period. Results showed a mean increase of 15mg/dL in FPG on the fat-free, high-carbohydrate diet, but this increase was not statistically significant. However, 24-hour urine-glucose excretion was increased significantly on the fat-free, high-carbohydrate diet (56g/24h). The authors concluded that glucose tolerance might deteriorate in untreated patients with fasting hyperglycemia on a fat-free, high-carbohydrate diet. Interestingly, as this paper was written at a time when the lower-fat, highercarbohydrate diet was increasing in popularity, the value of the fat-free, highcarbohydrate diet was reexamined by the authors in a small cohort of five subjects, who were restudied after institution of insulin or oral sulfonylurea therapy and in four subjects who were studied only while on therapy. In these subjects, FPGs were indeed decreased on the fat-free, high-carbohydrate diet, but the effects of the insulin and oral-agent therapy are obvious confounding factors in this analysis [21]. In 1989, Abbott et al. also addressed the effects of dietary saturated-fat reduction, with corresponding increases in complex-carbohydrate intake, in obese subjects with type 2 diabetes [22]. Nineteen Pima Indians, of whom 10 had a diagnosis of type 2 diabetes (untreated for at least four weeks prior to the study), were assigned to either an isocaloric high-fat diet (n = 3 with diabetes, n = 3 without diabetes) or an isocaloric high-carbohydrate, low-fat diet (n = 7 with diabetes, n = 6 without diabetes). The high-fat diet consisted of 43 percent carbohydrate, 42 percent fat (polyunsaturated to monounsaturated to saturated ratios were 6:12:21), and 15 percent protein. The high-carbohydrate, low-fat diet consisted of 65 percent carbohydrate, 21 percent fat (polyunsaturated to monounsaturated to saturated ratios were 6:8:6), and 14 percent protein. The diets were continued for five weeks. Six of the seven subjects with type 2 diabetes on the high-carbohydrate, low-fat diet had significant decreases in LDL cholesterol over the time of the study, (which did not
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occur with the diabetic patients on a high-fat diet). In spite of the LDL improvement, the authors noted no significant changes in fasting total plasma triglycerides and glucose in diabetic subjects when mean values were studied. However, there was wide variability in the individual patient responses: two of the diabetic subjects on the high-carbohydrate, low-fat diet had significant decreases in FPs, but two subjects also had significantly increased FPGs and triglycerides. Although these data are interesting, it is likely that this small study had insufficient power to truly reveal potential adverse (or beneficial) effects of the high-carbohydrate low-fat diet on glycemia [22]. Reaven et al. have long been concerned about the high-carbohydrate, low-fat diet with regard to its effects on triglyceride concentrations in diabetic patients [23–26]. This issue was addressed directly in an examination of the accentuation of postprandial lipemia by such diets in a group of patients with type 2 diabetes [27]. The authors studied a low-fat, high-carbohydrate diet consisting of 55 percent carbohydrate, 30 percent fat, and 15 percent protein, versus a diet of 40 percent carbohydrate, 45 percent fat, and 15 percent protein for six weeks in nine patients with type 2 diabetes using sulfonylurea monotherapy. Diets were equicaloric and consumed in random order. Results showed that mean hourly concentrations of glucose, insulin, and triglycerides, as well as chylomicron and chylomicron remnant fractions, were significantly higher after the low-fat, high-carbohydrate diet. The very-low-density-lipoprotein–triglyceride (VLDL-TG) production rate was higher, but the fractional catabolic rate was lower, after the low-fat, high-carbohydrate diet, which the authors speculate was secondary to higher-circulating insulin concentrations. Lipoprotein lipase activity was significantly increased as well. The authors concluded that their data provide a mechanism for the hypertriglyceridemic effect of higher-carbohydrate diets in patients with type 2 diabetes. Thus, they believed that multiple risk factors for cardiovascular disease can actually be exacerbated when such patients ingest these diets, which are recommended by some to reduce this risk [27].
B. MODIFIED FAT/HIGH-MONOUNSATURATED FATTY ACID (MUFA) DIETS Given the controversy surrounding low-fat diets in the diabetic population in terms of glycemic and triglyceridemic effects, along with concerns about patient adherence to such regimens, there has been increasing focus for diabetic patients on modifiedfat diets and those that stress the use of monounsaturated fatty acids. Walker et al. compared a high-carbohydrate, low-fat diet (24 percent protein, 50 percent carbohydrate, 23 percent fat [4 percent polyunsaturated, 9 percent saturated, and 10 percent monounsaturated]) with a modified-fat diet (22 percent protein, 40 percent carbohydrate, 36 percent fat [5 percent polyunsaturated, 11 percent saturated, and 20 percent monounsaturated]) in free-living patients with type 2 diabetes controlled by either diet alone or oral hypoglycemic agents [28]. Twenty-four subjects with a mean BMI of 29.2 ± 0.7kg/m2 consumed the high-carbohydrate, low-fat diet or the modified-fat diet for three months each, in a random crossover design with a one-month washout. The diets were isocaloric with the subjects’ usual diets, and they continued
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usual alcohol intake and physical activity. For each diet, weight was measured and blood samples were drawn at the beginning and end of the dietary period. Results showed that subjects had comparable mild weight loss on both diets (change during high-carbohydrate, low-fat diet period –0.7 ± 0.3 kg; change during modified fat diet period –1.3 ± 0.4 kg) and no significant changes in plasma insulin levels or hemoglobin A1c (HbA1c). Subjects on the high-carbohydrate, low-fat diet had slightly increased triglyceride levels at the end of the dietary period, and subjects on the modified-fat diet had slightly decreased triglycerides, but these values were not statistically significant. However, the study did find that the diets had differential effects on FPG levels. FPG was increased in subjects on the high-carbohydrate, lowfat diet (0.3 ± 0.3 mmol/L = 5.4 ± 5.4 mg/dL) and decreased on the modified fat diet (–0.9 ± 0.4 mmol/L = –16.2 ± 7.2 mg/dL), and this difference between the diets was significant. It is also noteworthy that the subjects also indicated better compliance and preference for the modified-fat diet. Thus, the authors concluded that the use of a modified-fat diet had metabolic effects that were better, or at least comparable, to those of the high-carbohydrate, low-fat diet [28]. Thus, the formerly strict low-fat (and correspondingly higher-carbohydrate) recommendations for patients with diabetes have undergone reevaluation. As for patients at risk for developing diabetes, it seems that patients already diagnosed with diabetes should attend not only to total fat intake but to fat subtypes as well when designing a dietary regimen.
C. LOW-CARBOHYDRATE DIETS As noted above, much of the nutrition literature of the last 50 years emphasized decreases in dietary-fat intake. However, that recommendation has long been a subject of scientific debate. At the present time, the public’s attention has actually shifted to low-carbohydrate diets, which has generated renewed interest in low-carbohydrate diets within the nutrition, endocrine, and cardiovascular literature as well. Golay et al. directly addressed the issue of macronutrient composition in a study of 43 obese patients (BMI > 30), who all received the same level of calorie restriction (1000 Kcal/day), with 22 patients randomly assigned to a diet that had 15 percent of energy intake as carbohydrate and 21 patients given a diet that had 45 percent intake as carbohydrate [29]. The authors found no significant difference between groups in the amount of weight loss at six weeks or the magnitude of the decrease in body-fat content (as measured by skinfold thickness and bioelectrical impedance analysis). However, the 15 percent carbohydrate intake group had significant decreases in FPG and insulin levels compared to baseline, while the 45 percent carbohydrate intake group had less improvement (smaller corresponding decreases) in FPG and no significant change in plasma insulin. This study demonstrates an attempt to limit the influence of potential confounding factors: All patients participated in structured programs, including nutritional education, behavioral teaching, and a prescribed physical-activity program. Furthermore, all patients were hospitalized during the entire six-week period, received standardized menus, had a dietitian present at each meal to ensure compliance, and completed a food record. However, this structured environment limits the applicability of the results, and the percentage
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of patients who had comorbidities, such as impaired glucose tolerance, is unclear (although the authors do note that there were no significant between-group differences in FPG and insulin levels at baseline ) [29]. Many other studies have attempted to assess the effects of low-carbohydrate diets in less structured (i.e., free-living) settings. Given the large number of studies and increased attention to macronutrient composition, Bravata et al. published a systematic review of the English-language literature on low-carbohydrate diets available from 1966 to February 2003, including all studies that provided data for calculation of both dietary carbohydrate content and daily calorie consumption [30]. They excluded studies with diets lasting fewer than four days, using less than 500 Kcal/d, or requiring hospitalization or confinement to a research or diet center. Carbohydrate thresholds of 20 g/d or less, 60 g/d or less, and more than 60 g/d were used to define lowest-, lower-, and higher-carbohydrate diets. Although 107 articles met inclusion criteria corresponding to 3268 study subjects, only 663 subjects received diets of 60 g/d carbohydrate or less, and only 71 subjects received diets of 20 g/d or less carbohydrate content. The major findings of this review were: 1) In general, lower-carbohydrate diets produced greater weight loss than higher-carbohydrate diets (16.9 ± 0.2 kg, CI 16.6–17.3kg; 1.9 ± 0.2 kg, CI 1.6–2.2 kg, respectively), but the studies were highly heterogeneous. However, when only studies with a randomized design were assessed (seven lower-carbohydrate diet studies and 75 higher-carbohydrate diet studies), the confidence intervals in the two groups overlapped, suggesting no significant difference in weight loss between the two groups. 2) Lowest-carbohydrate diets did not result in significantly greater weight loss than lower-carbohydrate diets. 3) The 22 diets with the largest mean weight loss varied widely in carbohydrate content but did share a number of other characteristics, including calorie restriction (mean 1077 Kcal/d), longer duration (mean 142 days), and inclusion of participants who were significantly overweight at baseline. 4) “No change was observed in either fasting serum glucose or insulin levels among recipients of either lower- or higher-carbohydrate diets — even among those participants with the greatest weight loss or … lowest-carbohydrate diets.” It should be noted that only one study analyzed glucose and insulin levels in patients with diabetes and obesity. 5) Longer diet duration was associated with reductions in FPG [30]. In their critique of the literature, Bravata et al. noted not only substantial heterogeneity in study designs but also a lack of intention-to-treat analyses, variability in definitions of participant characteristics (healthy volunteers, obese participants, participants with diabetes), and insufficient information on the effects of exercise. Overall, they concluded that there is not sufficient evidence available to recommend for or against the use of low=carbohydrate diets for long-term durations or in patients with diabetes. Subsequently, more carefully constructed randomized studies on the effects of low-carbohydrate diets have emerged. Samaha et al. performed a randomized study of 132 adult subjects with a body-mass index (BMI) of at least 35 kg/m2 [31]. Subjects were randomized to a low-fat diet (68 subjects) or a low-carbohydrate diet (64 subjects). The low-fat diet guideline included caloric restriction with a goal deficit of 500 calories daily, with 30 percent or less of the total calories derived from fat. The low-carbohydrate diet restricted subjects to no more than 30 grams of
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carbohydrate daily. Compliance was assessed by 24-hour dietary recall. Although not part of the specific inclusion criteria, diabetes or metabolic syndrome without diabetes were highly prevalent at baseline in the study subjects (prevalence of 39 percent and 43 percent, respectively), and randomization was stratified. The primary end point was weight loss at six months, and patients on the low-carbohydrate diet lost significantly more weight than those on the low-fat diet (mean, –5.8 ± 8.6 kg versus –1.9 ± 4.2kg) [31]. In addition, the mean FPG was decreased more in the low-carbohydrate group than the low-fat group at six months (–9 ± 19 percent versus –2 ± 17 percent). In subgroup analyses adjusted for baseline variables, this difference was significant for subjects with diabetes but not for those without the diagnosis. The statistical significance also was eliminated by analyses adjusting for the amount of weight lost. Insulin levels were also reduced more in the low-carbohydrate group as compared to the low-fat group, but this was only significant for subjects not taking diabetes medications. Insulin sensitivity was measured (by QUICK Index) only in subjects without diabetes. In that subgroup, there was a significantly larger increase in insulin sensitivity in those subjects eating the low-carbohydrate diet than the lowfat diet. However, limitations of this study included a significant dropout rate, which exceeded 33 percent in both groups at six months, the unblinded design, and unclear effects of confounding factors, such as physical activity and diabetes medications. The low-carbohydrate diet group also had a greater reduction in caloric intake, though not statistically significant when compared to the low-fat group. Stern et al. recently published a follow-up to the above study, which reported the results of the same randomized trial at one year [32]. They found that, in contrast to the six-month data, weight loss at one year was not statistically different between the diet groups. Furthermore, one-year changes in glucose and insulin levels (in subjects with or without diabetes) were not significantly different between groups, nor were there significant differences in insulin sensitivity (as assessed by the QUICK Index in subjects without diabetes). However, in subgroup analyses of the 54 subjects who had diabetes, the HbA1c decreased more in the low-carbohydrate compared to the conventional-diet group, although this finding did not remain significant when baseline values were carried forward for missing persons. Findings at one year that did remain significant between diet groups in all analyses were a smaller decrease in HDL levels and a larger decrease in TG levels in the lowcarbohydrate group than in the conventional-diet group. Nonetheless, this study at one year is subject to the same limitations as noted above in the description of the six-month results. In a separate study, Foster et al. performed a multicenter trial of 33 adults randomized to a low-carbohydrate diet and 30 randomized to a conventional diet [33]. In both groups, mean baseline BMI was approximately 34. The low-carbohydrate diet consisted of initial restriction of carbohydrate intake to no more than 20 grams daily, with subsequent increases as per the Atkins Diet program [34]. The conventional-diet group was told to consume 1200 to 1500 Kcal per day for women and 1500 to 1800 Kcal per day for men, with a macronutrient composition of 60 percent carbohydrate, 25 percent fat, and 15 percent protein. As in the Samaha study, Foster et al. found that subjects on the low-carbohydrate diet lost significantly more weight than subjects on the conventional diet at three and six
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months. However, when this trial was carried out to 12 months of follow-up, there was no statistically significant difference between groups. With regard to metabolic end points, unlike the Samaha study, Foster et al. found that there were no significant differences between groups at 3, 6, or 12 months. Specifically, there were no significant between-group differences in glucose and insulin measurements (calculated as the area under the curve after a 75-gram oral glucose tolerance test [OGTT] and insulin sensitivity as assessed by the QUICK index). However, the generalizability of this study is limited by several important factors: the complete exclusion of subjects with type 2 diabetes and those with hyperlipidemia requiring medication treatment; lack of physical-activity data, and a large attrition rate. At six months, the conventional-diet group had a 40 percent drop-out rate, and the low-carbohydrate diet group had a 27 percent drop-out rate; the figures were 43 percent and 39 percent at 12 months [33]. Most recently, Yancy et al. performed a randomized, controlled trial of 120 obese (BMI between 30 and 60 kg/m2), hyperlipidemic but otherwise healthy individuals who were prescribed either a low-carbohydrate diet or a low-fat diet [35]. The lowcarbohydrate diet restricted carbohydrate consumption to initially less than 20 grams daily with nutritional supplementation to simulate the Atkins Diet program [36]. Data collected with food records from a subsample of subjects showed the following mean macronutrient consumption: the low-carbohydrate group consumed 8 percent of daily energy intake as carbohydrate, 26 percent as protein, and 68 percent as fat, whereas the low-fat diet group consumed 52 percent carbohydrate, 19 percent protein, and 29 percent fat daily. Total estimated daily energy intake was 1461.0 ± 325.7 Kcal in the low-carbohydrate group and 1502.0 ± 162.1 Kcal in the low-fat group. Key findings included larger decreases in TG levels and higher HDL levels in the low-carbohydrate group than the low-fat diet group, as well as significantly increased weight loss in the low-carbohydrate group at 24 weeks (mean weight change –12.9 percent low carbohydrate versus –6.7 percent low fat). However, the authors caution that LDL should be monitored closely on the low-carbohydrate (higher-fat) diet because although mean LDL levels were stable in both groups, LDL did increase by more than 10 percent from baseline in 30 percent of the low-carbohydrate subjects who completed the study. Other cautions included a higher frequency of minor, adverse events in the low-carbohydrate group, such as headache, weakness, and a greater increase in mean blood urea nitrogen (BUN) than in the low-fat group. Again, the generalizability of this study is limited by several important factors: the lack of data regarding insulin sensitivity; the complete exclusion of subjects using any form of prescription medication in the 2 months prior to the study (presumably eliminating any patients with pharmacologically-treated type 2 diabetes); the significant dropout rate in both diet groups; and the effect of confounders, such as the daily nutritional supplement consumed by the low-carbohydrate groups and the variation in protein intake between the diet groups [35]. It should be noted that the above studies addressed weight loss as the primary outcome, with only a minor focus on cardiovascular or specific endocrine outcomes, such as insulin resistance. In addition, the number of patients with abnormal glucose metabolism in these studies is unclear.
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Wolever et al. performed a randomized study that does focus on endocrine outcomes in a population with impaired glucose tolerance (IGT) [37]. Furthermore, the study extended the discussion of carbohydrate effects on glycemia, because, rather than focusing solely on a low quantity of carbohydrates in the diet, the authors chose to reexplore the concepts of GI and GL. The study included men and nonpregnant women from 30 to 65 years old with BMI < 40 kg/m2 and serum triacylglycerols < 10 mmol/L; IGT was proven by a 75-gram OGTT (using old World Health Organization criteria of FPG less than 7.8 mmol/L but two-hour glucose > 7.8 and < 11.1). Thirty-four patients were randomized to a four-month trial of one of three different diets: 1) high-carbohydrate (60 percent of total energy), high GI (GI 61, GL 63); 2) high carbohydrate (60 percent of total energy), low GI (GI 53, GL 55); and 3) low carbohydrate (49 percent of total energy, GI 61, GL 52 ), high monounsaturated fatty acid (MUFA). Results showed that the low-GI diet and the high-MUFA diet both led to reductions in mean plasma glucose levels compared to baseline, whereas the high-GI diet led to a nonsignificant increase from baseline. Thus, the authors concluded that, in subjects with IGT who consumed normal, mixed meals, a reduction in GL by either an alteration of carbohydrate source or diminished intake had the same effect on postprandial blood glucose [37]. However, the study found no significant difference in HbA1c between the low-GI and high-GI diets. Furthermore, the changes in insulin levels were not so well-correlated with the glycemic indices. Whereas the mean 0-8-h plasma insulin levels were significantly reduced from baseline in the high-GI and high-MUFA groups, the decrease was nonsignificant in the low-GI group. Subsequently, Brand-Miller et al. published a meta-analysis of randomized controlled trials comparing high- and low-GI diets in the management of type 1 and type 2 diabetes [38]. The authors included studies of at least 12 days’ duration, published between 1981 and 2001, in which at least two meals per day were highGI (mean GI 83) or low-GI (mean GI 65) diets. Changes in HbA1c or fructosamine levels (not FPG levels) were the outcome measures assessed. In all, 14 studies were analyzed, involving 356 subjects, of whom 153 had type 2 diabetes. The analysis showed a small benefit derived from the use of low-GI diets. After an average of 10 weeks, subjects with type 1 and type 2 diabetes who consumed low-GI diets had HbA1c levels approximately 0.4 percent lower than those who consumed a high-GI diet. Fructosamine levels (in studies of approximately four weeks duration) were also lower by a mean difference of 0.2 mmol/l [38]. Although these findings appear to favor the use of low-GI diets, this meta-analysis was limited by many of the usual factors: difficulty in assessing true dietary compliance in each individual study, the small sample size of some of the included studies, and effects of confounding factors, such as weight loss and varying levels of fiber intake. In summary, a clear glycemic advantage from consumption of decreased-carbohydrate diets has not been definitively established. However, there is a suggestion from available studies that GI and GL may be important factors to consider and require further research.
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D. HIGH-PROTEIN DIETS Much of the interest in high-protein diets stems from theories regarding the interrelationships between glucose and amino-acid metabolism. Layman et al. describe the hypothesis wherein amino acids provide a major fuel and carbon source for hepatic gluconeogenesis [39]. To elucidate high-protein dietary effects on glucose and insulin homeostasis, Layman et al performed a study of 24 adult women who were more than 15 percent above ideal body weight. For 10 weeks, 12 women were assigned to a moderate-protein diet (Protein Group) containing protein as 30 percent of dietary energy, carbohydrate as 40 percent, and fats as 30 percent. The other 12 women formed a control high-carbohydrate group whose diet consisted of protein as 15 percent, carbohydrate as 55 percent, and fats as 30 percent of dietary energy. In all cases, the two diets were designed to produce the same daily energy deficit and matching weight loss (0.6 kg per week). FPG and insulin levels were measured. After the patients were fed test meals designed to be similar to a standard OGTT, postprandial plasma glucose and insulin levels were drawn. Ten weeks later, both groups had lost weight, (Protein Group 7.53 ± 1.44 kg; carbohydrate group 6.96 ± 1.36 kg), but the carbohydrate group had FPG levels that were 11 percent lower than the protein-group levels. However, after the test meal, plasma insulin was 42 percent higher than fasting-insulin levels in the protein group but 115 percent higher in the carbohydrate control group. The authors note the apparent contradiction in these results: If the protein diet led to better peripheral insulin sensitivity, as perhaps indicated by the lower postprandial insulin levels, then the finding of higher FPG in the protein group seems inconsistent. However, the authors believe that this finding actually implies a separate advantage of the protein diet: enhancement of hepatic gluconeogenesis, and hence protection against episodes of fasting hypoglycemia, through increased production and availability of the substraits alanine and glutamine [39]. Yet, it is not clear that this finding would be an advantage in all circumstances, and, as in other cases, the generalizability of this study is limited by the fact that the patient population studied was so restricted (patients with chronic medical conditions, routine medication use, or tobacco use were all excluded), the subjects had minimal daily physical activity, and all subjects received food prepared entirely in the food research lab for the first four weeks. Since Layman et al. showed a higher FPG from eating a higher-protein diet in a group of patients who had no known medical conditions and were actively losing weight, it seems reasonable to inquire whether increased protein intake could have adverse effects on glucose control in patients with overt diabetes. Surprisingly, recent data have actually shown either minimal or even beneficial glycemic effects of a highprotein diet in patients with type 2 diabetes. Parker et al. performed a study in which 54 obese men and women with type 2 diabetes underwent the same level of dietary energy restriction (1600 Kcal/day) for eight weeks, followed by four weeks of dietary energy balance [40]. The subjects were randomly assigned to a high-protein diet (28 percent protein, 42 percent carbohydrate, 28 percent fat) or a low-protein diet (16 percent protein, 55 percent carbohydrate, 26 percent fat). The percentages of fats from saturated, monounsaturated, and polyunsaturated fatty acids were similar in both groups. Nineteen of the subjects were men, 35 women, and 25 managed their diabetes
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with diet only, 26 were on oral agents, and four used insulin. At baseline and at the conclusion of the study, weights were measured, along with FPG and insulin levels, and all subjects underwent a 75-gram, three-hour OGTT as well as dual-energy x-ray absorptiometry (DEXA) scanning for body-composition measurements. The 25 subjects who were not using oral agents or insulin also underwent a continuous, low-dose insulin and glucose infusion test (LDIGIT) to determine steady-state plasma glucose and insulin concentrations. Although both diets led to comparable weight loss (5.2 ± 1.8 kg), there were some diet-specific gender effects on body composition: Women lost significantly more total and abdominal fat on the high-protein diet. Interestingly, despite the increased total and abdominal-fat mass reduction found in women on the high-protein diet, there were no significant differences between diets on the levels of reduction in plasma glucose or insulin concentrations measured via OGTT, HbA1c, or steady-state plasma glucose or insulin concentrations by LDIGIT. With regard to validity of the study findings, although objective data were reported to support good dietary compliance, there were still a number of potentially confounding factors, including the effects of the oral hypoglycemic agents or insulin used by many patients and exercise (patients were told to maintain exercise programs at levels as had been established prior to the study) [40]. Thus, the Parker study showed no difference between high- or low-protein diets in effects on glycemic parameters in patients with type 2 diabetes. If the hypothesis that amino acids provide a major fuel and carbon source for hepatic gluconeogenesis is true, why would this be so? Gannon et al. have addressed this question through a number of studies of both acute and chronic increases in dietary protein ingestion. To investigate acute effects, the authors studied 10 males with untreated type 2 diabetes who were given 50 grams of protein versus only water to ingest [41]. During the eight hours immediately following ingestion, samples were drawn for measurement of glucose, insulin, and other parameters. From the amount of protein ingested, the authors calculated the expected net amount of glucose that would be produced from amino-acid deamination (approximately 11 to 13 grams). However, the amount of glucose actually appearing due to protein ingestion was found to be only 2.6 grams. The authors thought that ingested protein had such a modest effect on circulating glucose because of intracellular fuel switching, in which the ingested protein-derived amino acid actually replaced the endogenous gluconeogenic substrates that would have otherwise been used [41]. To investigate chronic high-protein ingestion effects, Gannon et al. subsequently performed a study of 12 subjects with untreated type 2 diabetes in which diets were ingested for five weeks [42]. Subjects consumed a high-protein diet (protein:carbohydrate:fat = 30:40:30) and a control diet (15:55:30), with a washout period of two to five weeks between diets. Plasma glucose was measured at time points throughout a 24-hour period to allow calculation of a 24-hour net glucose area response, and glycated hemoglobin levels were measured as well. The high-protein diet led to a 40 percent decrease in the mean 24-hour net glucose area response and a significantly greater reduction in glycated hemoglobin when compared to the control diet [42]. As the studies above have shown possible glycemic benefits of high-protein diets, the question of the effect of a high-protein diet on weight has arisen as well. Johnston et al. reported that higher-protein diets can be advantageous from an
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energy-cost perspective. In their study of 10 healthy volunteers, it was found that a high-protein diet nearly doubled the level of postprandial thermogenesis (at 2.5 hours postmeal) in comparison to a high-carbohydrate diet [43]. The authors suggested that the apparent thermogenesis benefit of the high-protein diet supports its use in dietary regimens designed for weight loss. Finally, critical appraisal of the high-protein data leads to the following cautions as well: It is quite difficult to separate the effects of increasing protein in the diet from the effects of lowering carbohydrate intake or changing fat subtype (i.e., MUFA) intake, as these are often done concurrently. Further, the long-term systemic effects of increased protein ingestion (such as impact on renal physiology) require further exploration before a firm recommendation for use of these diets can be made
III. PHARMACOLOGIC MANAGEMENT OPTIONS: FROM DIET WITH EXERCISE TO ORAL AGENTS TO INSULIN Attention to nutrition as discussed above is important at all times in the proper management of type 2 diabetes mellitus. Just as lifestyle changes are beneficial in reducing the risk of type 2 diabetes, as demonstrated in the Finnish Diabetes Prevention Study [15] and Diabetes Prevention Program [16], so diet with exercise is a highly effective therapy for patients already diagnosed with type 2 diabetes mellitus. However, the stress of acute illness or progression of diabetes over time may render lifestyle changes insufficient as monotherapy. As shown in Figure 12.1, indications for the addition of pharmacological therapy can include progressive fasting or postprandial hyperglycemia on diet and exercise alone, a rising HbA1c, or development of microvascular or macrovascular complications of diabetes. Intensification of treatment can be accomplished with oral hypoglycemic agents alone or in combination with insulin.
A. ORAL HYPOGLYCEMIC AGENTS 1. Biguanides Metformin is presently the only biguanide available for use in the U.S. Metformin acts primarily by reducing hepatic glucose output and increasing peripheral glucose uptake [44]. This agent is considered a first-line medication in the treatment of obese patients with type 2 diabetes, because it does not promote weight gain, and because it may facilitate weight loss. Additionally, it has the advantage of not causing hypoglycemia. The most feared complication of metformin use is the development of lactic acidosis. In patients who have conditions predisposing to hypoxia, such as congestive heart failure requiring medical therapy, cardiovascular collapse, acute myocardial infarction, renal insufficiency, and septicemia, the incidence of lactic acidosis is presumably higher. According to the product labeling, metformin is contraindicated in these patients. Caution should also be used in patients older than 80, those with hepatic disease, and those with chronic obstructive pulmonary disease
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Diet and Exercise
Stress of acute illness, progression of diabetes, progressive fasting or post-prandial hyperglycemia, a rising HbA1c, or development of microvascular or macrovascular complications of diabetes
Oral Agents
Metformin
Sulfonylureas
Oral Agents in Combination with Insulin Therapy
Thiazolidinediones
Insulin Therapy
Other oral agents
FIGURE 12.1 Pharmacologic management options schematic: When diet with exercise is insufficient as monotherapy, intensification of treatment can be accomplished with oral hypoglycemic agents alone or in combination with insulin therapy. With failure of oral agents, insulin monotherapy may be required, in which case more complex insulin regimens are needed.
associated with hypoxemia. Metformin should also be stopped before and for 48 hours after contrast-media administration [45, 46]. 2. Sulfonylureas Sulfonylureas function by binding to and closing an ATP dependent potassium (KATP) channel. In the pancreatic beta cell, this action results in sustained membrane depolarization, activation of voltage-dependent calcium channels, calcium influx, and migration of insulin-containing vesicles to the cell surface, leading to insulin release. Sulfonylureas also increase insulin sensitivity. In the U.S., the most commonly used sulfonylureas are glyburide, glipizide, and glimepiride. Unlike the biguanides, sulfonylureas can be associated with hypoglycemic episodes, particularly if food intake is poor or variable. Thus, the lowest effective dose should be used, and these agents should be used with caution in patients with erratic food intake, such as some elderly individuals. Furthermore, the kinetics of sulfonylureas may be changed with renal or hepatic dysfunction. Thus, these agents should be avoided in patients with significant impairment [46].
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3. Thiazolidinediones Thiazolidinediones bind to peroxisome proliferator-activator receptors (PPAR). These agents enhance peripheral insulin sensitivity through a series of mechanisms that result in transcription of insulin-responsive genes [47]. In the U.S., both pioglitazone and rosiglitazone are presently available for use. The first thiazolidinedione originally released was troglitazone; however, this agent was removed from the market due to reports of liver failure after use of this medication. The presently available thiazolidinediones should not be used in patients with active liver disease or in those with transaminases increased more than 2.5 times normal [46]. It is also worth noting that the thiazolidinediones have been implicated in the exacerbation of fluid retention, a particular concern in patients with congestive heart failure. Additionally, despite the value of increasing insulin sensitivity in insulin-resistant patients, thiazolidinediones may not be ideal drugs to use as the initial choice of an oral antidiabetic agent in patients with significant obesity given their propensity to increase adiposity, particularly when used in combination with insulin. 4. Other Oral Hypoglycemic Agents Other oral hypoglycemic agents include the meglitinides (repaglinide, nateglinide) and alpha-glucosidase inhibitors (acarbose, miglitol). Although the potential for hypoglycemia in both classes is limited, their major role is in modifying postprandial hyperglycemia. Therefore, in patients with erratic food intake, there is no clear role for these agents. In that case, these agents should be discontinued in favor of a scheduled insulin regimen [46].
B. INSULIN THERAPY One of the first steps in determining an appropriate insulin regimen for a patient with type 2 diabetes consists of gathering important baseline data on the diabetes history. Crucial data items include the following: the patient’s usual weight, dietary habits, oral-agent regimen, if any, the presence and severity of diabetic complications, and an assessment of home glucose control, including frequency and severity of any hypoglycemic episodes. For individuals with type 2 diabetes, the total daily insulin dose can be estimated at 0.3 units/kg/day to 0.6 units/kg/day [46]. This range reflects varying degrees of insulin sensitivity in this patient population. Very insulin-resistant patients may require doses as high as 0.6 to 1.0 units/kg/day [48], but, in contrast, a patient who is insulin naïve may be more insulin sensitive and benefit from a lower starting dose. After estimating the total daily insulin dose, the next step is to determine the frequency of standing-dose insulin administration. Several options are available. Of note, once-daily insulin injection alone rarely provides adequate glucose control, but may be used in combination with oral hypoglycemic agents. Other options include two, three, or four injections daily, or the use of a subcutaneous insulininfusion pump, which is the most intensive alternative. Four injections daily can be administered using premeal regular insulin and bedtime Neutral Protamine
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Hadedorn, or premeal, ultra-short acting insulin (lispro or aspart) and bedtime longacting, peakless insulin (glargine). Education regarding management of potential hypoglycemia is important for patients taking oral hypoglycemic medications or insulin. Patients should be counseled to maintain a supply of glucose tablets or gel at home or in the car for treatment of hypoglycemia. For those at risk of significant hypoglycemia, a glucagon emergency kit may be useful. This kit consists of an intramuscular injection of glucagon to be used in an emergency for unconscious hypoglycemia. However, effective use of this device requires that the patient has adequate hepatic function as well as a caregiver to administer the injection. Finally, all patients taking hypoglycemic medications should obtain a Medic-Alert bracelet [46].
IV. CONCLUSION The debate regarding specific guidelines for the optimal intake of carbohydrate, dietary fat, and protein in the diet of patients with obesity and abnormal glucose metabolism will undoubtedly continue. Although there is now considerable controversy regarding the relative importance of the quantity or the quality of a particular dietary macronutrient, perhaps the best recommendation at present is to consider both amounts and subtypes when designing nutrition regimens for prevention or management of obesity-associated diabetes mellitus. Even as evidence may build in support of individual macronutrient effects on glycemia or weight loss, it is still important to emphasize the overarching principle of caloric restriction. Finally, one should be vigilant for the time at which diet therapy alone has failed and the addition of pharmacologic intervention is necessary.
REFERENCES 1. Schmidt-Nielsen, K, Harnes, HB, and Hackel, DB, Diabetes mellitus in the sand rat induced by the standard laboratory diets, Science, 143, 689, 1964. 2. Reaven, GM, et al., Characterization of a model of dietary-induced hypertriglyceridemia in young nonobese rats, J. Lipid Res. 20, 371, 1979. 3. Storlien, LH, et al., Fat feeding causes widespread in vivo insulin resistance, decreased energy expenditure, and obesity in rats, Am. J. Physiol., 251, E576, 1986. 4. Kraegen EW, et al., In vivo insulin resistance in individual peripheral tissues of the high fat fed rat: assessment by euglycaemic clamp plus deoxyglucose administration, Diabetologia, 29, 192, 1986. 5. Surwit, RS, et al., Diet-induced type II diabetes in C57BL/6J mice, Diabetes, 37, 1163, 1988. 6. Bray, G, Stern, JS, and Castonguay, TW, Effect of adrenalectomy and high-fat diet on the fatty Zucker rat, Am. J. Physiol., 262, E32, 1992. 7. Opara, EC, et al., L-glutamine supplementation of a high fat diet reduces body weight and attenuates hyperglycemia and hyperinsulinemia in C57BL/6J mice, J. Nutr., 126, 273, 1996. 8. Hu, FB, Van Dam, RM, and Liu, S, Diet and risk of type II diabetes: the role of types of fat and carbohydrate, Diabetologia, 44, 805, 2001.
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9. Mayer-Davis, EJ, et al., Dietary fat and insulin sensitivity in a triethnic population: the role of obesity. The Insulin Resistance Atherosclerosis Study (IRAS), Am. J. Clin. Nutr., 65, 79, 1997. 10. Marshall, JA, et al., Dietary fat predicts conversion from impaired glucose tolerance to NIDDM. The San Luis Valley Diabetes Study, Diabet. Care, 17, 50, 1994. 11. Feskens, EJ and Kromhout, D, Habitual dietary intake and glucose tolerance in euglycaemic men: the Zutphen Study, Int. J. Epidemiol., 19, 953, 1990. 12. Hu, FB, et al., Diet, lifestyle, and the risk of type 2 diabetes mellitus in women, N. Engl. J. Med., 345, 790, 2001. 13. Van Dam, RM, et al., Dietary fat and meat intake in relation to risk of type 2 diabetes in men, Diabet. Care, 25, 417, 2002. 14. Marshall, JA and Bessesen, DH, Dietary fat and the development of type 2 diabetes, Diabet. Care, 25, 620, 2002. 15. Tuomilehto, J, et al., Finnish Diabetes Prevention Study Group: Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance, N. Engl. J. Med., 344, 1343, 2001. 16. Diabetes Prevention Program Research Group, Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin, N. Engl. J. Med., 346, 393, 2002. 17. Jenkins, DJ, et al., Glycemic index of foods: a physiological basis for carbohydrate exchange, Am. J. Clin. Nutr., 34, 362, 1981. 18. Salmeron, J, et al., Dietary fiber, glycemic load, and risk of non-insulin-dependent diabetes mellitus in women, JAMA, 277, 472, 1997. 19. Gross, LS, et al., Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment, Am. J. Clin. Nutr. 79, 774, 2004. 20. Franz, MJ, et al., ADA Technical Review: Evidence-based nutrition principles and recommendations for the treatment and prevention of diabetes and related complications, Diabet. Care, 25, 148, 2002. 21. Brunzell, JD, et al., Effect of a fat free, high carbohydrate diet on diabetic subjects with fasting hyperglycemia, Diabetes, 23, 139, 1974. 22. Abbott, W, et al., Effects of replacing saturated fat with complex carbohydrate in diets of subjects with NIDDM, Diabet. Care, 12, 102, 1989. 23. Farquhar, JW, et al., Glucose, insulin, and triglyceride responses to high and low carbohydrate diets in man, J. Clin. Invest., 45, 1648, 1966. 24. Ginsberg, H, et al., Induction of hypertriglyceridemia by a low-fat diet, J. Clin. Endocrinol. Metab., 42, 729, 1976. 25. Coulston, A, et al., Persistence of the hypertriglyceridemic effect of high-carbohydrate, low-fat diets in patients with non-insulin-dependent diabetes mellitus (NIDDM), Diabet. Care, 12, 94, 1989. 26. Chen YD, et al., Effect of variations in dietary fat and carbohydrate intake on postprandial lipemia in patients with non-insulin-dependent diabetes mellitus, J. Clin. Endocrinol. Metab., 76, 347, 1993. 27. Chen, YD, et al., Why do low-fat high-carbohydrate diets accentuate postprandial lipemia in patients with NIDDM? Diabet. Care, 18, 10, 1995. 28. Walker, KZ, et al., Dietary composition, body weight, and NIDDM, Diabet. Care, 18, 401, 1995. 29. Golay, A, et al., [Reaven] Similar weight loss with low-or high-carbohydrate diets, Am. J. Clin. Nutr., 63, 174, 1996. 30. Bravata, D, et al., Efficacy and safety of low-carbohydrate diets, JAMA, 289, 1837, 2003.
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31. Samaha, F, et al., A low-carbohydrate as compared with a low-fat diet in severe obesity, N. Engl. J. Med., 348, 2074, 2003. 32. Stern, L, et al., The effects of low-carbohydrate versus conventional weight loss diets in severely obese adults: one-year follow-up of a randomized trial, Ann. Intern. Med., 140, 778, 2004. 33. Foster, G, et al., A randomized trial of a low-carbohydrate diet for obesity, N. Engl. J. Med., 348, 2082, 2003. 34. Atkins, RC, Dr. Atkins’ New Diet Revolution, Rev. ed., Avon Books, New York, 1998. 35. Yancy, W, et al., A low-carbohydrate, ketogenic diet versus a low-fat diet to treat obesity and hyperlipidemia., Ann. Intern. Med., 140, 769, 2004. 36. Atkins, RC, Dr. Atkins’ New Diet Revolution, Simon & Schuster, New York, 1998. 37. Wolever, T and Mehling, C, Long-term effect of varying the source or amount of dietary carbohydrate on postprandial plasma glucose, insulin, tracylglycerol, and free fatty acid concentrations in subjects with impaired glucose tolerance, Am. J. Clin. Nutr., 77, 612, 2003. 38. Brand-Miller, J, et al., Low-glycemic index diets in the management of diabetes, Diabet. Care, 26, 2261, 2003. 39. Layman, DK, et al., Increased dietary protein modifies glucose and insulin homeostasis in adult women during weight loss, J. Nutr., 133, 405, 2003. 40. Parker, B, et al., Effect of a high-protein, high-monounsaturated fat weight loss diet on glycemic control and lipid levels in type 2 diabetes, Diabet. Care, 25, 425, 2002. 41. Gannon, MC, et al., Effect of protein ingestion on the glucose appearance rate in people with type 2 diabetes, J. Clin. Endocrinol. Metab., 88, 1040, 2001. 42. Gannon, MC, et al., An increase in dietary protein improves the blood glucose response in persons with type 2 diabetes, Am. J. Clin. Nutr., 78, 734, 2003. 43. Johnston, CS, Day, CS, and Swan, PD, Postprandial thermogenesis is increased 100 percent on a high-protein, low-fat diet versus a high-carbohydrate, low-fat diet in healthy, young women, J. Am. Coll. Nutr., 21, 55, 2002. 44. Bailey, CJ and Turner, RC, Drug Therapy: Metformin, N. Engl. J. Med., 334, 574, 1996. 45. Glucophage (metformin hydrochloride) package insert, Princeton, Bristol-Myers Squibb, December 1998. 46. Lien, LF, Bethel, MA, and Feinglos, MN, In-hospital management of type 2 diabetes mellitus, Med. Clinics of N. Am., 88(4), 1085, 2004. 47. Saltiel, AR and Olefsky, JM, Thiazolidinediones in the treatment of insulin resistance and type II diabetes, Diabetes, 45, 1661, 1996. 48. Nathan, D, Insulin treatment of type 2 diabetes mellitus, in Ellenberg & Rifkin’s Diabetes Mellitus, 6th ed., Porte, D, Sherwin, R, and Baron A, Eds., McGraw-Hill, New York, 2003. p. 515–2.
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Management of Type 2 Diabetes in Underrepresented Minorities in the U.S. Samuel Dagogo-Jack, M.D., M.B.B.S., M.Sc., F.R.C.P., F.A.C.P.
CONTENTS I. Abstract ......................................................................................................228 II. Introduction................................................................................................228 A. Goals of Diabetes Management........................................................229 III. Barriers to Effective Diabetes Management in Ethnic Minorities ...........230 A. Undiagnosed Diabetes.......................................................................230 B. Obesity and Physical Inactivity ........................................................231 C. Socioeconomic, Cultural, and Psychological Barriers .....................231 D. Provider Factors ................................................................................232 IV. Strategies and Tactics for Diabetes Management .....................................233 A. Overall Strategy.................................................................................233 1. Goal Setting.................................................................................233 2. Internal Triage .............................................................................233 3. Awareness of Pseudohypoglycemia ............................................233 B. Specific Tactics..................................................................................234 1. Nonpharmacological Measures ...................................................234 V. Prevention of Complications ....................................................................240 A. Macrovascular Complications ...........................................................240 B. Microvascular Complications............................................................241 C. Special Focus on Kidney Disease.....................................................241 D. Prevention of Lower-Extremity Amputation ....................................242 VI. Conclusions ..............................................................................................243 Acknowledgement .................................................................................................243 References..............................................................................................................243
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I. ABSTRACT African Americans and other ethnic minority groups suffer disproportionately more from diabetes and its complications than do Caucasians. Pathophysiologically, these high-risk ethnic groups exhibit greater degrees of insulin resistance compared with persons of European ethnicity. There is compelling evidence that intensive glucose control dramatically reduces the risk of diabetes complications. Indeed, the ethnic difference in morbidity from diabetes complications disappears or is markedly attenuated when Caucasians and non-Caucasians are treated to identical degrees of glycemic control. Despite this knowledge, national data indicate a poor quality of glycemic control in diabetic patients from minority populations compared with nonHispanic whites. The evidence-based goal for glycemic control in persons with diabetes is maintenance of hemoglobin A1c (HbA1c) level of 7 percent or lower. A multimodality intervention is required to reach this goal. The key elements of a comprehensive diabetes-management strategy include monitoring, education, dietary modification, exercise, and medications. The mnemonic MEDEM can be used to recall these key elements. The efficacy of nonpharmacological measures (especially caloric restriction, exercise, and weight reduction) on glycemic control has been demonstrated in persons from underrepresented minority groups; these measures constitute the foundation of initial diabetes management and subsequent adjunctive therapy together with medications. There are now several classes of oral antidiabetic agents that work via different mechanisms. These agents can be classified into insulin secretagogues (sulfonylureas, repaglinide, and nateglinide), insulin sensitizers (biguanides, thiazolidinediones), and alpha-glucosidase inhibitors. All of the available agents are approved as initial therapy, as is insulin, depending on clinical presentation. Thus, the initial choice of medication for control of hyperglycemia in type 2 diabetes patients is a matter of clinical judgement. The progressive nature of diabetes requires the use of more than one agent. As much as possible, drug combinations should be selected for their therapeutic firepower and complementary mechanisms of action. Exogenous insulin need not be delayed unnecessarily if oral agents are ineffective. Published studies and clinical experience indicate that African Americans, Latinos, Asian Americans, Pacific Islanders, and Native Americans respond remarkably well to all of the available antidiabetic medications, especially those that increase insulin sensitivity. Thus, there is no evidence for ethnic disparity in the efficacy of agents that control blood-glucose levels in diabetes.
II. INTRODUCTION African Americans, Hispanic Americans, Asian Americans, Pacific Islanders, and Native Americans now constitute approximately ~ 30 percent of the total U.S. population. The population of these underrepresented minority groups has been increasing at a faster rate than the national average. Persons from underrepresented minority groups develop type 2 diabetes at a higher rate than European Americans (1–3). Diabetic patients from underrepresented minority groups have poorer access to medical care and poorer outcomes compared with patients from the majority population (4, 5).
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The prevalence of long-term microvascular complications of diabetes (retinopathy, neuropathy, nephropathy) is severalfold higher among minorities compared with non-Hispanic whites (6–8). The ultimate result of these microvascular complications is an increased rate of blindness, lower-extremity amputation, and end-stage renal failure in patients from minority ethnic backgrounds (6–7, 9, 10). There is less ethnic disparity in the prevalence of macrovascular complications of diabetes (coronary-artery, cerebrovascular, and peripheral vascular disease), but survival postmyocardial infarction is lower in underrepresented minorities compared with nonHispanic whites (11). Nationally, the per capita health-care cost in patients with diabetes is considerably higher than that incurred by patients without diabetes. The patients with the poorest state of glycemic control, 25 percent of the diabetes population (12), generate exponentially greater health-care costs than those with better control (13). Against this backdrop is the well-known triangular relationship that directly links poor diabetic control to the development of long-term complications and the resultant prohibitive rise in health-care costs.
A. GOALS
OF
DIABETES MANAGEMENT
The therapeutic goals in diabetes are alleviation of symptoms through normalization or near-normalization of fasting and postprandial blood-glucose levels, and prevention of acute and long-term complications. There is now compelling evidence that sustained control of blood glucose to target HbA1c levels of 7 percent or lower reduces the risk for diabetes complications (14–16). In the United Kingdom Prospective Diabetes Study (UKPDS), a 0.9 percent reduction in median HbA1c (7 percent in intensive group versus 7.9 percent in controls) resulted in 74 percent reduction in the risk of doubling of serum creatinine levels (among other benefits), which could considerably delay the progression to end-stage renal failure (16). Furthermore, blood pressure control to 144/82 mmHg (versus 154/87 mmHg in the comparison group) in persons with hypertension and diabetes reduced the risks of development of any diabetes-related end point by 24 percent, diabetes-related death (32 percent), stroke (44 percent), microvascular complications (37 percent), and heart failure (56 percent) (17). Based on these compelling data, the American Diabetes Association (14) has reiterated existing guidelines that the goal of diabetes management should be the attainment and maintenance of an HbA1c level of < 7 percent (18). Numerous other tasks are called for in these guidelines (Table 13.1), including monitoring of HbA1c; methods and frequency of surveillance for renal, retinal, neuropathic, cardiac, and circulatory complications of diabetes; optimal blood-pressure control; and implementation of self-management and lifestyle recommendations, among others (18). The HbA1c goal of < 7 percent is a minimal target, because updated data from the UKPDS indicate that the adjusted incidence of myocardial infarction decreased from 25/1000 person-years to ~ 15/1000 person-years when HbA1c was lowered further from 7 percent to 6 percent (19). In the same cohort, the incidence of microvascular complications decreased from 10/1000 to 5/1000 person-years with further reduction of HbA1c from 7 percent to 6 percent (19).
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TABLE 13.1 Guidelines for Monitoring and Surveillance of Diabetic Complications Complications
Method
Frequency
Goal
Hyperglycemia Retinopathy Nephropathy Neuropathy Hypertension Dyslipidemia Heart disease Diabetic foot
Hemoglobin A1c Dilated funduscopy Microalbuminuriaa Sensation testing Sphygmomanometry Fasting lipid profile Electrocardiogramc Clinical examination
2–4 tests/yr Yearly Yearly Every visit Every visit Yearly Yearly Every visit
< 7 percent Normal retina < 30 mg/g creatinine Intact sensation < 130/80 mmHg Normal lipidsb No ischemic changes No ulceration
a 24-hour urine (normal < 300 mg/day) or spot urine < 30 micrograms/mg creatinine. b Normal lipids: LDL < 100 mg/dl, triglycerides < 150 mg/dl, HDL > 40 mg/dl(men) and > 50 mg/dl (women). c Stress cardiac testing is warranted in symptomatic patients and those with additional risk factors.
The ideal treatment for type 2 diabetes should reverse insulin resistance (and the associated metabolic syndrome), normalize hepatic glucose production, and improve pancreatic beta-cell function (20, 21). Currently, no single medication has all these properties. However, a carefully selected combination of the available agents can deliver the desired goals. Thus, the current policy of diabetes management is maintenance of blood glucose as close to the normal range as possible without intolerable hypoglycemia. The reason so many diabetic patients are poorly controlled can be attributed, at least in part, to the fact that diabetes care involves a series of specialized tasks that are difficult to implement satisfactorily in the generalist setting. For persons from underrepresented minority groups, there are additional barriers to optimal diabetes control.
III. BARRIERS TO EFFECTIVE DIABETES MANAGEMENT IN ETHNIC MINORITIES A. UNDIAGNOSED DIABETES Some of the barriers to diabetes control in ethnic minorities are listed in Table 13.2. The high prevalence of undiagnosed diabetes among minority populations (22) is a major barrier to effective diabetes control, since late diagnosis increases the likelihood of diabetic complications. Currently, there are approximately 5.4 million Americans with undiagnosed diabetes, so this is a pervasive national problem (23). The duration from onset to diagnosis of type 2 diabetes in the U.S. averages seven years (23). The development of type 2 diabetes is preceded by intermediate metabolic
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TABLE 13.2 Barriers To Optimal Diabetes Management in Ethnic Minorities General Barriers Undiagnosed diabetes Pathophysiologic: Obesity, insulin resistance Physician practices Patient practices Socioeconomic Health illiteracy Lack of well-articulated goals
Psychological Barriers Health perceptions: affect receptivity to interventions Health beliefs: control willingness to change Locus of control: intrinsic locus predicts good outcome Cultural norms and preferences: influence diet, weight, and exercise behavior
perturbations that are recognizable as impaired glucose tolerance and impaired fasting glucose (collectively referred to as prediabetes). Persons with impaired glucose tolerance have a twofold increase in the risk for cardiovascular disease compared with persons with normal glucose tolerance (24). Undiagnosed diabetes itself is associated with a further increase in cardiovascular morbidity and mortality (22), as well as 25 percent to 50 percent incidence of diabetes complications (25). Thus, delayed diagnosis of diabetes permits adverse macrovascular and microvascular complications to become firmly established. Therefore, the recommendation (18) to screen all adults with fasting-glucose measurement ought to be vigorously implemented in persons from high-risk groups.
B. OBESITY
AND
PHYSICAL INACTIVITY
National surveys indicate that obesity is more prevalent among African Americans and Hispanic Americans than non-Hispanic white persons (26). The disparity in obesity rates is particularly pronounced among women (26). Similar surveys also indicate low rates of habitual physical activity nationally (27), which is even lower in minorities (28). Obesity and physical inactivity induce insulin resistance, which negates efforts to achieve good glycemic control in patients with type 2 diabetes. Weight reduction, caloric restriction, and increased physical activity make it easier to achieve adequate control of diabetes with existing medications.
C. SOCIOECONOMIC, CULTURAL,
AND
PSYCHOLOGICAL BARRIERS
Socioeconomic limitations affect access and quality of diabetes care received by patients from underrepresented minorities (29). Lack of health insurance or underinsurance is quite prevalent among underrepresented minorities (4, 5). Low literacy rates and limited English-language skills among nonnative speakers also militate against effective medical communication. The interplay of poverty and health illiteracy can have devastating effects on health outcome. For example, in one study of economically disadvantaged African Americans seen at an urban clinic, cessation of
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insulin was the major precipitating cause of diabetic ketoacidosis (DKA) (30). Further analysis indicated that 43 percent of patients had stopped taking insulin, because they had run out of supplies and had no means of replenishing their spent stock of insulin, and 25 percent stopped taking insulin because of a fundamental misunderstanding of the role of insulin therapy during sick days (30). Thus, twothirds of the cases of DKA among African Americans in that study was preventable, either through renewal of insulin supplies or education to improve self-management skills. Cultural practices and norms that tolerate or approve high body mass inadvertently complicate the effectiveness of antidiabetic interventions, since obesity induces insulin resistance (8). Contrary to common misconception, African Americans and Hispanic Americans with diabetes are generally compliant with medical recommendations and care tasks (7, 8). Among the psychological factors (31), lack of a locus of control is perhaps the greatest obstacle to diabetes management. The locus of control (32) in the context of diabetes care refers to the person or source that patients identify as holding the key to their health. For most chronic metabolic disorders that require the implementation of multiple concurrent behavioral and self-management tasks (e.g., diet, exercise, glucose monitoring, taking medications per schedule, etc.), the proper locus of control should be intrinsic or internal (i.e., centered within the patient). Externality in locus of control generally correlates with uniformly negative outcomes, including despair, poor achievement, helplessness, ineffective stress management, decreased self-control, and depression (32). Thus, patients who correctly accept responsibility and take control will do better than those who shift the locus of control to extrinsic or external sources. The latter often identify their doctors, nurses, or other health personnel as holding the key to their health and well-being, whereas diabetes requires that the patient assume center stage and become the locus of control. A consistent goal of the doctor-patient encounter in diabetes should be the gradual transformation of all patients to a clearly well-placed locus of control (interality).
D. PROVIDER FACTORS Reduced HbA1c testing frequency and poorer results have been reported in African Americans compared with Caucasians, even in the setting of presumed equal access to care (33). Such reports indicate that there are disparities in the quality of care rendered to persons with diabetes. However, national surveys do not indicate a widespread practice of systematic undertreatment of minority patients as an explanation for the increased morbidity from diabetes that is experienced by these patients (34). What is evident is a poor overall state of diabetes control in the nation at large (29, 35). Because persons from ethnic minority groups suffer disproportionately from diabetes complications, it is imperative for diabetes caregivers to use all available resources to achieve excellent diabetes control in these subjects.
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IV. STRATEGIES AND TACTICS FOR DIABETES MANAGEMENT A. OVERALL STRATEGY 1. Goal Setting Goals are the therapeutic road maps that direct and concentrate all efforts. Without a clearly defined goal, the doctor and patient are lost at sea. Achievable goals should be set and strategies and tactics marshaled toward attainment of those goals. A typical goal in a patient with initial HbA1c of 11 percent could be to reduce that number by 1 percent by the time of follow-up visit in two months. The applicable strategies include review of current medication and adherence to lifestyle recommendations. The specific tactics include maximizing current drug doses, substitution or addition of an agent working by a different mechanism, formal referral to dietitian for reinforcement, and reinforcement of physical-activity plan. 2. Internal Triage Effective diabetes-care delivery requires a paradigm shift from the existing clinical traditions. Because patients present in different states of glycemic control, internal triaging can be a powerful strategy. Methods that enable ready identification and classification of diabetic patients (e.g., color-coded charts, special chart stickers, electronic medical-record identifiers, etc.) within a practice allow clinicians to evaluate diabetes outcomes more efficiently. It should be feasible to categorize diabetic patients by quartiles of HbA1c (< 7 percent, 7–7.9 percent, 8–8.9 percent, > 9 percent) and to triage those in the highest two quartiles for more intensive, focused attention and possible joint management with an endocrinologist (36). Excellence in diabetes care requires frequent patient contacts, especially during the down time between office visits. These contacts may be accomplished by means of telephone, facsimile, or via the Internet. These interactions have a beneficial impact on patients, build trust between the patient and caregivers, and may help modify behavior (36). Patients with chronic poorly controlled diabetes (HbA1c > 8 percent) will benefit from joint evaluation and care by a specialist. 3. Awareness of Pseudohypoglycemia Subjective symptoms suggestive of hypoglycemia occur frequently when patients with poorly controlled diabetes experience improved glycemic control. These symptoms of pseudohypoglycemia occur at blood-glucose levels that are usually within the physiological range or even higher, and are attributable to altered glycemic threshold for release of counterregulatory hormones (37). Patients undergoing intensification of diabetes management should be warned of the phenomenon of pseudohypoglycemia; many such patients may have unexpressed fears that the symptoms they feel presage imminent hypoglycemic coma. These symptoms and concerns often lead patients to discontinue or inappropriately modify recommended regimens.
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No specific treatment other than reassurance is indicated for patients with such episodes of pseudohypoglycemia.
B. SPECIFIC TACTICS The management of type 2 diabetes hinges on nonpharmacological measures (diabetes education, diet, exercise, weight loss) and drug therapy. The mnemonic MEDEM (monitoring, education, diet, exercise, medications) (38) can be used to recall the key modalities of diabetes management. 1. Nonpharmacological Measures a. Monitoring As an integrated measure of glycemic burden over the preceding two to three months, the HbA1c is the gold standard monitoring tool for diabetes control. The recommended testing frequency is one to four times/year, depending on state of glycemic control (18). The minimal goal for prevention of long-term complications is an HbA1c value of < 7 percent. As already noted, the updated UKPDS data showed significant additional microvascular and macrovascular benefits when HbA1c was lowered from 7 percent to 6 percent (19). It is important for physicians who take care of high-risk groups with diabetes to develop a keen interest in setting and reaching HbA1c targets. Patients need to be told that, since blood-glucose levels fluctuate markedly in any given day, and from day to day, a convenient way of assessing average blood glucose over periods of two to three months is by measuring the HbA1c. Patients should be helped to fully comprehend the concept, meaning and goals of A1c testing. Self-monitoring of blood glucose (SMBG) predicts adherence to other medical recommendations and is associated with superior glycemic control (39). Patients who do not perform SMBG may also tend to ignore other aspects of self-management. Thus, successful initiation of SMBG in any patient represents a step toward improved glycemic control, perhaps through activation of behavioral and other mechanisms that enhance self-management skills. The standard recommendation for patients with type 1 diabetes is to perform self-testing of blood glucose three to four times daily. The optimal frequency of self-testing for type 2 diabetes patients has not been determined, and can be negotiated with patients. Primary-care physicians should encourage patients to perform and record SMBG results, and should review the home record with interest during office visits. It is especially important that patients be made to realize that the numbers are actually used to make changes in the treatment plan (34). b. Diabetes Education Referral for diabetes education is an integral part of diabetes management. The core message to get across to patients is that control of blood sugar matters. A patient with average blood-glucose levels of 200–250 mg/dl will have at least twofold greater risk of developing retinopathy, neuropathy, and nephropathy than a patient with average glucose levels of 150–160 mg/dl, over the course of several years. An
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effective diabetes educational intervention should increase patients’ understanding of the roles of HbA1c testing and SMBG in the management of diabetes and induce enhanced self-management skills. The quality, content, and impact of diabetes education received from various sources (certified diabetes educators, nutritionists, pharmacists, etc.) need to be assessed periodically by the treating physician (40). c. Diet and Exercise Interventions Restriction of total and saturated fat intake, with augmentation of complex carbohydrates and dietary fiber, has been demonstrated to enhance insulin action (41). Regular exercise, caloric restriction, and weight reduction are effective in preventing type 2 diabetes in high-risk African Americans, Hispanic Americans, Asian Americans, Pacific Islanders, Native Americans, and European Americans (41). These lifestyle measures also are potent adjuncts to medications for type 2 diabetes. To be effective, programs should include aerobic exercise at 50 percent to 70 percent of maximal oxygen uptake for 20–45 min three or more times per week. Also, the program should be tailored to individual patients’ physical condition, and should always include appropriate warm-up and cool-down periods. The cultural factors operating against weight-modification strategies in urban America require innovative solutions. A grassroots movement to promote widespread development and use of neighborhood fitness centers is one approach. Lobbying for legislation to defray the cost of purchasing home fitness equipment or fitness-club memberships as tax-deductible health expenses (at par with prescription medicines) is another strategy that can greatly increase the mass appeal of fitness campaigns. The dietary goals can be pursued through referral to dietitians and medical nutrition therapists. However, until clinical exercise physiologists become routinely available, physicians should become the major protagonists of exercise, issuing written prescriptions to help trigger the behavioral change (34). A good exercise prescription should have three elements: 1) a clear rationale — this can be established by briefly discussing the metabolic benefits of moderate exercise; 2) specificity — “walk for 10 min every Monday, Wednesday, Friday” is a better script than “exercise regularly”; and 3) scalability — the exercise prescription should gradually be scaled up. For example, “Increase walks to 20 min on Monday, Wednesday, Friday after one week.” A clear plan should be established for evaluation of adherence and efficacy of the program. A small investment in inexpensive home-exercise equipment (e.g., stationary bike) may be necessary if outdoor opportunities for exercise are limited or precarious. Of course, noninvasive cardiac screening before exercise is always prudent in patients who have been chronically sedentary. Exercise recommendations should be tailored to individual patients’ physical condition, and should always be delivered with the same conviction that accompanies prescription medicine. Overall, diabetes education and dietary and exercise counseling constitute the foundation of diabetes management, and their efficacy has been demonstrated in numerous studies (42, 43). Nonpharmacologic treatment modalities are effective in minority populations, as demonstrated in a study at Grady Memorial Hospital in Atlanta, Georgia (44). Using a lifestyle approach based broadly on the principles discussed earlier, Ziemer and colleagues demonstrated excellent response rates among African American patients with type 2 diabetes. Within 6 to 12 months of
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TABLE 13.3 Oral Medications for Treatment of Type 2 Diabetes Class/Generic Name Sulfonylureas Chlorpropamide Glipizide Glipizide extended-release Glyburide Glyburide, micronized Glimepiride Nonsulfonylurea secretagogues Repaglinide Nateglinide α-Glucosidase inhibitors Acarbose Miglito Biguanides Metformin Metformin, extended-release Thiazolidinediones Rosiglitazone Pioglitazone
Trade Name
Dose Range (Daily)
Diabinese Glucotrol Glucotrol XL Micronase Diabeta Glynase Amaryl
100–750 mg 5–40 mg 5–20 mg 1.25–20 mg 1.25–20 mg 1.5–12 mg 1–8 mg
Prandin Starlix
1–16 mg 120–360 mg
Precose Glyset
25–300 mg 25–300 mg
Glucophage Glucophage XR
850–2550 mg 500–2000 mg
Avandia Actos
4–8 mg 15–45 mg
initiation of the program, HbA1c levels decreased by nearly 2 percent, and the need for pharmacologic therapy was substantially reduced (44). d. Medications for Treatment of Type 2 Diabetes The maintenance of long-term glycemic control (necessary for prevention of complications) in persons with type 2 diabetes often requires the use of multiple agents in combination. Medications for combination therapy should be selected from drug classes that lower blood glucose by different mechanisms, to ensure additive or synergistic effects and to maximize nonglycemic benefits related to weight, lipid profile, and cardiovascular risk markers. The available agents that are currently approved for oral therapy of type 2 diabetes belong to six distinct chemical classes (Table 13.3). Functionally, these agents can be classified into insulin secretagogues (sulfonylureas, repaglinide, and nateglinide), insulin sensitizers (biguanides, thiazolidinediones), and alpha-glucosidase inhibitors (acarbose and miglitol). All of these agents have tissue-specific actions to improve blood-glucose control. Thus, the initial choice of medication for control of hyperglycemia in type 2 diabetes patients is a matter of clinical judgment. Monotherapy with maximum doses of insulin secretagogues, metformin, or thiazolidinediones yields comparable glucose-lowering effects (20, 21). Insulin
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secretagogues exert their glucose-lowering effects acutely, whereas the maximum effects of metformin or thiazolidinediones may not be observed until after several weeks of medication. Since residual pancreatic beta-cell function is required for the glucose-lowering effects of all insulin secretagogues, metformin, and thiazolidinediones, many patients with advanced type 2 diabetes will not respond satisfactorily to any of these agents. Insulin therapy may thus be an early choice for such patients. Moreover, the toxicity profile of a given oral agent may preclude its use in patients with comorbid conditions. The alpha-glucosidase inhibitors (acarbose, miglitol) are less potent in monotherapy but are useful options for combination therapy. An additional basis for selecting oral agents relates to their nonglycemic effects, especially those that impact on cardiovascular risk factors. Aggressive control of hypertension, dyslipidemia, and obesity should be integrated into routine diabetes-management practices. 1.
Insulin Secretagogues
The sulfonylureas bind to specific membrane receptors on beta cells and cause membrane depolarization by directly inhibiting KATP channels, which permits intracellular buildup of calcium. The resultant stimulus-secretion coupling leads to insulin secretion (45, 46). Overall, sulfonylurea therapy is well-tolerated and cost-effective. Some type 2 diabetes patients do not respond to sulfonylurea therapy (primary failure), while others will fail to do so after having responded for several years (secondary failure) (47, 48). The mechanism of primary or secondary sulfonylurea failure relates to progressive pancreatic beta-cell dysfunction in type 2 diabetes. Hypoglycemia, weight gain, and hyperinsulinemia are notable side effects of sulfonylureas. There is no clinical evidence that sulfonylurea drugs increase the risk for cardiovascular disease (16). Sulfonylureas have been the mainstay of type 2 diabetes therapy since the 1950s and are effective in all demographic groups. All the currently available sulfonylureas induce insulin secretion through interaction with cell-surface receptors on pancreatic β-cells, which is their primary mechanism for lowering blood glucose. There is no convincing evidence that the sulfonylureas alter insulin sensitivity directly. The nonsulfonylurea insulin secretagogues include repaglinide and nateglinide. These shorter-acting agents stimulate insulin secretion by mechanisms similar to those used by the sulfonylureas (49, 50). They have less tendency to induce weight gain or hypoglycemia compared with sulfonylureas. 2.
Metformin
Metformin, the only biguanide currently available in the U.S., exerts its glucoselowering effect primarily by reducing hepatic glucose production and, to a lesser extent, by increasing muscle-glucose utilization (51). Metformin is effective in persons from all ethnic groups (41). Achievable glycemic control using metformin monotherapy is comparable to that achieved using sulfonylurea, but metformin therapy does not induce weight gain and has a low risk of hypoglycemia (52). In the UKPDS (16), metformin-treated patients experienced a 39 percent reduction in the incidence of myocardial infarction compared with 16 percent reduction in those treated with sulfonylurea or insulin.
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Metformin is taken with food, and, beginning with a single 500-mg or 850-mg tablet, the dose is increased slowly every one to two weeks until optimal glycemic effect is achieved or maximum doses (2000–2550 mg/d) are reached. Gastrointestinal side effects are frequent, but tend to abate with time or upon dose reduction. Lactic acidosis, the most dreaded adverse effect, is rare (~ three cases per 100,000 patientyears) but potentially fatal (52). The risk for lactic acidosis is increased in patients with a history of renal dysfunction (serum creatinine > 1.4 mg/dl [women], > 1.5 mg/dl [men]), hepatic dysfunction, alcoholism, and tissue hypoxia from systemic illnesses. Metformin should not be used in such patients. Also, some patients who had responded initially to metformin may fail to do so with continued therapy, probably as a result of progressive beta-cell failure, since the glucose-lowering effect of metformin requires the presence of insulin. 3.
Thiazolidinediones
The thiazolidinediones (TZDs) reduce fasting and postprandial glucose levels and HbA1c, and enhance insulin sensitivity and whole-body glucose disposal, as well as improve pancreatic β-cell function (53–55). Monotherapy with the available TZDs, rosiglitazone and pioglitazone, in patients with type 2 diabetes results in a glucoselowering effect comparable with sulfonylurea or metformin monotherapy. The insulin sensitivity induced by TZDs is mediated by binding to nuclear receptors of the peroxisome proliferator-activated receptor-γ (PPAR-γ) class and enhanced expression and transcription of genes that regulate glucose and lipid metabolism (56). The beneficial effects of rosiglitazone has been demonstrated in type 2 diabetes patients from various ethnic minority groups, including African Americans, Hispanic Americans, and Asian Americans (57–59). Osei and colleagues (57) found a greater response to the glucose-lowering effect of rosiglitazone among African American patients with type 2 diabetes compared with non-African Americans. The potent insulin-sensitization effects of TZDs is accompanied by benefits on components of the metabolic syndrome, including improved enthothelial function, reduction in free fatty acids and blood pressure, and alteration of markers of inflammation, hypercoagulation, and atherosclerosis (56, 60, 61). Studies are in progress to determine whether these favorable effects will translate to a reduced risk of cardiovascular events in TZD-treated diabetic patients. The adverse effects of the TZD class include weight gain and edema from fluid retention. The weight can be minimized by caloric restriction and physical activity. Edema is uncommon (< 5 percent) during TZD monotherapy, but can occur in up to ~ 15 percent of persons treated with TZDs in combination with insulin or insulin secretagogues. Plasma-volume expansion is a class effect of the TZDs, and only in a small minority (< 1 percent) of patients treated with TZDs is the edema associated with congestive heart failure (62). Because increased plasma volume is undesirable in the setting of preexisting cardiac congestion, use of TZDs is not appropriate in patients with New York Heart Association (NYHA) class III or IV congestive heart failure. Baseline and periodical liver-function testing is required in patients treated with TZD; ALT levels > 2.5 × upper normal limit preclude the use of these agents.
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Combination Therapy
The UKPDS showed the futility of monotherapy as a strategy for long-term glycemic control in type 2 diabetes (63). After three years, only ~ 50 percent of patients enrolled in the UKPDS were able to maintain the HbA1c goal of 7 percent or lower; by nine years, the number had declined to ~ 25 percent. Thus, early use of drug combinations is the rational approach to sustained glycemic control and prevention of complications in patients with type 2 diabetes. Because of the longer latency of disease in minority populations with a high burden of undiagnosed diabetes (22), early use of combination therapy should be considered in these populations. Each of the individual drugs already discussed has been documented to be a suitable agent for use in combination with drugs from other classes. Perhaps the best-documented treatment strategy is one that combines an insulin-sensitizer agent with a secretagogue (64, 65). The use of two sensitizer drugs, such as a TZD and metformin, is an effective strategy that improves glycemic control while minimizing the risks of weight gain and hypoglycemia (66, 67). Indeed, double-sensitizer therapy has particular merit among high-risk ethnic populations with endemic insulin resistance (8). The recent introduction of fixed-dose combination agents facilitates the practice of combination therapy. Theoretically, use of these fixed-dose agents may augur well for long-term medication compliance in diabetes patients, who often also take several medications for comorbid conditions. Currently, there are three such fixed-dose combination agents: glyburide/metformin (Glucovance®; Bristol-Myers Squibb Company; Princeton, New Jersey), rosiglitazone/metformin (Avandamet™; GlaxoSmithKline, Research Triangle Park, North Carolina), and metformin/glipizide (Metaglip™; Bristol-Myers Squibb Company; Princeton, New Jersey). Other fixeddose combinations are in development. In using these fixed-dose combination products, care must be taken to ensure that patients meet the safety criteria for use of each individual component. Combination therapy will be most effective if initiated as part of a comprehensive diabetes-care plan, and after a careful consideration of possible barriers to metabolic control. The decision to continue a combination regimen should be based on evidence of continuing efficacy, safety, and tolerability, and such evidence should be reevaluated at frequent intervals. The efficacy of most combination regimens can be reliably evaluated over a three- to six-month period. Thus, patients who have been on an oral-drug combination regimen for three to six months and whose HbA1c exceeds 7 percent may be candidates for supplemental insulin therapy. 5.
Indications for Insulin Therapy in Type 2 Diabetes
In the UKPDS, estimates of pancreatic beta-cell function revealed that in most patients with type 2 diabetes β-cell function had decreased by ~ 50 percent at the time of diagnosis and continued to deteriorate over time (68). The progressive decline in beta-cell function predicts a future need for exogenous insulin in type 2 diabetes patients. Immediate insulin therapy is indicated for initial stabilization of type 2 diabetes patients with ketoacidosis, hyperosmolar state, or severe hyperglycemia. In otherwise stable patients, exogenous insulin can be considered as an adjunct to oral agents if glycemic control is suboptimal. Insulin therapy can be initiated in a number of ways. Patients with type 2 diabetes that has been managed with oral agents for
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many years are understandably reticent about the prospects of starting insulin. Care must be taken to explain the rationale and benefits of optimizing glycemic control and the demonstrated efficacy of insulin in accomplishing that objective. The physician may also need to address the exaggerated and often inaccurate concerns that some patients harbor regarding the safety of insulin. Preemptory discussion of the phenomenon of pseudohypoglycemia may also help to increase the patient’s confidence in the period following initiation of insulin therapy. The most widely used approaches include: 1) basal insulin (e.g., glargine) at bedtime, with continuation of oral agents; 2) split-mixed regimens that deliver a mixture of regular insulin or analogue (lispro, aspart) and an intermediate-acting insulin (NPH), delivered in two injections 12 hours apart; or 3) basal-bolus regimens consisting of basal insulin and premeal boluses of short-acting insulin. Combination regimens of exogenous insulin with sulfonylurea, metformin, TZDs, and alphaglucosidase inhibitors are in widespread use. Oftentimes, the insulin requirement can be significantly reduced by concurrent use of a TZD or metformin. The use of sulfonylurea, metformin or TZD plus bedtime basal insulin is an efficacious strategy for lowering glucose levels, but it must be noted that the sulfonylurea-plus-insulin regimen has no impact on the underlying insulin resistance in type 2 diabetes. Basal insulin can be started as bedtime NPH or glargine at a low initial dose (~ 10 units) and increased by ~ 4 units every few days (while continuing oral agents) until a fasting blood-glucose level of 80–120 mg/dl is achieved (69). Obviously, patient cooperation in monitoring and relaying home blood-glucose levels to the clinic is critical to the success of this titration approach. In the Treat-to-Target trial (69), the average bedtime dose of basal insulin (NPH or glargine) needed to achieve a fasting plasma glucose level of ~ 100 mg/dl was approximately 50 units. Patients who do not achieve a fasting glucose target of 80–120 mg/dl despite injecting > 50 units of basal insulin at bedtime may require multiple injections of mixed short- and longer-acting insulin preparations for optimal control. Typically, large daily doses of insulin (> 100 U/day) are required to maintain optimal glycemic control in patients with type 2, although concurrent use of insulin-sensitizer drugs may decrease the insulin requirement. The notable side effects of insulin therapy include weight gain and hypoglycemia, the latter being infrequent in patients with type 2 diabetes. There is no evidence that insulin therapy increases cardiovascular risk in patients with diabetes. Indeed, in the UKPDS there was a 16 percent reduction in myocardial infarction in the group treated with insulin and sulfonylurea, compared with the diet-treated control group (16).
V. PREVENTION OF COMPLICATIONS A. MACROVASCULAR COMPLICATIONS A comprehensive approach to modification of cardiovascular risk factors is recommended, because most diabetic patients die from heart disease or stroke. Therapeutic interventions include smoking cessation, control of dyslipidemia (LDL-cholesterol goal in diabetes is < 100 mg/dl), blood pressure control (goal < 130/80), aspirin
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prophylaxis, and maintenance of HbA1c of < 7 percent. The value of pursuing more stringent glycemic control (HbA1c < 6 percent) to further reduce cardiovascular disease in diabetes is currently being investigated. Coronary-artery disease and myocardial infarction present in atypical ways in diabetes, so symptoms are unreliable. A high index of suspicion and a low threshold for ordering stress cardiac testing is appropriate in diabetic patients. Intensive glucose control in patients with acute myocardial infarction has been demonstrated to reduce short-term and long-term mortality in diabetic patients (70). Thus, excellent glycemic control not only is necessary to prevent the development of complications, but also helps improve survival in persons with diabetes who have suffered acute myocardial infarction.
B. MICROVASCULAR COMPLICATIONS The microvascular complications (retinopathy, nephropathy, and neuropathy) develop after several years of uncontrolled diabetes. The usually gradual time course of these complications affords an opportunity for early detection and tertiary prevention (i.e., prevention of morbidity and mortality from progression of diabetic complications). The best prophylaxis against microvascular complications is tight glycemic control (15, 16). There is also tremendous value in early detection through surveillance and prompt action (Table 13.1).
C. SPECIAL FOCUS
ON
KIDNEY DISEASE
The ethnic disparity in end-stage kidney disease (which disproportionately afflicts African Americans) is staggering (71). The scarcity of donor kidneys for transplantation means that thousands of patients spend several years on dialysis without a chance of receiving kidney transplants. Thus, the emphasis should be on prevention of kidney disease, since cure cannot be offered to all affected persons. Both microalbuminuria, the earliest (and reversible) stage of kidney disease, and gross proteinuria precede end-stage renal failure by variable, but lengthy, intervals. This knowledge creates a window of opportunity for timely interventions to prevent further decline in renal function. Initial screening for microalbuminuria is recommended at diagnosis in patients with type 2 diabetes, and in persons with type 1 diabetes of five years or longer duration. Annual follow-up measurements are recommended thereafter (18). Three screening methods are available: 1) measurement of the microalbumin-to-creatinine ratio in a random spot urine specimen; 2) 24-hour urine collection, which allows simultaneous measurement of creatinine clearance; and 3) timed, less than 24-hour collection (e.g., overnight, or four-hour samples). For many years, the mainstay of surveillance was measurement of albumin excretion in a 24-hour or timed urine specimen. Such measurements (especially the 24-hour collections) were cumbersome and notoriously inaccurate for large-scale population screening. A major advance in the field has been the validation of spot urine specimens for screening. Simultaneous measurement of microalbumin and creatinine concentrations in spot urine samples yields informative results when microalbuminuria is expressed as a ratio of creatinine excretion. A first-void or
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morning collection is preferable because of diurnal variation in albumin excretion. The normal range is a spot urine microalbumin concentration of < 30 microgm per mg creatinine, which is equivalent to < 30 mg/24h. The convenience of spot urine screening offers great opportunity for disease surveillance during office visits. Because day-to-day variations occur in albumin excretion, it is prudent to obtain repeat (confirmatory) measurements. Measured under the right conditions, a spot urine microalbumin level of 30–300 microgm/mg creatinine indicates incipient nephropathy. The measurement may be repeated for confirmation. Levels greater than 300 microgm microalbumin/mg creatinine are consistent with gross proteinuria and established nephropathy; precise quantitation of proteinuria in a 24-hour urine collection is indicated for proper management of such patients (72). Interventions that have been proven to delay the decline in renal function include tight control of blood glucose (HbA1c < 7 percent), blood pressure (< 120/80 mmHg), dyslipidemia, smoking cessation, and other risk factors. It is now firmly established that angiotensin converting enzyme (ACE) inhibitors (73) and angiotensin receptor blockers (ARB) (74) are most effective in preserving renal function in diabetic patients with microalbuminuria as well as those with more advanced forms of proteinuria and nephropathy. ACE inhibitors are well-tolerated by normotensive diabetic patients with microalbuminuria. The concurrent use of an ACE inhibitor and an ARB has been reported to yield additive benefits (75) and may be considered for optimal nephroprotection in high-risk patients with persistent or refractory microalbuminuria.
D. PREVENTION
OF
LOWER-EXTREMITY AMPUTATION
Diabetes accounts for ~ 50 percent of cases of nontraumatic lower-extremity amputations in the U.S. As already noted, ethnic minority patients undergo lower-extremity amputation at multiple times the rate seen in diabetic Caucasians. The risk factors for lower-extremity amputation in persons with diabetes include peripheral neuropathy, peripheral vascular disease, deformities, trauma, and deep-tissue infections. With the possible exception of trauma, most of these risk factors are impacted by the state of metabolic control. Poor control of blood glucose is associated with increased risk of infections, impaired wound healing, and development of long-term diabetic complications, such as neuropathy and peripheral vascular disease. Additional risk factors for peripheral vascular disease include hypertension, cigarette smoking, and elevated blood cholesterol levels. The interventions (20, 34) that increase the chances of limb preservation and reduce amputation risk include: 1) tight control of blood glucose (and of blood pressure); 2) smoking cessation; 3) daily foot inspection by patients; 4) appropriate footwear; and 5) regular physical examinations by physician, including an assessment of arterial pulses and skin sensation (using a 5.07/10 gm monofilament). Patients should be referred to podiatrists for evaluation of seemingly mild foot lesions before they develop into limb-threatening, gangrenous ulcers. Aggressive in-patient treatment with broad-spectrum parenteral antibiotics, debridement, and local wound care may help salvage limbs that would otherwise have been amputated.
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VI. CONCLUSIONS Diabetes and its complications disproportionately affect persons from underrepresented ethnic minority groups. Although genetic factors probably account for the increased susceptibility to diabetes, studies have shown that controlling bloodglucose levels to comparable degrees eliminates or dampens the ethnic disparities in diabetes complications (7, 8, 76). Moreover, lifestyle and pharmacological interventions for prevention of type 2 diabetes were equally efficacious in persons of African, Asian, European, Hispanic, and Native American ancestry (41). Thus, there is no evidence of ethnic disparities in the responsiveness to behavioral or pharmacological intervention for the prevention or treatment of type 2 diabetes. In this regard, the continuing burden of diabetes and its complications among persons from underrepresented minorities indicates a failure of current health priorities, practices, and implementation. A multimodality intervention approach is recommended for optimization of glycemic control and prevention of metabolic, renal, retinal, neuropathic, and cardiovascular complications. The key elements of a comprehensive diabetes-management strategy include monitoring, education, dietary modification, exercise, and medications. Owing to the progressive nature of type 2 diabetes, achievement of optimal glycemic targets often requires the use of multiple medications. Aggressive therapy for comorbid conditions (especially hypertension and dyslipidemia) is an integral part of the comprehensive strategy.
ACKNOWLEDGEMENT Dr. Dagogo-Jack is supported in part by NIH Clinical Research Center Grant MO1 RR00211.
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61. Hirose, H, Kawai, T, Yamamoto, Y, et al., Effects of pioglitazone on metabolic parameters, body fat distribution, and serum adiponectin levels in Japanese male patients with type 2 diabetes, Metabolism, 513:314–317, 2002. 62. Nesto, RW, Bell, D, Bonow, RO, et al., Thiazolidinedione use, fluid retention, and congestive heart failure: a consensus statement from the American Heart Association and American Diabetes Association, Circulation, 108:2941–2948, 2003. 63. Turner, RC, Cull, CA, Frighi, V, Holman, RR, for the UK Prospective Diabetes Study (UKPDS) Group, Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49), JAMA, 281:2005–2012, 1999. 64. Luna, B and Feinglos, MN, Oral agents in the management of type 2 diabetes mellitus, Am. Fam. Phys., 63:1747–1756,2001. 65. Wolffenbuttel, BHR, Gomis, R, Squatrito, S, Jones, NP, and Patwardhan, RN, Addition of low-dose rosiglitazone to sulphonylurea therapy improves glycaemic control in type 2 diabetic patients, Diabet. Med., 17:40–47, 2000. 66. Fonseca, V, Rosenstock, J, Patwardhan, R, and Salzman, A, Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial, JAMA, 283:1695–1702, 2000. 67. Jones, TA, Sautter, M, Van Gaal, LF, and Jones, NP, Addition of rosiglitazone to metformin is most effective in obese, insulin-resistant patients with type 2 diabetes, Diabet. Obes. Metab., 5:163–170, 2003. 68. UK Prospective Diabetes Study Group, UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease (erratum appears in Diabetes 45:1655, 1996), Diabetes, 44:1249–1258, 1995. 69. Riddle, MC, Rosenstock, J, Gerich, J, et al., The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients, Diabet. Care, 26:3080–3086, 2003. 70. Malmberg, K, Prospective randomised study of intensive insulin treatment on long term survival after acute myocardial infarction in patients with diabetes mellitus. DIGAMI (Diabetes Mellitus, Insulin Glucose Infusion in Acute Myocardial Infarction) Study Group, B.M.J., 314:1512–1515, 1997. 71. United States Renal Data System, Am. J. Kidney Dis., 42(6 Suppl. 5):1–230, 2003. 72. Kussman, MJ, Gildstein, HH, and Gleason, RE, The clinical course of diabetic nephropathy, JAMA, 236:1861–1863, 1976. 73. Lewis, EJ, Hunsicker, LG, Bain, RP, and Rohde, RD, The effect of angiotensinconverting-enzyme inhibition on diabetic nephropathy, N. Engl. J. Med., 329:1456–1462, 1993. 74. Brenner, BM, Cooper, ME, de Zeeuw, D, Keane, WF, Mitch, WE, Parving, H-H, Remuzzi, G, Snapinn, SM, Zhang, Z, and Shahinfar, S, Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy, N. Engl. J. Med., 2001;345:861–869. 75. Rosner, MH and Okusa, MD, Combination therapy with angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists in the treatment of patients with type 2 diabetes mellitus, Arch. Intern. Med., 163:1025–1029, 2003. 76. Cruickshank, JK and Alleyne SA, Black West Indian and matched white diabetics in Britain compared with diabetics in Jamaica: body mass, blood pressure, and vascular disease, Diabet. Care, 10:170–179, 1987.
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Management of Diabetes in Developing Countries Jean Claude Mbanya, M.D., M. Phil., Ph.D. and Eugene Sobngwi, M.D., M. Phil., Ph.D.
CONTENTS I. Introduction................................................................................................249 II. Epidemiology.............................................................................................250 III. Pathophysiology.........................................................................................251 A. The So-Called Tropical Diabetes......................................................251 B. Ketosis-Prone Atypical Diabetes Mellitus or Type 1B Diabetes ..............................................................................252 IV. Clinical Presentation..................................................................................253 A. At Diagnosis......................................................................................253 B. Complications of Diabetes ................................................................253 V. Management of Diabetes in a Developing Country .................................254 A. Organization of Diabetes Care..........................................................254 B. Cultural Aspects of Diabetes Care....................................................255 C. Diabetes Education............................................................................255 D. Lifestyle Management of Diabetes ...................................................256 1. Dietary Management ...................................................................256 2. Physical Activity..........................................................................257 VI. Drug Management of Diabetes .................................................................259 A. Oral Hypoglycemic Drugs ................................................................259 B. Insulin Therapy..................................................................................259 C. Management of Ketosis-Prone Diabetes...........................................260 VII. Cost of Diabetes Care................................................................................261 VIII. Conclusions................................................................................................263 References..............................................................................................................263
I. INTRODUCTION The concept of developing countries is wide by definition and therefore is likely to lead to inappropriate generalization. In fact, important differences exist between countries classified as developing, and even within a single country, there might be a wide socioeconomic gap between geographical areas and between individuals. 249
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The present chapter will attempt to tackle some of the main issues related to the management of diabetes that are common to most developing countries, but with emphasis on Sub-Saharan Africa (SSA).
II. EPIDEMIOLOGY Developing countries are experiencing one of the most rapid demographic and epidemiological transitions, which is characterized by increasing life expectancy and lifestyle changes due to economic development. These factors, including the advent of urbanization, industrialization, and mechanization, leading to improvements in nutrition and sanitation, have led to the decline in the prevalence of infectious diseases and the emergence of diseases of aging, notably noncommunicable diseases, such as diabetes. At the beginning of the last century, diabetes mellitus was considered as a rare medical condition in Africa, as illustrated by the famous statement of Dr. Cook, who wrote: “… diabetes is very uncommon but very fatal” in his 1901 notes on the diseases met in Africa (1). However, there is currently a global trend toward the increase of the incidence and prevalence of diabetes mellitus in these populations. The estimated prevalence of diabetes in Africa is 1 percent in rural areas, up to 5 percent in urban SSA, and 8 percent to 13 percent in more developed areas such as South Africa and in population of Indian origin (2, 3). The incidence of type 1 diabetes mellitus varies from 4 to 10/100,000 among the 0- to 19-year-old population in Africa with a high mortality rate (4, 5). While the majority of the patients (70 percent to 90 percent) present with typical type 2 diabetes, up to 25 percent of patients are considered to have type 1 diabetes, but among these patients, it is currently estimated that around 15 percent may have atypical presentations of diabetes, especially type 1B, also called ketosis-prone atypical diabetes, and tropical diabetes (3, 6). The identified risk factors are not markedly different from those reported in other populations. Age and ethnicity are the main nonmodifiable determinants. In Africa, the highest prevalence is found in adult populations of Indian origin, followed by black populations and Caucasians (7, 8). This suggests a genetic predisposition that has not been confirmed yet. Among the modifiable risk factors, residence seems a major determinant, since urban residents have a 1.5-fold to fourfold higher prevalence of diabetes compared to their rural counterparts (9). This is attributable to lifestyle changes associated with urbanization and Westernization characterized in Africa by changes in dietary habits involving an increase in consumption of refined sugars and saturated fat, a reduction in fiber intake, and drastic reduction in physical activity. Rural dwellers have higher physical-activity-related energy expenditure compared to urban subjects (10, 11). Consequently, obesity prevalence is at least four times higher in urban compared to rural areas (12). At present, the population of Africa is predominantly rural (34 percent urban), but by 2025 more than 70 percent of the population will live in the urban areas (13). Life expectancy at birth is rapidly increasing; in 1960 it was around 35 years in Cameroon and rose to approximately 55 years in 1990. The changes in the age structure of the population and rapid urbanization in developing countries will lead to an increase in the prevalence of diabetes, such that by the year 2025 the majority of the world diabetes population will be living in the developing countries (14, 15).
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It is estimated that, while there will be a 42 percent increase of diabetes prevalence in the developed countries, this increase will be more than 170 percent in the developing countries between 1995 and 2025, such that by the year 2025, more than 75 percent of people with diabetes will reside in developing countries. Eight of the top 10 countries for estimated number of adults with diabetes by the year 2025 will be in the developing world (14).
III. PATHOPHYSIOLOGY There are no reported significant specificities in the pathophysiology and phenotype of classical type 1 and type 2 diabetes. Nevertheless, in type 2 diabetic patients of African ancestry, the beta-cell failure mechanism tends to predominate over the insulin-resistance mechanism (16, 17). It would, however, appear that the pathophysiology of diabetes in developing countries is different because up to 20 percent of the patients may be difficult to classify due to atypical presentations of diabetes. They include patients with tropical diabetes mellitus that has been linked to malnutrition; and an atypical diabetes presenting as type 1 diabetes at onset, with a subsequent clinical course of type 2 diabetes, or prolonged remission classified as idiopathic type 1, or type 1b, or ketosis-prone atypical diabetes.
A. THE SO-CALLED TROPICAL DIABETES It was first described in 13 patients from Jamaica, and subsequently in Indonesia, Uganda, India, and several other countries (18). The 1985 World Health Organization (WHO) Study Group report on diabetes recognized tropical diabetes as a specific type and labeled it as malnutrition-related diabetes mellitus and subdivided it into protein-deficient pancreatic diabetes and fibrocalculous pancreatic diabetes (19). There are still many controversies surrounding this form of diabetes. The usual description of protein-deficient diabetes mellitus or malnutritionmodulated diabetes mellitus is that of a clinical syndrome occurring in the young, malnourished subjects in the developing world with early onset, usually below the age of 30 years. These individuals require high doses of insulin (> 1.5U/Kg/day) to obtain adequate glycemic control, but they are not ketotic-prone even if insulin is withdrawn. They have a low body-mass index with other clinical features of malnutrition, often with growth retardation. There is absence of imaging evidence of pancreatic calculi or ductal dilatation. The pathogenesis of this form of diabetes is unknown (18). Fibrocalculous pancreatic diabetes (FCPD) is highly prevalent in developing countries of the tropical belt and is characterized by chronic calculus pancreatopathy not due to alcoholism or other recognized, ascribable causes, such as hyperparathyroidism. The pathogenesis of FCPD is uncertain, although nutritional, environmental, and genetic factors have been postulated. Malnutrition has been identified as an etiological factor; however, there is very little evidence to support this association. Fibrocalculous pancreatic diabetes is usually seen in young and malnourished individuals in their 20s and not uncommonly in middle age and rarely in children and adolescents in whom there is diabetes and pancreatic or ductal dilatation. The
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FIGURE 14.1 Pancreatic calcification (arrows) in a patient with fibrocalculous pancreatic diabetes.
diagnosis of FCPD is based on the demonstration of large, multiple, and intraductal pancreatic calculi in the presence of diabetes (Figure 14.1). Exocrine pancreaticfunction tests, when performed, are invariably abnormal (18).
B. KETOSIS-PRONE ATYPICAL DIABETES MELLITUS DIABETES
OR
TYPE 1B
The most often reported atypical form of diabetes in populations of African ancestry is characterized by an initial clinical presentation of type 1 diabetes with severe symptomatic hyperglycemia and ketosis, and a subsequent long-term remission with or without relapses, compatible with type 2 diabetes. Type 1B diabetes has mostly been described in populations of African ancestry, and seldom in Asians and Caucasians (20). In adults, the age at diagnosis varies from 30 to 60 years, also with a strong male preponderance (M/F sex ratio 1.5 to 3). Where reported, the prevalence of family history of diabetes is high, approaching 80 percent. Adults with atypical diabetes are less often obese than children. Depending on the population studied, obesity is present in not more than 56 percent of the patients with ketosis. The mean body-mass index at diagnosis was 26, 28–30, and 37 in the Paris, New York, and Atlanta cohorts, respectively. In Asians, at diagnosis, age is lower (15–23 years in Japanese, and 16–46 years in Chinese), and BMI is around 29 kg/m2 (21–25). Unlike patients with true young-onset type 1 diabetes, there is no evidence of autoimmune destruction of pancreatic beta cells. Antiglutamic acid decarboxylase
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(GAD) or islet cell antibodies (ICA) are an exceptional finding. However, the HLA alleles associated with susceptibility to type 1 diabetes are present in high frequency in some populations with this form of diabetes. Because of these mixed features, this clinical entity has been referred to as type 1.5, phasic insulin-dependent diabetes mellitus, atypical diabetes, and now idiopathic type 1 diabetes mellitus or type 1B (20). Insulin resistance is found mostly in the obese patients and is not a constant metabolic characteristic of this form of diabetes. By contrast, insulin secretion is always affected. At presentation, the basal C-peptide is higher than that of patients with classical type 1 diabetes and lower than in nondiabetic control populations. There is no acute insulin response to intravenous glucose, but a significant response to IV glucagon persists. During remission there is a partial recovery of insulin responsiveness to glucose stimulation (threefold increase). The response to glucagon is also improved. The defect of insulin secretion is at least partially reversible and may not be due to definitive beta-cell destruction (26).
IV. CLINICAL PRESENTATION A. AT DIAGNOSIS The classical symptoms of diabetes, including polyuria and polydipsia, are similar to those seen elsewhere in the world. However, difficult access to health care or late report to medical facilities leads to a high frequency of severe presentations at diagnosis. Most patients may present with sepsis or diabetic coma (diabetic ketoacidosis and hyperosmolar nonketotic states), while a minority are asymptomatic and are therefore identified at screening. In some cohorts, infection may be the revealing mode of diabetes in up to 22 percent of the patients (27), sometimes with mucormycosis and deep palmar infections that are rarely seen in developed countries (28). Neuropathic symptoms, foot ulcerations, and stroke are frequent causes of consultation or admission leading to the diagnosis of type 2 diabetes, and 20 percent to 25 percent of type 2 diabetic patients present at diagnosis already with retinopathy (29). Type 1 patients may present with ketoacidosis and a worse outcome than in developed countries, particularly due to late diagnosis and misdiagnosis. Ketoacidosis is often misdiagnosed as malaria, gastroenteritis, and pneumonia. In addition, the combination of weight loss and sepsis sometimes leads to the erroneous diagnosis of AIDS in diabetic patients and contributes to the delay in seeking medical care in the tropics where HIV/AIDS is now endemic. Atypical presentations of diabetes are sometimes misleading, especially in type 1B diabetes with patient’s profile similar to those of type 2 diabetic patients (age, BMI, family history of type 2 diabetes), while there is an acute onset as in classical type 1 diabetes with severe symptoms and ketosis.
B. COMPLICATIONS
OF
DIABETES
Type 1 diabetes is still associated with a high mortality rate in difficult socioeconomic situations. For example, Gill et al. reported 16 percent mortality in 64 type 1 diabetic patients over a 10-year follow-up, one-half due to sepsis and ketoacidosis (30). Among
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144 patients admitted for acute complications in a Nigerian hospital, 25 were deceased (17 percent), including two who could not afford insulin (31). Life expectancy at diagnosis of type 1 diabetes does not exceed five years in several SSA countries (32). Because of late diagnosis of diabetes, up to 21 percent to 25 percent of type 2 patients and 9.5 percent of type 1 may already present with retinopathy at diagnosis (33–35). The overall reported prevalence of diabetic retinopathy varies between 15 and 55 percent in Africa, with 15 percent of the patients with retinopathy having severe forms (macular edema or ischemia or proliferative retinopathy). In cohorts of patients with mean known duration of diabetes of 5–10 years, 32 percent to 57 percent have incipient nephropathy, and about one-third of the patients admitted to most dialysis units in Africa have diabetes (29). The frequency of symptoms of peripheral neuropathy varies from 9.5 percent to 36.4 percent, and erectile dysfunction has been reported in up to 49 percent of diabetic patients (29). Cerebrovascular disease is the most frequent macrovascular complication of diabetes in SSA. Mortality from stroke in Africa is threefold to sixfold that of England and Wales (36). By contrast, coronary heart disease, which is on the rise, is still rare but might be underestimated due to the scarcity of appropriate diagnostic facilities. The prevalence of electrical ischemia (EKG effort testing) is between 5.1 percent and 8.7 percent. Left-ventricular hypertrophy and dysfunction has been demonstrated in up to 50 percent of asymptomatic patients in some cohorts of diabetic patients in Africa and may account for the excess of congestive heart failure (37). Diabetic foot is one of the most frequent causes of admission, with up to 12 percent of hospital diabetic populations having active foot ulceration. It is estimated that it causes lower-extremity amputation in 1.4 percent to 6.7 percent of the patients. In a 2250-patient cohort, the mean age at amputation was 37 years in type 1 and 59 years in type 2 diabetic patients, with only 20 percent due to ischemic gangrene (38). Arteriopathy contributes to a lesser extent than neuropathy and infection to the development of foot lesions. Though genetic predisposition may not be ruled out, high blood pressure and inadequate metabolic control are among the major determinants of the progression of long-term complications of diabetes in SSA. The prevalence of hypertension is high and blood pressure is frequently inappropriately controlled (39). Similarly, inadequate blood glucose control is frequently reported, due to poor compliance and difficult access to appropriate care and affordability of treatment.
V. MANAGEMENT OF DIABETES IN A DEVELOPING COUNTRY A. ORGANIZATION
OF
DIABETES CARE
Developing countries have seen rapid improvements in economic and educational standards over the past 10 years. However, economic status should strongly affect outcomes by working through several proximal determinants including access to health services, but this has not been the case with most developing countries where there has been a lack of proportional investments in health.
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Currently, the health-care delivery system in most developing countries is structured around acute and episodic illnesses. The development of a diabetes-care system that will cater to the acute and chronic management of diabetic patients depends on financial constraints and the availability of health infrastructure and trained staff. The health infrastructure in developing countries is poorly equipped and lacks trained staff to deliver optimal diabetes care. Diabetes-care delivery is integrated in the overall national health-care structures. The concept of a specialized diabetes-care center and team is a novelty and, where available, limited funding renders it nonfunctional. The health-care system in most developing countries is state funded, and, therefore, priority is given to the unfinished agenda of communicable diseases. There is usually no medical insurance or free national health service; therefore, the patient has to pay for all aspects of medical care. Thus, when a diabetic patient and the family cannot afford the cost of medication, the situation may be fatal. The creation of a community-based system with appropriate financing in developing countries should allow more cost-effective and rational use of scare resources. This is of great importance in developing countries where the main increase in diabetes prevalence will occur in young and middle-aged individuals.
B. CULTURAL ASPECTS
OF
DIABETES CARE
There is a strong interplay between health beliefs, knowledge, lay perceptions, and health behavior. Owing to misconceptions reflected in popular health beliefs, many people in developing countries fail to take appropriate measures for the prevention and control of diabetes and its risk factors. Sugar, in its most direct forms, is strongly perceived as the singular cause of “the sugar disease.” This picture is illustrated by the health beliefs associated with diabetes in Cameroon (Figure 14.2). A strong belief in and practice of home management or self-care and seeking initial help from traditional practitioners may cause patients to delay for too long in finally arriving at a health facility. This leads to the development of complications at diagnosis. Obesity is still strongly perceived as a sign of good living, because it confers respect and influence. This situation seems to be encouraged, partly by a strong rural-urban connectedness. In Africa, people are never permanently urbanized. The link between the city and the village remains strong, and urban residents do usually shuttle back and forth between the cities and their villages of origin. As they get back to their villages, they are assessed by their relations whether they are living well in the city. The indicator often used for this assessment is body weight. Hence, weight gain amounts to good living, and weight loss is reckoned to mean poor living. In addition to this kind of evaluation, social status and admiration are often associated with signs of good living. Indeed, across cultures in Africa, overweight and obesity are differently understood and culturally defined (40).
C. DIABETES EDUCATION Diabetes education is the cornerstone of successful diabetes treatment. In developing countries the challenge is to disseminate this knowledge and simultaneously to provide optimal care for all people with diabetes at all levels of the society. The knowledge and care is aimed at impacting the accumulative and negative impact of the short- and long-
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BEHAVIOURA L FACTORS A SSOCIATED WITH M EN
NO SPORTS/ LACK OF EXERCISE
IN THE BODY
TOO M UCH ALCOHOL
GOD
FAILED PANCREAS
IN THE BLOOD
INSULIIN
NOT SWEATING
FROM THE BLOOD
TOO M UCH SUGAR OVERWEIGHT
PHYSICAL FACTORS
TOO LITTLE SUGAR
SUPERNATURAL FACTORS INHERITED
DIET & CONSUM PTION
INDIVIDUAL FACTORS
CARELESS EATING
SOCIAL FACTORS SWEET THINGS
POVERTY
sugar illness
WEA LTH
FIGURE 14.2 Causal web health belief diabetes in Cameroon.
term complications on the individual, family, and society. In most developing countries there is a lack of health infrastructure to cater to diabetes; scarcity of diabetes educators and other diabetes specialists and multidisciplinary support teams; low educational level, often including illiteracy of the patients; poor social awareness; and patient treatment adherence and cultural beliefs compounded by lack of reliable and affordable supply of medication and monitoring equipment that limit the attainment of this aim. It is important to point out that substantial difference exists among the different developing countries as well. Nevertheless, even where there is a complete lack of diabetes educators, it is possible to identify a nursing staff member with interest and experience in diabetes and who is a good communicator to lead a program of educating the educator. Diabetes education involving the patient, family, health-care staff, and community should be considered as an integral and equally important component of diabetes treatment, especially in developing countries.
D. LIFESTYLE MANAGEMENT
OF
DIABETES
1. Dietary Management Owing to cultural inclinations, most people are conservative about their diet and so bother less about issues related to balanced diets. Nutritional policy in most developing countries has had to target micronutrient deficiencies and malnutrition as a whole, which historically have been the main challenge and contribute to a greater
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burden of ill health. As a result, attention has not been focused on tackling bad nutritional habits, overweight, or obesity among those at risk of developing diabetes. The situation in SSA is characterized by a complex coexistence of both malnutrition and obesity in spite of the prevailing poor socioeconomic status of the region. Diet constitutes a key element of culture. Health education aimed at influencing the diet of the people must begin by understanding the predominant compositions of the current diet. Those who have had their traditional diets modified through dietary acculturation with exotic combinations, frying of foods and the acquisition of new tastes leading to a high intake of saturated fat, oils, and salts and a reduced consumption of vegetables and fibers, must be educated in a culturally relevant manner to adjust their dietary habits in order to live healthily. Dietary guidelines for public-health intervention are necessary. The onus is on policy makers, health professionals, nutritionists, health educators, and communicators. Basic survival is still a problem for most people living in developing countries. Therefore, traditional perceptions and cognitive imagery about the risk factors of diabetes, especially obesity, is unlikely to alter in any way significantly unless aggressive health-promotion campaigns are conducted. Diet and other lifestyle factors form the basis of treatment of diabetes — especially type 2 diabetes. The traditional diet in most developing countries, especially of Africa, is rich in staples consisting of cereals (rice, cornmeal, or flour, sorghum and millet) roots and tubers (yams, plantains, potatoes, and cassava), accompanying meat, fish, or vegetables, and is ideal for patients with diabetes. This traditional African diet, which is mainly high in starch and dietary fiber and low in fat and sugar, is, for the most part, similar to the WHO, American Diabetes Association, and Diabetes U.K. dietary recommendations for people with diabetes. Thus, with slight modifications and without fear of making changes to entrenched eating habits, it is relatively easy to draw up dietary guidelines for patients in Africa with diabetes. However, the urban city dwellers have absorbed Westernized-lifestyle cultures, and their dietary habits are more European or American than African (41). In such patients, the recommendations of expert groups from Europe and America on low-fat, high-carbohydrate, etc., are applicable. It is worth noting that seasonal variations in the production of foodstuffs, fruits, and vegetables are important factors in determining the availability and the frequency with which they are consumed. The diversity and complexity of diets in developing countries makes it impossible to prescribe a standard diet for the management of people with diabetes living in these countries. The situation is worsened by the lack of dieticians in most health institutions. The nurse or doctor (with little training in dietetics) is therefore responsible for supervising the diet of patients. Whatever the individual patient’s dietary targets, successful implementation depends on the acceptability of the prescribed diet and on continuous counseling. 2. Physical Activity Epidemiological data have provided evidence of strong association between physical inactivity and obesity and diabetes mellitus in developing countries. The dramatic
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difference in the prevalence of diabetes mellitus in urban and rural dwellers is underlined by an important gap between their physical activity levels (10, 42). Unlike rural populations who often depend upon subsistence farming or other physically demanding activities for living, a majority of those in urban centers have less demanding, professional occupations involving mostly sitting or mechanized activities. In addition, in most rural areas of developing countries, the main transportation means is walking. There is a large reduction in walking time and pace in urban communities in SSA, as compared with a rural SSA community (a reduction by a factor of two to four for walking at a slow pace and by a factor of six to more than 10 for walking at a brisk pace). The main difference resides in the use of walking as transportation means (43). In all age groups, in addition to total physical activity, walking energy expenditure is inversely associated with body-mass index and fasting blood glucose in the general population (Figure 14.3). A dual approach of physical activity and diabetes in developing countries should be proposed: (1) a population-based promotion of physical activity, especially in urban communities where traditional lifestyle no longer predominates for the prevention of type 2 diabetes and (2) as a therapeutic strategy for those living with diabetes. BMI (kg.m-²) 30 p for trend <0.0001
25
1st tertile 2nd tertile 3rd tertile
20
15 < 30 yr
30 - 49 yr
> = 50 yr
Fasting blood glucose (mmol.l-1) 5.2 5.1 5 4.9 4.8 4.7 4.6 4.5 4.4 4.3 4.2
p for trend = 0.006 p for trend = 0.004
1st tertile 2nd tertile 3rd tertile
< 30 yr
30 - 49 yr
> = 50 yr
FIGURE 14.3 Mean (and standard error) body mass index and fasting blood glucose by tertiles of walking energy expenditure in women of < 30, 30–49 and > 50 year age groups in a population of Cameroon. (Adapted from Sobngwi, E, Gautier, JF, and Mbanya, JC, N. Engl. J. Med., 348(1):77–79, 2003).
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The prescription of physical activity in diabetic patients should always distinguish between types of diabetes and take into account the other pharmacological treatments received by the patient. Advice on frequency, duration, and intensity should follow the current recommendations of all diabetes boards (ADA, Diabetes U.K.). Facilities to perform the type of exercise recommended are seldom available in resource-limited settings. In addition, cultural background, which may be age or gender dependent, may hinder participation in some activities. Effort should therefore be made to identify culturally acceptable, economically affordable, and safe activities that can be proposed to each patient in his/her environment. If necessary, an evaluation of the intensity that is suitable for the individual may be undertaken using simple tools, such as the measurement of pulse rate while performing the activity. Guidelines concerning adverse effects, adaptations of pharmacological treatment (particularly insulin and insulin secretagogues) do not vary. Emphasis on urinary-ketone surveillance before activity in type 1 patients should not be neglected.
VI. DRUG MANAGEMENT OF DIABETES A. ORAL HYPOGLYCEMIC DRUGS Oral hypoglycemic agents now cover a wide range of pharmacological classes that offer the opportunity to target different aspects of the pathophysiology of type 2 diabetes. However, not all these agents are always available in developing countries. Nevertheless, in almost all countries, at least sulfonylureas and metformin are available at low cost. Evidence-based guidelines for the management of type 2 diabetes at primary-care level that have been developed using these 2 classes of agents and insulin in simple algorithms have been shown to be effective especially in SSA. Despite the difficulties that still exist concerning the provision of insulin, insulin treatment of type 2 diabetic patients should always be considered early enough to avoid long-term complications that are more costly to the patients and the health systems.
B. INSULIN THERAPY One of the major challenges facing insulin-treated patients in developing countries is the lack of a constant access to insulin at affordable cost, leading to underutilization and avoidable metabolic complications. A survey on insulin access by the International Diabetes Federation’s Insulin Task Force in 73 countries revealed that insulin was always accessible in only 41 countries in cities and 31 countries in rural areas. In five countries, it was not accessible (less than 25 percent of the times) in the cities, and in 21 countries in rural areas (Figure 14.4). In 25 SSA countries, insulin was often unavailable in half the large city hospitals, and only five countries reported regular insulin availability in rural areas (44). The reasons for this poor insulin access in developing countries included cost, taxation, and distribution. The problem of storage is relatively easy to overcome using suitable vessels, including clay pots (a porous vessel filled with water or sand and water) or holes in the ground.
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El Salvador
Type 1 Type 2
Bolivia Guyana Ukraine Zambia Togo Congo, Democratic Republic of 0
20
40
60
80
100
FIGURE 14.4 Access (percent) to insulin in some developing countries. (Adapted with permission from IDF Diabetes Atlas, 2003).
The first rule for the management of type 1 diabetes and all insulin treatedpatients in clinical practice in developing countries is that the scientific evidence obtained from large-scale, randomized trials in Western countries should be the standard to achieve in order to avoid long-term complications When insulin is available, not all types can be found. Thus, the second rule for the choice of insulin regimens in a given patient is the availability of prescribed insulin. The third important issue is to make sure that the proposed insulin regimen is feasible with regard to the type of employment (farming, for example, poses specific problems) and specific insight should be given to regularity of meals, seasonality, etc. The fourth issue is monitoring that needs to be organized in a cost-effective manner adapted to the resources of individual patients. Urinary monitoring may be the only feasible option in some cases and should not be neglected. The issues of storage of insulin vials and hygienic conditions should be clearly discussed with the patient. Because there may still be few places where syringes are not yet all adapted to 100UI/ml insulin, the particular point of consistency between insulin concentration and syringes should be addressed. In the case of ketosis-prone atypical diabetes, patients should receive specific education with respect to possible remission. All other rules of insulin therapy in developed setting apply to type 1 patients in developing countries. Overall, the rules to take into account when managing diabetic patients with insulin in developing countries are the same as in developed countries, with the added specificities related to difficulty of access to insulin, technical problems, and sometimes nutritional difficulties arising from poor environment and, finally, seasonality of lifestyle in most rural areas.
C. MANAGEMENT
OF
KETOSIS-PRONE DIABETES
The initial presentation of ketosis-prone diabetes is usually acute with important symptoms, such as polyuria, polydipsia, and weight loss. The random blood glucose is very high, often above 30 mmol/l, ketone bodies are present in the urine, and
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there may be ketoacidosis with low pH and serum bicarbonates. Thus, the initial presentation requires insulin treatment with appropriate fluid and electrolyte management when necessary. The resolution of ketosis is usually obtained within less than 24 hours. Intensive, subcutaneous insulin therapy should ideally be proposed to the patients with appropriate education for the recognition of hypoglycemia, self-monitoring, and adaptation of insulin dose and clear information about possible remission. In fact, the shortand medium-term clinical course after the resolution of ketosis is characterized by a good glycemic control under subcutaneous insulin treatment, with gradual lowering of the dose of exogenous insulin. The presence of frequent hypoglycemic episodes despite the reduction of exogenous insulin dose is the hallmark of this phenomenon. Within a few days or months of insulin treatment, withdrawal of insulin therapy is possible in at least one-half of patients without worsening blood-glucose control. The patient is considered to have entered remission. The period of remission varies from a few months to more than 10 years but may be interrupted by episodes of provoked or unexplained hyperglycemic and ketotic relapse where short-term insulin treatment is required for glycemic control. There is evidence from randomized controlled trials versus placebo that lowdose oral sulfonylureas may improve the duration of remission. Other oral hypoglycemic agents seem to also prolong the remission period. Thus, it is advisable to maintain a treatment by any oral hypoglycemic agent during remission even when metabolic control is achievable by diet therapy alone. Subsequent follow-up is similar to that of type 2 diabetes. With regards to the investigations to be undertaken, coexisting disease that may precipitate ketosis (especially infectious diseases) should always be ruled out. In children and young adults, screening for beta-cell autoimmunity (antiGAD) permits the identification of true type 1 diabetes patients that may require lifetime insulinreplacement therapy. Pancreatic imaging (abdominal ultrasound or plain X-ray) to rule out possible chronic pancreatitis is of interest in patients with signs of undernutrition or history of heavy alcohol consumption. C-peptide measurements after stimulation by IV glucagon are predictive of further remission and might be of interest. However, in routine practice, recurrent hypoglycemia and rapid normalization of HbA1c levels despite reduction of exogenous insulin dose is the best marker of possible remission (45).
VII. COST OF DIABETES CARE The emergence of diabetes in developing countries and its consequent heavy burden of morbidity and premature mortality will result in extraordinarily high socieconomic costs, in terms of both medical care and loss of human resources. In SSA, the gross national product varied from $483 in Tanzania to $3040 in South Africa, with the percentage of gross domestic product spent on health care ranging from 0.7 percent in Nigeria to 7.15 percent in South Africa. The per capita expenditure is relatively low in international terms (46–48) (Table 14.1). It follows from these figures that the region has limited resources to invest in diabetes care. The late diagnosis of diabetes, coupled with inequalities in accessing the main antidiabetes drugs, including insulin, a drug
61.1 252.6 8.6 42.7 268.1 5.5 2.2 32.3 190.4 75.0 18.4 117.3 209.4 33.5 886.4 134.8 9.6 88.7 40.8 55.4
PPP = Purchasing Power Parity (international dollars)
2.14 4.80 0.23 1.27 4.95 0.16 0.07 2.79 3.65 2.52 0.79 0.98 12.52 0.82 57.56 2.47 0.63 0.65 0.52 2.06
Cameroon Congo, Democratic Rep of Congo, Republic of Côte d’Ivoire Ethiopia Gabon Gambia Ghana Kenya Madagascar Mali Mozambique Nigeria Senegal South Africa Tanzania Togo Uganda Zambia Zimbabwe
a
Type 1
Country
Type 2 (20–79 Age Group)
Total Number of People with Diabetes (000’s)(47)
1395 733 846 1484 566 5615 1428 1735 964 741 673 740 740 1297 8296 483 1352 1072 678 2489
GNP per Capita(48) PPPa $ 1998 1.0 1.2 1.8 1.4 1.7 0.6 1.4 1.8 2.2 1.1 2.0 2.1 0.2 2.6 3.2 1.3 1.1 1.8 2.3 3.1
Public 4.0 1.3 3.2 2.6 2.4 – 1.7 2.9 1.0 1.0 1.8 – 0.5 2.1 3.5 – 2.1 2.9 1.8 3.3
Private 5.0 2.5 5.0 3.7 4.1 – 3.1 4.7 1.0 2.1 3.8 – 0.7 4.7 7.1 – 3.2 4.7 4.1 6.4
Total
Health Expenditure (46) as Percent of GDP from 1990–98
83 – 62 66 42 – 46 82 10 – 28 – 6 66 571 – 46 50 33 191
Health Expenditure (46) per Capita PPP $ 1990–98 0.1 0.1 0.3 0.1 0.0 0.2 0.0 – 0.0 0.3 0.1 – 0.2 0.1 0.6 0.0 0.1 0.0 0.1 0.1
Physicians(46) 1990–98 Per 1000 people
2.6 1.4 3.4 0.8 0.2 3.2 0.6 1.5 1.6 0.9 0.2 0.9 1.7 0.4 – 0.9 1.5 0.9 – 0.5
Hospital Beds(46) 1990–98 Per 1000 people
TABLE 14.1 Prevalence Estimates of Diabetes and Socioeconomic Indicators for Year 2000 in Some Sub Saharan African Countries
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declared by the WHO as an essential drug for the treatment of diabetes, leads to early presentation of diabetic complications (29). The lack of a free national health service in most countries of the region means that the burden of diabetes care is on the patient or the family. A preliminary study from Cameroon shows that diabetes care is paid for by patients (50 percent), family (44 percent), employer (2 percent), charities (2 percent), and others, including government (2 percent) (49). In some instances, if the family is unable to pay for diabetes care, this might result in the death of the patient.
VIII. CONCLUSIONS The emergence of diabetes as a public-heath problem in developing countries has led to the doubling or tripling of disease burden. It is a nightmare to deliver proper diabetes care in these countries because of cost constraints, lack of availability of health infrastructure, and lack of trained staff. There is an urgent need to mobilize resources to properly manage diabetes in these countries.
REFERENCES 1. Cook, AR, Notes on the diseases met with in Uganda, Central Africa, J. Trop. Med., 4:175–178, 1901. 2. Motala, AA, Omar, MA, and Pirie, FJ, Diabetes in Africa. Epidemiology of type 1 and type 2 diabetes in Africa, J. Cardiovasc. Risk, 10(2):77–83, 2003. 3. Sobngwi, E, Mauvais-Jarvis, F, Vexiau, P, Mbanya, JC, and Gautier, JF, Diabetes in Africans. Part 1: epidemiology and clinical specificities, Diabet. Metab., 27(6):628–34, 2001. 4. Elamin, A, Omer, MI, Zein, K, and Tuvemo, T, Epidemiology of childhood type I diabetes in Sudan, 1987-1990, Diabet. Care, 15(11):1556–9, 1992. 5. Kadiki, OA, Roaeid, RB, Bhairi, AM, and Elamari, IM, Incidence of insulin-dependent diabetes mellitus in Benghazi, Libya (1991-1995), Diabet. Metab., 24(5):424–7, 1998. 6. Papoz, L, Delcourt, C, Ponton-Sanchez, A, Lokrou, A, Darrack, R, Toure, IA, et al., Clinical classification of diabetes in tropical West Africa, Diabet. Res, Clin, Pract., 39(3):219–27, 1998. 7. Omar, MA, Seedat, MA, Motala, AA, Dyer, RB, and Becker, P, The prevalence of diabetes mellitus and impaired glucose tolerance in a group of urban South African blacks, S. Afr. Med. J., 83(9):641–3, 1993. 8. Ramaiya, KL, Denver, E, and Yudkin, JS, Diabetes, impaired glucose tolerance and cardiovascular disease risk factors in the Asian Indian Bhatia community living in Tanzania and in the United Kingdom. Diabet. Med., 12(10):904–10, 1995. 9. Mbanya, JC, Cruickshank, JK, Forrester, T, Balkau, B, Ngogang, JY, Riste, L, et al., Standardized comparison of glucose intolerance in west African-origin populations of rural and urban Cameroon, Jamaica, and Caribbean migrants to Britain, Diabet. Care, 22(3):434–40, 1999. 10. Sobngwi, E, Mbanya, JC, Unwin, NC, Kengne, AP, Fezeu, L, Minkoulou, EM, et al., Physical activity and its relationship with obesity, hypertension and diabetes in urban and rural Cameroon, Int. J. Obes. Relat. Metab. Disord., 26(7):1009–16, 2002.
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11. Benefice, E and Cames, C, Physical activity patterns of rural Senegalese adolescent girls during the dry and rainy seasons measured by movement registration and direct observation methods, Eur. J. Clin. Nutr., 53(8):636–43, 1999. 12. Aspray, TJ, Mugusi, F, Rashid, S, Whiting, D, Edwards, R, Alberti, KG, et al., Rural and urban differences in diabetes prevalence in Tanzania: the role of obesity, physical inactivity and urban living, Trans. R. Soc. Trop. Med. Hyg., 94(6):637–44, 2000. 13. Cities in a globalizing world, global report on human settlements 2001, London; Sterling, Virginia, Earthscan Publications, 2001. 14. Wild, S, Roglic, G, Green, A, Sicree, R, and King, H, Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabet. Care, 27(5):1047–53, 2004. 15. King, H, Aubert, RE, and Herman, WH, Global burden of diabetes, 1995-2025: prevalence, numerical estimates, and projections, Diabet. Care, 21(9):1414–31 1998. 16. UK Prospective Diabetes Study, XII: Differences between Asian, Afro-Caribbean and white Caucasian type 2 diabetic patients at diagnosis of diabetes. UK Prospective Diabetes Study Group, Diabet. Med., 11(7):670–7, 1994. 17. Joffe, BI, Panz, VR, Wing, JR, Raal, FJ, and Seftel, HC, Pathogenesis of non-insulindependent diabetes mellitus in the black population of southern Africa, Lancet, 340(8817):460–2, 1992. 18. Alberti, KGMM, Tropical pancreatic diabetes, in Diabetes in Africa, Gill, G, Mbanya, JC, and Alberti, KG, Eds., FSG Communications, Cambridge, 1997. 19. Diabetes mellitus, Report of a WHO Study Group, Geneva, World Health Organization, 1985. 20. Sobngwi, E, Mauvais-Jarvis, F, Vexiau, P, Mbanya, JC, Gautier, JF, Diabetes in Africans. Part 2; Ketosis prone atypical diabetes mellitus, Diabet. Metab., 28(1):5–12, 2002. 21. Banerji, MA, Chaiken, RL, Diabetes in Africa, Lebovitz, HE, Long-term normoglycemic remission in black newly diagnosed NIDDM subjects, Diabetes, 45(3):337–41, 1996. 22. Umpierrez, GE, Casals, MM, Gebhart, SP, Mixon, PS, Clark, WS, and Phillips, LS, Diabetic ketoacidosis in obese African-Americans, Diabetes, 44(7):790–5, 1995. 23. Sobngwi, E, Vexiau, P, Levy, V, Lepage, V, Mauvais-Jarvis, F, Leblanc, H, et al., Metabolic and immunogenetic prediction of long-term insulin remission in African patients with atypical diabetes, Diabet. Med., 19(10):832–5, 2002. 24. Tan, KC, Mackay, IR, Zimmet, PZ, Hawkins, BR, and Lam, KS, Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus (in process citation), Diabet. Care, 23(3):335–8, 2000. 25. Yamada, K and Nonaka, K, Diabetic ketoacidosis in young obese Japanese men, Diabet. Care, 19(6):671, 1996. 26. Sobngwi, E and Gautier, JF, Adult-onset idiopathic Type I or ketosis-prone Type II diabetes: evidence to revisit diabetes classification, Diabetologia, 45(2):283–5, 2002. 27. Nambuya, AP, Otim, MA, Whitehead, H, Mulvany, D, Kennedy, R, and Hadden, DR, The presentation of newly-diagnosed diabetic patients in Uganda, Q.J.M., 89(9):705–11, 1996. 28. Tropical diabetic hand syndrome — Dar es Salaam, Tanzania, 1998-2002, MMWR, Morb. Mortal. Wkly. Rep., 51(43):969–70, 2002. 29. Mbanya, JC and Sobngwi, E, Diabetes microvascular and macrovascular disease in Africa, J. Cardiovasc. Risk, 10(2):97–102, 2003. 30. Gill, GV, Huddle, KR, and Rolfe, M, Mortality and outcome of insulin-dependent diabetes in Soweto, South Africa, Diabet. Med., 12(6):546–50, 1995.
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31. Ndububa, DA and Erhabor, GE, Diabetic mortalities in Ilesa, Nigeria: a retrospective, Cent. Afr. J. Med., 40(10):286–9, 1994. 32. Gill, G, Mbanya, JC, and Alberti, KG, Diabetes in Africa, FSG Communications, Cambridge, 1997. 33. Kalk, WJ, Joannou, J, Ntsepo, S, Mahomed, I, Mahanlal, P, and Becker, PJ, Ethnic differences in the clinical and laboratory associations with retinopathy in adult onset diabetes: studies in patients of African, European and Indian origins, J. Intern. Med., 241(1):31–7, 1997. 34. Lester, FT, Clinical features, complications and mortality in type 1 (insulin-dependent) diabetic patients in Addis Ababa, Ethiopia, 1976-1990, Q.J.M., 83(301):389–99, 1992. 35. Lester, FT, Clinical features, complications and mortality in type 2 (non-insulin dependent) diabetic patients in Addis Ababa, Ethiopia, 1976-1990, Ethiop. Med. J., 31(2):109–26, 1993. 36. Walker, RW, McLarty, DG, Kitange, HM, Whiting, D, Masuki, G, Mtasiwa, DM, et al., Stroke mortality in urban and rural Tanzania. Adult Morbidity and Mortality Project, Lancet, 355(9216):1684–7, 2000. 37. Mbanya, JC, Sobngwi, E, Mbanya, DNS, and Ngu, KB, Left ventricular mass and systolic function in African diabetic patients: association with microalbuminuria, Diabet. Metab., 2001;27:378–382, 2001. 38. Lester, FT, Amputations in patients attending a diabetic clinic in Addis Abeba, Ethiopia, Ethiop. Med. J, 33(1):15–20, 1995. 39. Edwards, R, Unwin, N, Mugusi, F, Whiting, D, Rashid, S, Kissima, J, et al., Hypertension prevalence and care in an urban and rural area of Tanzania, J. Hypertens., 18(2):145–52, 2000. 40. Renzaho, MN and Adré, Fat, rich and beautiful: changing socio-cultural paradigms associated with obesity risk, nutritional status and refugee children from Sub-Saharan Africa, Heal. Pl., 9(1):45–53, 2003. 41. Mennen, LI, Mbanya, JC, Cade, J, Balkau, B, Sharma, S, Chungong, S, et al., The habitual diet in rural and urban Cameroon, Eur. J. Clin .Nutr., 54(2):150–4, 2000. 42. Levitt, NS, Steyn, K, Lambert, EV, Reagon, G, Lombard, CJ, Fourie, JM, et al., Modifiable risk factors for Type 2 diabetes mellitus in a peri-urban community in South Africa, Diabet. Med., 16(11):946–50, 1999. 43. Sobngwi, E, Gautier, JF, and Mbanya, JC, Exercise and the prevention of cardiovascular events in women, N. Engl. J. Med., 348(1):77–79, 2003. 44. Access to insulin, a report on the IDF Insulin Task Force on insulin 1994-1997, International Diabetes Federation, Brussels, 1998. 45. Gautier, JF, Sobngwi, E, and Vexiau, P, How to treat and manage the black diabetic patient, J. Annu. Diabetol. Hotel Dieu, 165–178, 2001. 46. World Bank Development Indicators — 2000, The World Bank, 2000. 47. International Diabetes Federation, Diabetes Atlas 2000, International Diabetes Federation, Brussels, 2000. 48. World Bank Atlas — 2002, The World Bank, 2002. 49. Nkegoum, AV, Coût direct et indirect du diabéte en l'absence de complications chroniques à Yaoundé, Cameroun, (MD thesis), Univeristy of Yaoundé I, Yaoundé, Cameroon, 2002.
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Diabetes in Pregnancy Roger Harms, M.D.
CONTENTS I. Introduction................................................................................................267 II. Classification of Diabetes ..........................................................................268 III. Pregnancy’s Impact on Diabetes ...............................................................268 A. Diabetic Nephropathy .......................................................................269 B. Diabetic Neuropathy .........................................................................269 C. Diabetic Retinopathy.........................................................................269 D. Coronary-Artery Disease...................................................................270 IV. The Impact of Diabetes Mellitus on Pregnancy .......................................270 V. Management of Gestational Diabetes .......................................................272 VI. Type 1 and 2 Diabetes Mellitus ................................................................275 VII. Pregnancy and Diabetes in Perspective.....................................................278 References..............................................................................................................279
I. INTRODUCTION Pregnancy is a challenge and an opportunity for the woman with diabetes. Although her disease represents a challenge to daily living that is greatly enhanced in its complexity by the addition of a developing fetus, the motivation, focus, and intensity of contact with health-care providers that pregnancy provides combine to deliver the most teachable moment for her diabetes care. In providing the environment that leads to the best pregnancy outcome, the diabetic woman develops the knowledge and skills to protect herself from long-term complications and extend her lifespan. It is imperative that the health-care team help her take advantage of this opportunity. The effort is rewarded with a new citizen with full capacity to contribute to society, and a healthier woman who will continue to do so. Diabetes is one of the most common medical complications of pregnancy, affecting 5 percent of all pregnancies in one of its forms.1 Before insulin became available, at least one of five women with diabetes perished during their pregnancy or postpartum, and almost two-thirds of their infants died.2 Today, with excellent care, the diabetic gravida can look forward to a negligible risk of personal mortality and can confidently expect a healthy child. These changes are the direct result of appropriate care and represent one of the greatest victories of modern medicine. This dramatic improvement arose with the development of advanced insulin therapies, technological advances in monitoring the maternal glycemic state 267
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and fetal growth and oxygenation, modern obstetrical care, and advances in neonatology. The health-care provider should always bear in mind the history of diabetes in pregnancy so as to approach the problem with appropriate rigor and focus.
II. CLASSIFICATION OF DIABETES Diabetes mellitus is a heterogeneous condition with two basic pathophysiologies, each giving rise to hyperglycemia and the potential for complicated end-organ dysfunction. Type 1 diabetes mellitus is characterized by complete insulin deficiency arising from the destruction of the islets of Langerhans in the pancreas by an autoimmune process. Complete dependence on insulin therapy is almost immediately apparent. Type 2 disease is a manifestation of insulin resistance that is often genetic in origin. This resistance to the action of insulin may be treated by a spectrum of approaches from diet to oral hypoglycemic agents to insulin supplementation. The insidious nature of this condition gives rise to potential end-organ disease before its recognition. Gestational diabetes is thought by many experts to be the early revelation of the propensity to develop type 2 diabetes.3 In this condition, glucose intolerance develops as a result of the natural insulin resistance provided by the hormonal products of the placenta, human placental lactogen in particular. The development of type 2 diabetes in more than 50 percent of women with gestational diabetes in five to 10 years postpartum is strong evidence for a common etiology for both conditions. Beyond the taxonomy of disease, the effects of the condition on the vascular space of the gravida carries with it a potential to strongly affect the developing fetus. Women with nephropathy, retinopathy, or hypertension may have fetuses that are restricted in growth due to poor placental perfusion. Diabetic women without endorgan disease are at risk to give birth to macrosomic neonates due to chronic hyperglycemia and hyperinsulinemia in the developing fetus. It is important to evaluate the full spectrum of diabetes in the gravid woman in order to anticipate and prevent neonatal complications.
III. PREGNANCY’S IMPACT ON DIABETES The endocrinologic changes of pregnancy are almost uniformly antagonistic to the action of insulin. The human placenta is an extremely powerful endocrine organ producing very large quantities of human placental lactogen (HPL). HPL acts as an analog to growth hormone, giving rise to peripheral insulin resistance in all cases. Elevated levels of corticosteroids, epinephrine, and progesterone further promote hyperglycemia and inhibit insulin action. Insulin resistance increases with the production of these placental products and becomes maximal in the third trimester. This phenomenon becomes manifest in the increasing incidence of gestational diabetes as pregnancy proceeds, and the marked increase in insulin dosage required by diabetic patients in late pregnancy. These metabolic changes result in elevated postprandial glucose levels in all gravidas, but somewhat less intuitive is the effect of pregnancy on fasting sugars. Probably due to facilitated diffusion across the placenta and obligate fetal glucose utilization, the fasting glucose is reduced approximately 20 percent early in gestation
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and persists throughout.4 This phenomenon, combined with the common nausea and emesis of early pregnancy, can lead to significant problems with hypoglycemia in women with pregestational diabetes. Another effect of high levels of HPL is the propensity toward accelerated starvation in the metabolic millieu of pregnancy. The result is a tendency to ketosis, which may result in diabetic ketoacidosis in women with relatively modest insulin deficiency. Urine ketones should be tested during pregnancy whenever intake is restricted by illness or if hyperglycemia has been unchecked for more than eight hours. Immediately after delivery, the abrupt decline in placental-hormone production gives rise to dramatic improvement in insulin sensitivity, often resulting in a rapid fall in insulin requirement, occasionally allowing 24 to 48 hours of freedom from insulin treatment. There is little evidence that pregnancy provokes any long-term, negative effect on the prognosis of diabetes mellitus. Indeed, many women become so fully informed about their disease that their long-term control, reflected in glycosylated hemoglobin levels, is improved for years. Some specific complications of diabetes deserve comment here.
A. DIABETIC NEPHROPATHY This complication of diabetes is the most common cause of end stage-renal disease in the United States.5 Characterized by proteinuria, the presence of diabetic nephropathy has impact on pregnancy with a marked increase in preeclampsia, fetal-growth restriction, and iatrogenic shortening of gestation due to worsening maternal disease. Abnormal creatinine clearance and proteinuria is a poor prognostic factor for the fetus, but unless creatinine exceeds 1.5 at the onset of pregnancy, there is no evidence that pregnancy accelerates progression to renal failure.6 Increasing renal blood flow greatly increases proteinuria in all cases, but this resolves after delivery. Diabetic women should be screened for microalbuminuria regularly, including at the onset of pregnancy.
B. DIABETIC NEUROPATHY There is no evidence of progression of neuropathy during the course of pregnancy, but most women with this complication will have other vascular abnormalities that increase the risk of hypertensive disease developing during gestation. Women with gastroparesis may have significant problems with first-trimester nausea and vomiting, occasionally leading to the need for enteric or parenteral nutrition.7 Evaluation of deep-tendon reflexes and sensory function in the lower extremities should be done at the onset of pregnancy.
C. DIABETIC RETINOPATHY This diabetic complication is an extremely common cause of blindness due to proliferative vascular disease with hemorrhage in the retina and vitreous. Premonitory retinal changes do not appear to progress in pregnancy, but proliferative disease seems to accelerate over a short period if uncontrolled prior to pregnancy.8 Retinoscopy by an ophthalmologist is necessary in all pregnant diabetic patients to evaluate retinal changes. If present, intense monitoring is indicated.
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D. CORONARY-ARTERY DISEASE This condition is one of the most common causes of death in diabetic women and may be present even in the young gravid diabetic subject. Pregnancy increases myocardial oxygen consumption and as such represents a significant risk to those with occlusive disease. Hypertensive diabetic patients should be particularly suspected of coronary-artery disease, and exercise electrocardiography should be considered.9
IV. THE IMPACT OF DIABETES MELLITUS ON PREGNANCY All forms of diabetes place the pregnant woman at increased risks for gestational complications and expose her fetus to significant risk of perinatal morbidity. These risks do vary according to the severity of diabetes along a spectrum. Gestational diabetes gives rise to significant risk of fetal macrosomia, whereas severe pregestational diabetes with hypertension and renal disease may result in a growth-retarded fetus, delivered prematurely by cesarean section, due to placental insufficiency. The risk of diabetes eventually developing in the offspring is perhaps as high as 50 percent in the case of type 2 disease, and at least 3 percent to 5 percent in the child of a mother with type 1 diabetes. The leading cause of perinatal mortality for the infant of a diabetic mother is the risk of congenital abnormality.10 More than 50 percent of pregnancies in the United States are unplanned. This statistic is indicative of societal failure in the general population, but in the diabetic population it may well be tragic. Fatal malformations and those involving more than one organ system are six times as likely in the diabetic population.10 The rate of congenital anomalies is directly related to the level of glucose control as measured by glycosylated hemoglobin levels. In a study by Miller et al.,11 if less than 8.5 percent, the anomaly rate was 3.4 percent, whereas if more than 9.5 percent, the rate climbed to 22 percent. Common congenital anomalies include cardiac defects (Figure 15.1), neural-tube defects (Figure 15.2), and a CNS abnormality almost unique to diabetic patients, caudal regression syndrome.12
FIGURE 15.1 Lumbar neural-tube defect in fetus of a woman with type 1 diabetes.
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FIGURE 15.2 Fetal cardiac ultrasound revealing a large ventricular septal defect.
Many studies since this one have confirmed that glycemic control approximating the normal range at conception and throughout organogenesis is very protective against congenital anomalies. Supplementation with folic acid at the four-milligram dose, which is protective in high-risk groups, may yield further benefit. These facts demand that everyone involved in the treatment of diabetic women and girls must emphasize the importance of planned pregnancy and pregnancy preparation to avoid the single most significant risk to her offspring. Hyperglycemia later in pregnancy also results in fetal morbidity related to macrosomia. Facilitated diffusion of glucose across the placenta leads to the fetus increasing its production of insulin, which is its most significant growth factor. Excess caloric intake leads to storage of glycogen in the liver and marked deposition of fat in the torso. The morphometric effect of this pathologic growth is a maldistribution of mass in the shoulders, chest, and abdomen, such that these diameters may well exceed that of the calvarium. Although obstructed labor and cesarean delivery may ensue, the most profound concern is the significant risk of shoulder dystocia. This obstetric complication may lead to fetal hypoxia or traumatic injury to the brachial plexus, leading to lifelong handicap. Macrosomic fetuses are also at risk of metabolic complications at birth, including profound hypoglycemia, hypocalcemia, and hyperbilirubinemia. Diabetes mellitus was the most common cause of intrauterine fetal demise prior to 1980. The combination of increased oxygen requirement in the fetus exposed to high glucose and insulin levels and placental dysfunction in the presence of hyperglycemia can still provoke this tragedy. Happily, improved glycemic control has negated much of this risk in recent years, and antepartum fetal surveillance has allowed intervention to save fetuses at risk for this outcome. Fetal glycosuria is probably manifest in the increased risk of polyhydramnios in pregnancies complicated by diabetes. This hydramnios has less negative implications for fetal disease than when it is seen without diabetes. Rarely is this fluid volume severe enough to provoke preterm labor, but that complication should be considered, as it is slightly more common in this population.
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More commonly, prematurity arises from evidence of placental dysfunction, leading to abnormal antenatal testing and induction of labor or operative delivery. This clinical scenario arises eight times more frequently in diabetes.13 Fetuses of diabetic mothers appear to have delayed production of surfactant, leading to a higher incidence of respiratory-distress syndrome in neonates born at a given gestational age up to 38.5 weeks.14 Amniocentesis for maturity is indicated before elective or semielective delivery in all cases before 39 gestational weeks have been completed. A few fetuses whose mothers have vascular disease manifested by hypertension or renal dysfunction will suffer from chronic placental insufficiency and be severely growth restricted. These fetuses are at significant risk for intrauterine fetal demise and demand intensive prenatal testing to prevent this outcome. Maternal risks derived from diabetes in pregnancy are strongly related to the presence of vascular disease prior to pregnancy. All diabetic gravidas have a slightly higher incidence of preeclampsia, but those with vascular disease develop preeclampsia in up to 17 percent of cases.15 Preeclampsia may exacerbate background placental insufficiency and lead to fetal compromise.
V. MANAGEMENT OF GESTATIONAL DIABETES Gestational diabetes is defined as carbohydrate intolerance first recognized during pregnancy.5 Since all pregnancy results in some degree of carbohydrate intolerance, the diagnosis is arbitrary with the intent to detect all or nearly all insulin resistance that will result in fetal morbidity with an acceptable false-positive rate. Criteria for diagnosis have not been standardized, but all are in agreement that diagnosis is dependent on screening for carbohydrate intolerance in a large population, constituting universal or near universal screening. The incidence of gestational diabetes has been rising and will continue to rise with the high rates of obesity in the developed world. The introduction of dietary excess to populations in Asia, Africa, and many native populations who seem particularly at risk will further increase its incidence. Currently, almost 5 percent of pregnancies in the United States are affected by this complication.16 The American Diabetes Association suggests that women under 25 without a first-degree relative with type 2 diabetes who have no history of poor obstetric outcome, and those who are not members of high-risk ethnic groups need not be screened.17 In practice, universal testing is probably most efficient. There is also universal agreement that detection of the condition gives rise to the opportunity to alter a hyperglycemic environment for the fetus and thereby decrease the risk for perinatal morbidity and mortality. Standard screening in the United States consists of a one-hour, 50-gm oral glucose challenge test between 24 and 28 weeks of gestation. The challenge is provided without regard to fasting or time of day, and the cutoff for a positive screen is most commonly 140 mg/dL venous plasma glucose one hour after the oral-glucose load. For high-risk situations, such as previous macrosomic child or significant obesity, this screen should be performed early in the second trimester and repeated in this time frame if the first test is normal.
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TABLE 15.1 Carpenter/Coustan Modified Criteria for Diagnosis of GDM18 FPG 95 mg/dl 1 hr 180 mg/dl 2 hr 155 mg/dl 3 hr 140 mg/dl
It is acknowledged that using a cutoff of 140 mg/dL will result in a false-negative rate of 10 percent to 15 percent, but it only requires 15 percent of screened patients to undergo the inconvenient, three-hour glucose tolerance test. A cutoff of 130 mg/dL will increase the sensitivity to near 100 percent at the cost of identifying one out of four pregnancies for a three-hour test.16 The three-hour glucose tolerance test consists of an overnight fasting sample and a 100 gm oral-glucose load, followed by plasma glucose levels at one, two, and three hours from the oral intake. If two of these glucose values are abnormal, the diagnosis of gestational diabetes is made. The majority of American practices have adopted the Carpenter/Coustan standards for interpretation of the test.18 (Table 15.1). There is no agreement on the appropriate action to take if there is only one abnormal value on the three-hour test. Retesting is cumbersome, but there is clearly an increase in the incidence of macrosomia in women with this finding. As dietary treatment for gestational diabetes is essentially risk free, many physicians will choose to consider patients with one abnormal value as having gestational diabetes.19 Similarly, women who have a one-hour screening result in excess of 200 mg/dL can be safely managed as having gestational diabetes without further testing. Once the diagnosis is established, the goal of therapy is to bring the patient’s metabolic environment as close to the euglycemic state as possible. The first line of treatment is dietary, with restriction of caloric intake to 2000–2200 Kcal per day, excluding high concentrations of simple sugars in favor of complex carbohydrates high in fiber content. Exercise is an important adjunct to this prescription, with brisk walking for 25–30 minutes at least every other day as a good recommendation. Many patients will attain euglycemia through these interventions, but the results of treatment must be monitored to optimize care. Home capillary glucose monitoring must be initiated promptly. Fasting and two-hour postprandial glucose levels should be obtained daily for the first two weeks of diet therapy. If fasting levels are consistently below 95 fasting and 120 postprandial, monitoring can decrease in frequency. If these thresholds are not consistently reached, an assessment of dietary compliance must be made and, if adequate, further treatment begun. Insulin therapy has been the mainstay of therapy beyond diet. Insulin resistance progresses in pregnancy and results in few episodes of hypoglycemia in this population. A reasonable starting point for daily insulin therapy is 0.8 U/kg in the first trimester, 1.0 U/kg in the second, and 1.2 U/kg in the third trimester. This dosage is distributed as two-thirds fasting in the morning, with one-third of the amount as regular or Lispro insulin and two-thirds as NPH. The remaining one-third is equally
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divided between regular or Lispro insulin at dinner and NPH at bedtime. This dosage should be adjusted as capillary blood-glucose monitoring indicates. Recently, many centers have begun to utilize oral hypoglycemic agents as an alternative to insulin therapy. Both glyburide and metformin have been used for this application. Glyburide does not cross the placenta and may have a slight safety advantage as a result. Beginning with 2.5 mg twice daily and increasing as needed to the maximum dose of 10 mg twice daily has been shown to be comparable to insulin treatment in regard to neonatal outcomes.20 Patients treated with glyburide should be viewed as having the same risk profile as those placed on insulin for the purposes of fetal monitoring. Fetal-growth monitoring is appropriate for women with gestational diabetes, serving to assess the treatment’s impact on restraint of the development of macrosomia. Rapid fetal growth despite treatment should give rise to an investigation of compliance and appropriate calibration of home glucose monitors. The fetus who manifests macrosomia and polyhydramnios should be considered at increased risk for poor outcome, even when other parameters of therapy appear optimal. In general, diet controlled gestational diabetic women do not require antenatal testing of fetal status at least until 40 weeks gestation. Prior history of fetal loss or the concomitant presence of hypertension should move this patient into the same risk category as patients requiring pharmacologic treatment. Induction of labor should be considered at term, but if fetal-growth parameters are favorable and cervical Bishop’s score is not, continuing the pregnancy with antenatal testing is appropriate. Patients who require treatment with oral hypoglycemics or insulin to satisfactorily regulate their blood sugars should be considered to be at risk for intrauterine fetal death, and antenatal testing with nonstress tests, biophysical profile, or contractions stress tests should begin by 32 weeks gestation or when such treatment is initiated. Most of these patients are best served by delivery before their due date, but if delivery is contemplated before 39 weeks proven gestational age, an amniocentesis for maturity should be acquired, unless other complications make delivery emergent. A great deal of effort has been directed at the prevention of shoulder dystocia in pregnancy complicated by diabetes. Although fetal weight is a better predictor of the development of shoulder dystocia in diabetics, it remains a measurement that is very unreliable. Ultrasound estimation of fetal weight in the best of hands is only accurate plus or minus 10 percent to 15 percent, which can easily exceed 500 grams in this population. Many physicians find this error large enough to consider it of questionable clinical relevance. Despite this inaccuracy, considering the gravity of a severe shoulder dystocia, it is reasonable to consider elective cesarean delivery in this special population when estimated fetal weight is greater than 4500 grams. Factors, such as success of a prior delivery, gestational age at delivery, and clinical pelvimetry, should still be considered in managing labor and delivery for these patients. However, arrest of progress in the second stage should not be approached with operative vaginal delivery, as both vacuum-assisted and forceps deliveries greatly increase the risk of shoulder dystocia. Intrapartum management of maternal blood glucose is important in the prevention of neonatal hypoglycemia. Neonatal insulin levels are not elevated when maternal glucose is in the normal range during labor. Most women with gestational
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diabetes on diet therapy or glyburide will have euglycemia in labor if they receive no glucose orally or as an infusion during labor. Capillary blood-glucose levels should be evaluated every one to two hours in labor, and if higher than 120 mg/dL, insulin infusion should be initiated Neonatal care requires early and frequent assessment of the baby’s metabolic state. Appropriate treatment of neonatal hypoglycemia is imperative to avoid longterm complications. Postpartum care of the gestational-diabetic subject is not complex, as normal carbohydrate metabolism is very likely to ensue with delivery of the placenta. Breast-feeding should be strongly encouraged. No methods of birth control are contraindicated in this group, unless the patient has other risk factors, such as smoking or advanced age. Up to two-thirds of these patients will have gestational diabetes in a subsequent pregnancy.21 The most critical aspect of postpartum care pertaining to the patient’s gestational diabetes is assurance that normal glucose tolerance persists. Since up to 15 percent of women with gestational diabetes will still display glucose intolerance after delivery, the American Diabetes Association recommends a 75-gram oral glucose tolerance test be administered six to eight weeks postpartum.17 If normal values are detected, the woman should be counseled regarding the future risk of developing type 2 diabetes. If overweight, the patient may be able to postpone or prevent the onset of that disease by weight management and exercise.21 In any event, screening for glucose intolerance should occur every three years in this population.
VI. TYPE 1 AND 2 DIABETES MELLITUS The most important therapeutic intervention in the management of pregestational diabetes is effective, preconceptual counseling. As discussed previously, the most common cause of perinatal mortality today is congenital abnormalities of the developing fetus. A planned pregnancy, synchronized with optimal glucose control, is the most powerful intervention in diabetic pregnancy care. In the great majority of cases, obstetrical-care providers will not have the opportunity to affect this treatment, and thus the responsibility falls to the providers of diabetes care. A glycosylated hemoglobin in the normal range at conception and in the first trimester strongly predicts a normally developing fetus.11 When conception has occurred, the diabetic patient should be seen as soon as feasible by an obstetrician with interest in diabetes, in consultation with a diabetologist with interest in pregnancy, and a dietician with good understanding of both conditions. If control has not already been optimized, intensive education and aggressive insulin therapy is urgent. Infusion-pump therapy has been very successful in pregnancy, but if contraindicated or unacceptable to the patient, multiple daily injections with appropriate combinations of long-acting, intermediate, and short-acting insulins must be adopted. Intensive diabetes education and management may require hospitalization to accomplish. Capillary glucose monitoring is required daily in the fasting state and two hours after each meal. Fasting targets of 60–95 mg/dL and postprandial levels less than 120 mg/dL should be the goal. Glycosylated hemoglobin should be measured every trimester at a minimum to monitor long-term success of therapy. Urinary ketones
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should be assessed any time two successive glucose values exceed 200 mg/dL, or if illness or nausea of pregnancy lead to prolonged fasting. In addition to the assessment of glycemic control, urinalysis, urine culture, 24hour urine protein, and a dilated ophthalmoscopic exam is indicated at the first visit.22 If diabetes has been present for more than five years, assessment of thyroid function is also indicated. Any evidence of vascular disease by history or examination warrants electrocardiographic assessment for coronary-artery disease. These tests should be reviewed with the patient promptly and plans modified according to those findings. If proteinuria exceeds 190 mg/24 hrs there is a substantial risk of hypertensive complications of pregnancy and the concomitant risk of fetal-growth restriction and uteroplacental insufficiency.23 If a patient has been placed on an angiotensin converting enzyme inhibitor to protect her renal function, this must be stopped in pregnancy to avoid potentially fatal impact on fetal renal function. Absolute knowledge of gestational age is required to manage the diabetic gravida, and transvaginal ultrasound assessment of crown-rump length by 11 weeks should be used whenever there is any doubt about the current length of gestation. Nuchal translucency measurement between 11 and 14 weeks can be an early warning of cardiac defects in the embryo when there is evidence that poor glycemic control was present at the time of organogenesis. There is a high risk for neural-tube defect in the diabetic pregnancy as well, but screening alphafetoprotein (AFP) levels in the second trimester have limited value. Interpretations of AFP levels must take into consideration the presence of diabetes, but the test is designed to detect risk in a low-risk population. The patient with diabetes is probably better served by an intensive ultrasound anatomic survey at 19 weeks, which has a higher reliability to detect neural-tube defects and a significant opportunity to examine the fetus for other anomalies.24,25 Fetal echocardiography should also be considered in light of the high risk of congenital heart disease, especially in women with high first-trimester glycohemoglobin levels. Ultrasound assessment of growth after 28 weeks can be informative about the effect of the disease on the developing fetus. Some fetuses manifest macrosomia and polyhydramnios despite evidence of good glucose control. These fetuses are at higher risk of both intrauterine and neonatal complications.26 Detection of fetal-growth delay is most likely in women who manifest end-organ disease, but greatly increases the risk of placental insufficiency near term and should be recognized early to optimize care. Antenatal fetal assessment with nonstress tests, biophysical profiles, or contraction stress tests are indicated from the point in gestation where delivery would be considered to benefit the fetus. Although intrauterine fetal demise is now quite rare, the potential remains, and consensus judgement favors choosing one of these methods. Good evidence is not available to favor one of these testing methodologies over another, but all appear to be effective in detecting fetuses at risk for intrauterine demise.27 At Mayo Clinic, we use NST with amniotic-fluid assessment twice each week after 32 weeks gestation for diabetic women in good control. End-organ disease, poor compliance, or evidence of fetal-growth restriction would lead to earlier testing. Diabetic ketoacidosis is more likely in pregnancy due to the insulin resistance of the hormonal millieu. Its treatment is unchanged from the nonpregnant state with
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the exception of the need for continuous fetal monitoring when gestational age allows for the potential to intervene on behalf of the fetus. Blood-pressure monitoring is appropriate in all pregnancies, but is even more important in pregnancies complicated by diabetes. Preeclampsia is more likely to occur in diabetic pregnancies, and unmasking of background hypertension is not uncommon in the third trimester. Although treatment of hypertension may be very important if retinopathy exists, in general, medical treatment is restricted to those with blood pressures exceeding 160/100. Preterm labor appears to be more frequent in pregnancies of diabetic women, in addition to the higher incidence of indicated iatrogenic shortening of gestation. Beta adrenergic tocolytic agents can give rise to profound hyperglycemia that can provoke fetal demise. These agents should be avoided in diabetes in favor of magnesium sulfate or a calcium channel blocker. Although less dramatic, treatment with potent corticosteroids to promote fetal-lung maturity must also be used with caution and close monitoring for acute hyperglycemia.28 Timing of delivery is an area of some controversy in the management of diabetes in pregnancy. Although there is little evidence to support early induction to avoid fetal demise in well-controlled diabetic mothers whose fetuses have normal testing, there is some evidence that induction of labor decreases the risk of macrosomia and shoulder dystocia.29 Acute hyperglycemia can lead to fetal demise at any time, within hours. For these reasons, most practitioners choose to move toward delivery in diabetic women by the time 39 weeks of gestation have been completed. As in gestational diabetes, amniocentesis is required prior to 39 weeks to proceed with elective delivery. Route of delivery considerations are identical to those for gestational diabetes, as discussed above. Instrumental vaginal delivery is ill-advised in most cases, as an arrest of progress in the second stage is a warning sign for shoulder dystocia. An estimated fetal weight in excess of 4500 grams may justify an elective cesarean delivery to avoid the same complication.30,31,32 Intrapartum management of insulin-dependent diabetes is of great importance in avoiding neonatal metabolic complications. Usual insulin dosages are not given during labor, and capillary blood glucose is evaluated hourly throughout. Five percent glucose is used in intravenous fluids unless blood sugar exceeds 150 mg/dL. If glucose levels exceed 100 mg/dL, continuous intravenous infusion of regular insulin is given at 1.0 unit per hour adjusted as the patient responds (Table 15.2). It is very important to stop insulin infusion with delivery to avoid profound maternal hypoglycemia. After delivery, glucose infusion is continued and blood glucose is assessed every four hours if NPO or before meals, at bedtime, and at 3 a.m. if taking food. Insulin should be given in the postpartum time frame with relaxed goals of control. No insulin is given until blood glucose exceeds 180 mg/dL (Table 15.3). When requirement for insulin is reestablished, a return to a schedule of longer-acting insulin is begun the following day at approximately 67 percent of prepregnancy doses. Contraception is very important for the diabetic woman, as planning her next pregnancy is imperative. Diabetes is not, in itself, a contraindication to any contraceptive method. For women over 35, smokers, and those with vascular complications of diabetes, estrogen containing hormonal contraceptive should be avoided. The risks
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TABLE 15.2 Intrapartum Insulin Infusion Algorithm Standard Blood or Plasma Glucose mg/dL
IV Infusion Rate ml/hr
Insulin Infusion Rate Units/Hr
8 6 4 3 2.5 2 1.5 1 0 0
8 6 4 3 2.5 2 1.5 1 0 0
>400 351–400 301–350 250–300 200–249 150–199 120–149 100–119 70–99 <70
TABLE 15.3 Postpartum Insulin Dosage Algorithm Blood Glucose mg/dl
Insulin (units)
180–200 201–250 251–300 >300
4 6 8 10
of noncompliance with other contraceptive methods must be weighed against the risks of unplanned pregnancy in these situations. Breast-feeding should be encouraged in any event.
VII. PREGNANCY AND DIABETES IN PERSPECTIVE Evidence suggests that pregnancy complicated by diabetes is likely to become a more frequent event in the future. Happily, we now have the tools to help such pregnancies come to a most salutary completion in the vast majority of cases. It is very much within the grasp of diabetic women and their care team to expect an outcome for their fetus that is comparable to that of the general population. Intrinsic to the success of reaching that goal is the education of the diabetic patient and the empowerment of her own decision-making regarding the management of her disease. Well-educated diabetic patients understand far better than their physicians the anticipated impact on their disease of a given quantum of exercise, a specific carbohydrate load, and a given unit of insulin. Although pregnancy changes these variables profoundly, the educated patient will recognize the patterns far before those of us in the medical-care team will make similar connections. Enabling our
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patients to understand their disease, monitor their sugars, and make therapeutic decisions pays dividends for a lifetime. The motivated diabetic patient who understands the goals of her treatment in pregnancy not only contributes profoundly to the delivery of a normal infant, but she obtains the tools to apply to her ongoing care. The result is a far healthier and long-lived mother for that wonderful new baby. It behooves all of us who care for pregnant women with diabetes to have a broad view of the goals of our therapeutic interaction. The benefits to a developing fetus of tight glycemic control is a microcosm of the effects of control on the long-term health of the maternal organism. This therapeutic relationship provides the opportunity to profoundly benefit the lives of both of our patients.
REFERENCES 1. Engelgau, MM, Herman, WH, Smith PJ, et al., The epidemiology of diabetes and pregnancy in the U.S., 1988, Diabet. Care, 18:1029, 1995. 2. White, P, Classification of obstetric diabetes, Am. J. Obstet. Gynecol.,130:228, 1978. 3. Harris, MI, Gestational diabetes may represent discovery of preexisting glucose intolerance. Diabet. Care, 11:402, 1988. 4. Langer O, Levy, J, Brustman, L, et al., Glycemic control in gestational diabetes mellitus — how tight is tight enough: small for gestational age versus large for gestational age? Am. J. Obstet. Gynecol., 161:646, 1989. 5. Gabbe, SG and Graves CR, Diabetes mellitus in pregnancy, Obstet. Gynecol., 102(4):857–868, 2003. 6. Gordon, M, Landon, MB, Samuels, P, Hissrich, S, and Gabbe, SG, Perinatal outcome and long-term follow-up associated with modern management of diabetic nephropathy, Obstet. Gynecol., 87:401–9, 1996. 7. Airaksinei, KEJ, Anttila, LM, Linnaluoto, MK, Jouppila, PI, Takkunen, JT, and Salmela, PI, Autonomic influence on pregnancy outcome in IDDM, Diabet. Care, 13:756–61, 1990. 8. Miodovnik, M, Rosenn, B, Berk, M, Kranias, G, Khoury, J, Lipman, M, et al., The effect of pregnancy on microvascular complications of insulin dependent diabetes (IDDM): A prospective study, Am. J. Obstet. Gynecol., 178:S53, 1998. 9. Gordon, MC, Landon, MB, Boyle, J, Stewart, K, and Gabbe, SG, Coronary artery disease in insulin-dependent diabetes mellitus of pregnancy (Class H): A review of the literature, Obstet. Gynecol. Surv., 51:437–44, 1996. 10. Kitzmiller, JL, Buchanan, TA, Kjos, S, Combs, CA, and Ratner, RE, Pre-conception care of diabetes, congenital malformations, and spontaneous abortions, Diabet. Care, 19:514–40, 1996. 11. Miller, E, Hare, JW, Cloherty, JP, Dunn, PJ, Gleason, RE, Soeldner, JS, et al., Elevated maternal hemoglobin A1c in early pregnancy and major congenital anomalies in infants of diabetic mothers, N. Engl. J. Med., 304:1331–4, 1981. 12. Molsted-Pedersen, L, Tygstrup, I, and Pederson, J, Congenital malformations in newborn infants of diabetic women, Lancet i:1124–6, 1964. 13. Sibai, BM, Caritis, SN, Hauth, JC, et al., Preterm delivery in women with pregestational diabetes mellitus or chronic hypertension relative to women with uncomplicated pregnancies, The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network, Am. J. Obstet. Gynecol., 183:1520, 2000.
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14. Robert, MF, Neff, RK, Hubbell, JP, Taeusch, HW, and Avery, ME, Association between maternal diabetes and the respiratory-distress syndrome in the newborn, N. Engl. J. Med., 294:357, 1976. 15. Acker, DB and Barss, VA, Obstetrical complications, in Diabetes Complication Pregnancy, 2nd ed., Brown, FM and Hare, JW, Eds., Wiley-Liss, New York, 1995, p.153. 16. American College of Obstetricians and Gynecologists Committee on Practice Bulletins — Obstetrics, Gestational diabetes ACOG practice bulletin No. 30., Coustan, DR, American College of Obstetricians and Gynecologists, Washington, 2001. 17. American Diabetes Association, Gestational diabetes mellitus, Diabet. Care, 26(Suppl. 1):S103–5, 2003. 18. Carpenter, MW and Coustan, DR, Criteria for screening tests for gestational diabetes, Am. J. Obstet. Gynecol., 1982; 144:768–73, 1982. 19. Langer, O, Anyaegbunam, A, Brustman, L, and Divon, M, Management of women with one abnormal oral glucose tolerance test value reduces adverse pregnancy outcome, Am. J. Obstet. Gynecol., 161:593–9, 1989. 20. Langer, O, Conway, DL, Berkus, MD, Xenakis, EMJ, and Gonzales, O, A comparison of glyburide and insulin in women with gestational diabetes mellitus, N. Engl. J. Med., 343:1134–8, 2000. 21. American Diabetes Association and National Institute of Diabetes, Digestive and Kidney Diseases. The prevention or delay of type 2 diabetes, Diabet. Care, 25(4):742–9, 2002. 22. The Diabetes Control and Complications Trial Research Group, Effect of pregnancy on microvascular complications in the diabetes control and complications trial, Diabet. Care, 23:1084, 2000. 23. Preconception care of women with diabetes, Diabet. Care, 26 (Suppl. 1):S91, 2003. 24. Greene, MF and Benacerraf, BR, Prenatal diagnosis in diabetic gravidas: utility of ultrasound and maternal serum alpha-fetoprotein screening, Obstet. Gynecol., 77:520, 1991. 25. Albert, TJ, Landon, BM, Wheller, JJ, et al., Prenatal detection of fetal anomalies in pregnancies complicated by insulin-dependent diabetes mellitus, Am. J. Obstet. Gynecol., 174:1424, 1996. 26. Benedetti, TJ and Gabbe, SG, Shoulder dystocia: A complication of fetal macosomia and prolonged second stage of labor with mid-pelvic delivery, Obstet. Gynecol., 52:526 1978. 27. Landon, MB and Vickers, S. Fetal surveillance in pregnancy complicated by diabetes mellitus: is it necessary? J. Matern. Fetal Neonat. Med., 12:413, 2002. 28. Bedalov, A and Balasubramanyam, A, Glucocorticoid-induced ketaacidosis in gestational diabetes: sequela of the acute treatment of preterm labor. A case report [published erratum appears in Diabet. Care, 20(8):1343, 1997], Diabet. Care, 20:922, 1997. 29. Kjos, SL, Henry, OA, Montoro, M, et al., Insulin-requiring diabetes in pregnancy: a randomized trial of active induction of labor and expectant management, Am. J. Obstet. Gynecol., 169:611, 1993. 30. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin No. 40, Shoulder dystocia, November 2002. 31. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin Number 22, Fetal macrosomia, 2000. 32. American College of Obstetricians and Gynecologists, ACOG Practice Bulletin No. 30 (replaces Technical Bulletin Number 200, December 1994), Clinical management guidelines for obstetrician-gynecologists, gestational diabetes, September 2001, Obstet. Gynecol., 98:525, 2001.
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Web-Based Simulations for Dynamic Variations in Blood-Glucose Concentration of Patients with Type 1 Diabetes Ali Cinar, Ph.D.
CONTENTS I. Introduction................................................................................................282 II. Models for Describing Dynamic Variations in Blood-Glucose Concentration.............................................................................................282 A. Detailed Glucose Model....................................................................283 B. Detailed Insulin Model......................................................................285 C. Overall Model for Glucose and Insulin............................................286 D. Healthy-Person Model.......................................................................287 1. Islet Insulin Secretion Model......................................................287 2. Pancreatic Insulin Release Model...............................................287 E. Exercise Model..................................................................................288 III. Simulation Software for Illustrating Dynamic Variations in Blood-Glucose Concentration ...................................................................289 A. GLUCOSIM ......................................................................................289 IV. Illustrative Case Studies ............................................................................291 A. Case 1: Simulation with Continuous Insulin Regulation by a Pump Under Feedback Control ................................................292 B. Case 2: Insulin Injection to Subcutaneous and Intraperitoneal Areas .........................................................................292 C. Case 3: Comparison of Three Control Algorithms in the Presence of Various Meals and Exercise ..........................................294 V. Conclusion .................................................................................................295 Acknowledgments..................................................................................................296 References..............................................................................................................296
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I. INTRODUCTION Software for assisting patients with diabetes can be clustered into three groups: 1) software for daily logs of food intake and computation of the insulin dose to be administered based on recent food consumption; 2) software for interpreting data collected from a subject; and 3) simulation software for illustrating dynamic variations in blood-glucose concentration. Studying the variations in blood-glucose and insulin concentrations in response to external inputs, such as food intake or insulin injection, is important, especially for new patients, in order to understand the effects of food type and amount consumed and the effects of insulin type, dose, and time of administration relative to food-intake time. This chapter is focused on simulation software that empowers patients to look at alternative scenarios in food-intake and insulin administration and observe dynamic variations in blood-glucose concentration. Observing rapid variations in glucose concentration, the onset and magnitude of hyperglycemia and hypoglycemia, and changes in diet and insulin-administration time that can cause or prevent dangerous excursions in glucose levels provide significant educational benefits. The chapter is structured as follows. First, the mathematical models for describing the dynamic response at the whole-body level that are available in the literature are summarized and the models used in GLUCOSIM are discussed. Then, various simulation software that can be executed on the Web are reviewed. The next section discusses GLUCOSIM, a simulation package developed at Illinois Institute of Technology [1–3]. GLUCOSIM’s potential is highlighted for simulating closed-loop control of insulin delivery when it is interfaced with continuous glucose-concentration measurement sensors and automatic controllers that regulate insulin delivery from insulin pumps. Finally, some case studies are reported to illustrate the use of GLUCOSIM. In the development of mathematical models, average patient/person characteristics are considered. No particular attempt has been made for parameter optimization, but violation of the system’s physiology has been avoided. The model proposed can easily be adapted and used to mimic a specific data set by simply making use of parameter estimation techniques. However, the simulation results should not be used for making medical decisions about or determining insulin administration to an individual.
II. MODELS FOR DESCRIBING DYNAMIC VARIATIONS IN BLOOD-GLUCOSE CONCENTRATION Modeling glucose-insulin interaction in the human body requires an understanding of the physiological and metabolic processes that influence the variations observed over time in blood-glucose concentration. An integrated network of chemical reactions and transport processes is used to develop a quantitative model to describe the observed behavior. A number of mathematical models of type 1 diabetes have been reported in the literature [5–13]. Most models developed for describing the dynamic interaction between blood-insulin and glucose-concentration variations are compartmental models. A two-compartment model was developed by partitioning the whole
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system into an insulin system and a glucose system linked by two measured variables, insulin and glucose concentrations [8]. This minimal model was used for interpreting the results of an intravenous glucose-tolerance test, and it has been improved over the years [9]. More extensive compartmental models that enable the computation of glucose and insulin concentrations in various organs and systems of the body have been developed [5, 6]. They are more appropriate for the objectives of GLUCOSIM. GLUCOSIM is based on the compartmental models of Puckett [5]. A detailed mathematical model is constructed based on pharmacokinetic diagrams of glucose and insulin (Figure 16.1). Mass balances for glucose and insulin are written around each compartment, representing various organs and the circulation system to express their transport through the major vessels and to the capillaries. Insulin and glucoseconcentration dynamics in various compartments (organs) are computed. The advantage of this type of detailed model is that the model design is based on an understanding of the physiology and simulations that can yield insight into the physiological processes. Their main disadvantage is that variations in personal physiological parameters are not taken into account. Therefore, the outputs are average values, and the models should not be used for providing medical advice for an individual. An overall mathematical model is also derived by assuming steady state in all organs and folding the resulting algebraic equations of all compartments into the remaining two differential equations for blood-glucose and insulin concentrations. In addition, a healthy-person model and a model modification for people performing moderate exercise are incorporated in GLUCOSIM.
A. DETAILED GLUCOSE MODEL The body has been divided into seven physiologic compartments (tissues/organs) [5,13]: 1) heart (H), which represents the rapidly mixing vascular volumes of the heart, lungs, and arteries; 2) brain (NS), which represents the central nervous system; 3) liver (L); 4) pancreas (PN); 5) gastrointestinal tract (GT); 6) kidney (K); and 7) periphery (PR), which includes skeletal muscle and adipose tissue. A schematic representation of a pharmacokinetic model for glucose is shown in Figure 16.1a. Using this diagram, mass-balance equations around each compartment (tissue/organ) can be written for glucose in blood. Mass balance for a specific tissue/organ can be represented as: dGout 1 = (Qin,gGin − Qout ,gGout + rreproductionn within tissue − rutilization within tissue dt Vg
) (16.1)
Here, V, Q, and G represent the effective volume, effective flow rate, and bloodglucose concentration; subscripts in and out indicate variables into and out of the compartment (tissue/organ), respectively; and subscript g indicates glucose. The rate of utilization or production of glucose within that tissue is denoted by r. It is assumed that glucose equilibration exists across the red blood-cell membrane, and thus glucose is uniformly distributed throughout the entire water volume in whole blood.
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GH
GB
r
HGU
HEART G NS
GB
r
NSGU
BRAIN GB
Hepatic Artery GB
GB GL
rLGU
PANCREAS
GPV
rLGP
LIVER
GGT
GB
r
GA
GI TRACT GK
GB
rKGU
Food Ingestion
KIDNEY rGE
GPR
GB
rPRGU
PERIPHERY (a) IB
IB
HEART
IB
Hepatic Artery IB
IB IL
PANCREAS
rLIR
LIVER
IB
IB
GI TRACT Insulin IK
IB
rKIR
KIDNEY ISC
IB
rIA SUBCUTANEOUS TISSUE
IPR
Insulin
IB rPRIR
PERIPHERY (b)
FIGURE 16.1 Schematic representation of the pharmacokinetic models of (a) glucose and (b) insulin. Different insulin injection locations are shown for subcutaneous and intraperitoneal injections.
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Since the water volume of blood is roughly 84 percent, blood volumes and flow rates were reduced by 16 percent for effective values of volume and flow rates [5]. Major tissues, including liver, muscle, adipose, heart, kidney, and brain, remove glucose from blood and store or oxidize it for energy. To formulate tissue-glucose uptake/utilization models, the tissues have been grouped into three categories: 1) insulin- and glucose-independent uptake: central nervous system and red blood cells; 2) glucose-dependent uptake: kidneys; and 3) insulin- and glucose-dependent uptake: remaining major tissues. Based on the pharmacokinetic diagram of glucose (Figure 16.1a), the rate of change of glucose concentration in circulating blood (B) can be expressed as: 1 dGB = [–QH (GH − GB ) + QK (GK − GB ) + QNS (GNS − GB ) + QPR (GPR − GB ) dt VB + QL GL – (QHA + QPN + QGT ) GB ] (16.2) It is assumed that Qin,g = Qout,g = Qg. The subscripts in and out for G in Equation 16.1 are replaced by the symbols of the previous and succeeding compartments. For example, in the term QH (GH – GB), GH is the glucose-concentration input from the heart compartment, and GB is the glucose concentration leaving the system from circulating blood (B).
B. DETAILED INSULIN MODEL A schematic representation of pharmacokinetic model of insulin is presented in Figure 16.1b. For simplicity, the only insulin input to patients with type 1 diabetes is assumed to be by injections. The only difference of this diagram from the pharmacokinetic diagram of glucose is that subcutaneous tissue is included instead of brain, and insulin is injected through this tissue. Since the blood-brain barrier capillary structure is impermeable to insulin passage into cerebrospinal fluid [14], the brain compartment has been omitted from insulin formulation. The three-pool insulin input model is based on the model of Puckett and Lightfoot [13] to describe the absorption of short-acting insulin. It includes three pools (the pocket formed by injected insulin solution [P], the interstitium [S], and the capillary [blood]) in which insulin is distributed because their concentrations may differ due to slow transfer from one region to another. Mass-balance equations for insulin are derived similarly to the glucose model. For the calculation of effective volumes and flow rates, it is assumed that insulin is uniformly distributed in plasma volume of the whole blood because, unlike glucose, the red blood-cell membrane is impermeable to insulin. Since the average red blood-cell content of the whole blood is about 40 percent by volume, blood volumes and flow rates are reduced by 40 percent to be used as effective volumes and flow rates in insulin model. Furthermore, in order to obtain effective volumes for glucose and insulin models for different body weights, a calibration curve proposed by Bischoff [15] that gives a relationship for organ volumes as a function of mammal body weight has been used [2]. A general mass
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balance for insulin for a specific tissue/organ is similar to Equation 1, with appropriate changes in the subscripts. Based on the pharmacokinetic diagram of insulin (Figure 16.1b), the rate of change of insulin concentration in circulating blood is expressed as: 1 dI B = dt VB
[QSC ( I SC − I B ) + QK ( I K − I B ) + QPR ( I IR − I B ) + QL I L – (QHA + QPN + QGT )I B ] (16.3) The detailed model that integrates the glucose and insulin models has 21 ordinary differential equations solved simultaneously that represent the concentration dynamics in various organs with variable volumes as a function of patient’s weight and the distribution of glucose and insulin throughout the body. The constants and physiological parameters used in the model are provided in the GLUCOSIM Web site. The values of constants and parameters are based on an average person. Different cases can be studied with this model to investigate the effects of body weight, carbohydrate intake, insulin dosage, timing of meal, and duration of exercise on glucose–insulin interaction in individuals with type 1 diabetes.
C. OVERALL MODEL
FOR
GLUCOSE
AND INSULIN
The overall mathematical model for glucose in blood is developed by assuming that dG/dt = 0 in each tissue/organ 1 dGB = − rHGU − rKGU − rGE − rNSGU − rPRGU − rLGU + rLGP + rGA VB dt
(16.4)
where the first letter in the subscript denotes the compartment, G indicates glucose, U utilization, E excretion, P production, and A absorption. Similarly, for the insulin in blood dI/dt = 0 in each tissue/organ, yielding 1 dI B = − rIA − rKIR − rPRIR − rLIR VB dt
(16.5)
where K, PR, and L in the subscript denote kidney, periphery and liver, respectively, I denotes insulin, A absorption, and R removal. Because of the assumption that rapid changes occur within the tissue, all inputs and removals can be represented as direct source or sink terms in the mass balance for the blood circulation. The overall model provided in GLUCOSIM for comparison studies with the detailed model consists of Equation 16.4 and Equation 16.5.
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D. HEALTHY-PERSON MODEL The detailed mathematical model developed for a patient with type 1 diabetes is revised to simulate glucose–insulin interaction in an average healthy person. The pharmacokinetic diagrams of glucose and insulin (Figure 16.1) are used, with the only difference being the replacement of insulin injection with pancreatic insulin release [2]. Two submodels for pancreatic insulin release [16, 17] have been integrated to the detailed mathematical model. 1. Islet Insulin Secretion Model This submodel is based on islet insulin secretion by rat islets [16]. This model treats the islet insulin release rate as a proportional-derivative control system. Insulin secretion (I) in response to glucose concentration variations (X) is represented by the equation ⎡ Kp Td s ⎤ I (s) = ⎢ + ⎥ X (s) ⎣ (1 + T1 s ) (1 + T2 s ) ⎦
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E. EXERCISE MODEL Healthy people usually do not experience metabolic complications during physical activity. During most forms of exercise, the plasma glucose concentration is maintained at a fairly stable level [18]. Diabetic patients, however, are faced with the risk of exercise-induced hypoglycemia or, under certain conditions, severe ketoacidosis [19]. For subjects with type 1 diabetes, the ability to adjust the therapeutic regimen (insulin and diet) to allow safe participation and high performance has recently been recognized as an important management strategy [20]. Metabolic response to exercise will vary according to factors such as an individual’s nutritional state, age, specific pathology, and work capacity [21]. In a healthy person, increased glucose uptake by the working muscle is precisely matched by adequate amounts of glucose originating from the liver or intestinal absorption. Thus, normoglycemia can be maintained, and a sufficient energy supply is available for vital organs [22]. Insulin plays a central role in the regulation of glucose homeostasis during exercise. With the onset of exercise, insulin secretion decreases almost instantaneously, because during exercise, insulin becomes much more efficient, therefore, more glucose can be transported with lesser amounts of available insulin [23, 24]. Exercise activates noninsulin mediated glucose transport pathways that increase the effective insulin efficiency [25]. Both the overall and detailed models in GLUCOSIM have been modified to include the effect of exercise on glucose–insulin interaction in individuals with type 1 diabetes. Among various possible intensities of exercise, moderate exercise has been considered for modeling purposes. Moderate exercise is achieved when oxygen consumption by the body is at 50 percent of its maximum value. Both the overall and detailed models have been extended by including changes in 1) insulin absorption from the subcutaneous tissue; 2) total glucose uptake; and 3) the volumetric flow rates of blood through different organs. Experimental data from Berger et al. [23] have been used to get a first estimate of parameter τS in the subcutaneous transport model of Puckett & Lightfoot [13] and parameter k in the insulin and glucose-dependent uptake model [5]. Values of these parameters for different duration of exercise are available. As a first attempt, volumetric flow rates of blood in each organ have been increased by 25 percent during the exercise. It is assumed that the new, steady state is attained shortly after the start of the exercise. Postexercise complications have not been considered. The circulating levels of insulin for subjects with type 1 diabetes do not react to exercise, unlike nondiabetic subjects that spontaneously regulate the release of insulin from the pancreatic β-cells. The acute risks of exercise in type 1 diabetes include both hypoglycemia and hyperglycemia [26]. When a person with type 1 diabetes exercises with too little insulin in the circulation, the already elevated blood-glucose and ketone body levels can become even greater. On the other hand, if too much insulin is present, hypoglycemia may ensue. Studies show that in diabetic patients, exercise induces a marked fall of bloodglucose concentration. During exercise, blood glucose homeostasis is usually achieved by an appropriate increase of splanchnic glucose production in response to a rise in peripheral glucose utilization. Any change in blood-glucose levels during physical activity reflects an imbalance between these processes [23].
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III. SIMULATION SOFTWARE FOR ILLUSTRATING DYNAMIC VARIATIONS IN BLOOD-GLUCOSE CONCENTRATION Advances in information technology and devices have revolutionized software and electronic devices available to individuals afflicted with type 1 diabetes. Many Web sites provide useful information about available software [27]. Most software tools are focused on daily diaries of activities and personalized advisers for suggesting the dose of insulin to be taken in response to food intake and activities stated by the patient [28, 29]. Reference materials, advice, and support groups are also available on the Web [27]. Few software tools have focused on patient education based on simulation of insulin–glucose dynamics [30, 31]. GLUCOSIM is a new simulation software for insulin–glucose dynamics, enabling the user to experiment not only with food consumed and insulin injected, but also with futuristic, automatic control of insulin pumps based on controllers that regulate pump operation based on continuous glucose measurements.
A. GLUCOSIM GLUCOSIM was developed at IIT starting in 1999 to assist biomedical and chemicaengineering students in visualizing dynamic variations in blood-glucose concentration in response to external variations, such as food consumption and insulin injection. GLUCOSIM includes modules for patients with type 1 diabetes and for healthy subjects who have insulin generation in the pancreas and a module for the oral glucose tolerance test. It can also illustrate effects of moderate level exercise. GLUCOSIM was prototyped in Matlab. At present, most of these features are available on the Web by executing the software on a server at IIT. A self-contained version in C is also being developed. The Web-based module may be visited at www.chee. iit.edu/~control/software (or http://216.47.139.198/glucosim/index.html) and further information may be requested from
[email protected]. The flow of decisions in using GLUCOSIM (Figure 16.2) provides the opportunity to learn about diabetes from various resources, follow a demo (in MATLAB version), and execute simulations for healthy subjects and patients with type 1 diabetes. Effects of food amounts and types, body weight, exercise, insulin-injection times, doses, insulin type, the location of the injection (subcutaneous or intraperitoneal), injection by syringe or pump, and manual or automatically controlled pump can be investigated in simulations with diabetic patients. The interaction of the user with the software is kept as simple as possible. Menus, buttons, and sliders are used as controlling elements. Simulation results are displayed graphically. The numerical values and graphs can be saved and downloaded by users. User inputs for simulation of single or multiple meals and injections (Figures 16.3 and 16.4) are: 1. Carbohydrate content of the meal: There is also a nutritional database where the user can find the carbohydrate content of a specific meal. 2. Time of meal and injection: The user can enter a value between 0–24 hours for time of meal and insulin injection.
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FIGURE 16.2 General layout of GLUCOSIM and user interaction.
3. Insulin type and dose: Two types of insulin are available, i.e., regular and ultralente. 4. Body weight. 5. Duration of exercise: The exercise option, which is specifically designed for moderate exercise, is available for only patients with type 1 diabeties. 6. Duration of simulation: It is possible to simulate a case for a maximum of 24 hours with up to four insulin injections. One objective of GLUCOSIM is to provide engineering students interested in medical applications an environment for testing design alternatives through simulation studies. The inputs to GLUCOSIM listed above are relevant for illustrating the impact of food, insulin dose, and exercise made by the user. Models of various controllers have been included in GLUCOSIM to enable the user with design of feedback controllers that regulate the operation of an insulin pump. Research of continuous bloodglucose monitoring sensors is an active research area, and it is expected that sensors that can continuously monitor the concentration of blood glucose at frequent intervals and report it using wired or wireless transmission will be available in a few years. Automatic pumps to deliver insulin are already available in the market. The controllers in GLUCOSIM assume the existence of continuous blood-glucose concentration measurement information and of pumps with adjustable insulin delivery that could be regulated by automatic feedback controllers. Alternative control algorithms have been developed based on traditional proportional-integral-derivative (PID) controllers, internal model controllers (IMC), and model predictive controllers (MPC) [32]. Users can tune these controllers by varying their parameters or restructure them by modifying control equations that relate the difference between glucose measurements and desired values and the insulin flow rate from the pump.
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FIGURE 16.3 Input page of GLUCOSIM, data entry for meal times and CHO content, body weight, and duration of simulation (continued in Figure 16.4).
When the simulation is finished, data may be saved in ASCII and graphic forms to recall and display the profiles or download to the computer of the user for further analysis.
IV. ILLUSTRATIVE CASE STUDIES Three case studies illustrate some of the capabilities of GLUCOSIM. First, the display of various plots for a simulation with continuous insulin regulation by a pump under feedback control is shown in Figure 16.5. Next, a comparative case study between injection to subcutaneous and intraperitoneal areas for automatic feedback controlled insulin delivery is illustrated in Figure 16.6. Finally, the comparison of automatic feedback controlled insulin delivery by three different control
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FIGURE 16.4 Continuation of input page of GLUCOSIM, data entry for insulin-injection times, dose and type, exercise start time, and exercise duration.
algorithms when the patient ate various meals and snacks and exercised during the simulation period is shown in Figure 16.7.
A. CASE 1: SIMULATION WITH CONTINUOUS INSULIN REGULATION BY A PUMP UNDER FEEDBACK CONTROL Four plots in Figure 16.5 (starting from the top left and going clockwise) illustrate the blood-glucose concentration, insulin-injection rate, blood-insulin concentration, and glucose absorption in the digestive track (intestine). The user can modify any of the inputs that he/she had given, run the simulation again, and compare the effects of the change made. Other variables, such as the amount of glucose in the stomach, liver glucose production, and total glucose uptake, can also be plotted to provide a more comprehensive picture.
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FIGURE 16.5 Display of simulation results of GLUCOSIM. The insulin-injection rate plot (upper right) indicates that a pump under automatic control is used.
concentration is close to values that would be considered as hypoglycemia. In contrast, the fast diffusion via the intraperitoneal route reduces both the peak and the response time. The potential for hypoglycemia is also reduced significantly.
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C. CASE 3: COMPARISON OF THREE CONTROL ALGORITHMS IN THE PRESENCE OF VARIOUS MEALS AND EXERCISE The performance of PID, IMC, and MPC control is compared for insulin delivery via the intraperitoneal route for a 70-kg individual with type 1 diabetes during a 15hour (900-min) simulation. The simulation starts at 8 a.m., breakfast at 8:30a.m. (Time: 30 min, 400 mg/kg [carbohydrate content of meal] CHOM), exercise at 9 a.m. for 30 min (Time: 90 min), snack at noon (Time: 240 min, 100 mg/kg CHOM), lunch at 1:30 p.m. (Time 330 min, 800 mg/kg CHOM), snack at 6 p.m. (Time: 600
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min, 100 mg/kg CHOM), dinner at 8 p.m. (Time: 720 min, 800 mg/kg CHOM), and a final snack at 10 p.m. (Time: 900 min, 100 mg/kg CHOM). The MPC gives the best regulation by providing large doses of insulin when needed.
V. CONCLUSION Simulating the behavior of the human glucose–insulin system enhances the understanding of the dynamic effects in both healthy persons and patients with type 1
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diabetes. In this chapter, Web-based simulation of the dynamics of the glucose–insulin system is described, and the GLUCOSIM simulator, based on a compartmental mathematical model, is presented. GLUCOSIM can illustrate the effects of body weight, food, insulin dose, type and delivery time, and moderate exercise. It can also illustrate the effects of an insulin pump and its operation with automatic feedback controllers, and insulin-injection sites. The behavior of blood-glucose concentration variations in individuals depends on many factors. These simulators provide a good display of dynamic variations and interaction between insulin and glucose, but they should not be used for medical decisions. Their value is in education of students and the public, professionals in health care, and new patients.
ACKNOWLEDGMENTS The financial support provided by NSF (EEC-0080527) is gratefully acknowledged. Graduate students Baris Agar, Meriyan Eren, Ceylan Erzen, and Eric Tatara and postdoctoral research associates Gulnur Birol and Inanc Birol contributed to the development of GLUCOSIM. Their creative thinking and hard work enabled the development of this versatile and user-friendly simulator.
REFERENCES 1. Agar, B, Eren, M, and Cinar, A, “GLUCOSIM: Educational software for diabetes and simulation of glucose dynamics in blood,” 64th American Diabetes Association Meeting, Orlando, FL, Diabetes, 53(Suppl. 2):A513, 2004. 2. Erzen, FC, “Studies on modelling glucose insulin interaction in human body and development of a simulation package,” M.S. thesis, Illinois Institute of Technology, Chemical and Environmental Engineering Department, 2000. 3. Erzen, FC, Birol, G, and Cinar, A, Development and Implementation of an Educational Simulator: GLUCOSIM, Chem. Eng. Educ., 37 (4)300–305, 2003. 4. Agar, B, Birol, G, and Cinar, A, Virtual Experiments for Controlling Blood Glucose Level in Type I Diabetes, Proc. 2nd Joint EMBS-BMES Conference, Houston, October 2002. 5. Puckett, WR, Dynamic Modeling of Diabetes Mellitus, Ph.D. thesis, University of Wisconsin-Madison, Department of Chemical Engineering, 1992. 6. Sorensen, JT, A Physiologic Model of Glucose Metabolism in Man and Its Use to Design and Assess Improved Insulin Therapies for Diabetes, Ph.D. thesis, Massachusetts Institute of Technology, Department of Chemical Engineering, 1985. 7. Guyton, JR, Foster, RO, Soeldner, JS, Tan, MH, Kahn, CB, Konez, L, and Gleason, RE, A model of glucose-insulin homeostasis in man that incorporates the heterogeneous fast pool theory of pancreatic insulin release, Diabetes, 27:1027–1042, 1978. 8. Bergman, RN, Ider, YZ, Bowden, CR, and Cobelli, C, Quantitative estimation of insulin sensitivity, Am. J. Physiol., 236:E667–77, 1979. 9. Carson, C and Cobelli, C, Modelling Methodology for Physiology and Medicine, Academic Press, San Diego, 2001. 10. Leaning, MS and Boroujerdi, MA, A system for compartmental modelling and simulation, Comp. Meth. Prog. Biomed., 35:71–92, 1991.
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11. Ackerman, E, Gatewood, LC, Rosevear, JW, and Molnar, G, Model studies of bloodglucose regulation, Math. Biophys., 27:21–37, 1965. 12. Hillman, RS, The dynamics and control of glucose metabolism, M.S. thesis, Massachusetts Institute of Technology, Department of Chemical Engineering, 1978. 13. Puckett WR and Lightfoot, EN, A model for multiple subcutaneous insulin injections developed from individual diabetic patient data, Am. J. Physiol., 269:E1115–E1124, 1995. 14. Davson, H, and Spaziani, E, The blood-brain barrier and the extracellular space of the brain, J. Physiol., 149:135–143, 1959. 15. Bischoff, KB, Some fundamental considerations of the applications of pharmacokinetics to cancer chemotherapy, Can. Chemo. Rep., 59:777–793, 1975. 16. Nomura, M, Shichiri, M, Kawamori, R, Yamasaki, Y, Iwama, N, and Abe, H, A mathematical insulin-secretion model and its validation in isolated rat pancreatic islets perfusion, Comput. Biomed. Res., 17:570–579, 1984. 17. Carson ER and Cramp, DG, A systems model of blood glucose control, Int. J. Biomed. Comput., 7:21–34, 1976. 18. Richter, EA and Galbo, H, Diabetes, insulin and exercise, Sports Med., 3:275–288, 1986. 19. Sonnenberg, GE, Kemmer, FW, and Berger, M, Exercise in type 1 (insulin-dependent) diabetic patients treated with continuous subcutaneous insulin infusion, Diabetologia, 33:696–703, 1990. 20. American College of Sports Medicine and American Diabetes Association, Diabetes mellitus and exercise, joint position statement, 1997. 21. Wasserman, DH and Zinman, B, Exercise with individuals with IDDM, Diabet. Care, 17:924–937, 1994. 22. Kemmer, FW, and Berger, M, Exercise and diabetes mellitus: Physical activity as part of daily life and its role in the treatment of diabetic patients Int. J. Sports Med., 4:77–88, 1983. 23. Berger, M, Berchtold, P, Cuppers, HJ, Drost, H, Kley, HK, Muller, WA, Wiegelmann, W, Zimmermann-Telschow, H, Gries, FA, Kruskemper, HL, and Zimmermann, H, Metabolic and hormonal effects of muscular exercise in juvenile type diabetics, Diabetologia, 13:355–365, 1977. 24. Levitt, NS, Hirsch, L, Rubenstein, AH, and Polonsky, KS, Quantitative evaluation of the effect of low-intensity exercise on insulin secretion in man, Metabolism, 42:829–833, 1993. 25. Coughran, C, Exercise and insulin, 2000, retrieved June 22, 2000, World Wide Web, www.faqs.org/faqs/diabetes/faq/part1/section-15.html. 26. Franz, MJ, Fuel metabolism, exercise and nutritional needs in type 1 diabetes, Can. J. Diabet. Care, 22:59–63, 1998. 27. www.mendosa.com/software.htm. 28. Rutscher, A, Salzsieder, E, and Fischer, U, KADIS: Model-aided education in type I diabetes, Comput. Meth. Progr. Biomed., 41:205–215, 1994. 29. Cavan, DA, Hejlesen, OK, Hovorka, R, Evans, JA, Metcalfe, JA, Cavan, ML, Halim, M, Andreassen, S, Carson, ER, and Sonksen, PH, Preliminary experience of the DIAS computer model in providing insulin dose advice to patients with insulin dependent diabetes, Comput. Meth. Progr. Biomed., 56:157–164, 1998. 30. Biermann, E and Mehnert, H, Diablog: a simulation program of insulin-glucose dynamics for education of diabetics, Comput. Meth. Progr. Biomed., 32:311–318, 1990.
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31. Lehmann, ED, Preliminary experience with the Internet release of AIDA — an interactive educational diabetes simulator, Comput. Meth. Progr. Biomed., 56:109–132, 1998 (www.2aida.org/aida/intro.htm). 32. Marlin, TE, Process Control, 2nd ed., McGraw-Hill, New York, 2000.
Section III The Role of Oxidative Stress in the Pathogenesis and Treatment of Diabetes and Its Complications
Introduction A byproduct of the metabolic processes in the cell is the phenomenon of oxidative stress, which is generally defined as the overproduction of reactive oxygen species in the face of diminished levels of the neutralizing substances called antioxidants. This section begins with an elegant overview of how oxidative stress that is associated with nutrient stimulation of insulin secretion paradoxically affects the regulation of insulin secretion, a situation that could potentially contribute to β-cell failure in diabetes. This is followed by a clinical illustration of how oxidative stress is associated with type 1 diabetes and its neuropathic complications. There is also a detailed review of the association between oxidative stress and type 2 diabetes, which includes the role that it may play in the pathogenesis of type 2 diabetes. The putative role of oxidative stress in type 2 diabetes is then used as a rationale to explore the potential use of antioxidant regimens as adjunct therapy for glycemic control in type 2 diabetes. Mortality in type 2 diabetes is largely attributed to the cardiovascular complication of the disease, which has a strong link with oxidative stress that also plays a significant role in other vascular complications of diabetes. Appropriately, a detailed discussion of the pathogenesis of vascular disease, as attributable to oxidative stress, is provided along with strategies for the management of these complications. Two other major complications of diabetes associated with oxidative stress, neuropathy and nephropathy, are discussed in two separate chapters. In these chapters, there is a detailed review of the pathophysiologic mechanisms linking oxidative stress and disease, which is followed by the different treatment options that are based on the mechanistic rationales. Finally, one significant diabetic complication that has not usually received as much attention as the other complications of diabetes is gastropathy. As apparent in the chapter provided in this section, diabetic gastropathy has also been linked to oxidative stress, and the authors provide a very detailed outline of this phenomenon, as well as the strategies used to manage that diabetic complication.
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CONTENTS I. II. III. IV. V. VI. VII. VIII.
Introduction................................................................................................303 Glucose Uptake and ATP/ADP Regulation...............................................304 Connection of ROS Production in β-Cells with GSIS Mechanism .........306 Manifestations of Oxidative Stress and Apoptosis ...................................308 Dual Role of the GSIS Mechanism ..........................................................309 Dual Role of β-Cell Mitochondria Uncoupling........................................311 The GSIS-ROS Hypotheses and Repair Problems ...................................311 Preservation of β-Cell Function and Islet Mass Versus Enhancement of GSIS: Mutually Exclusive Goals? .................................312 IX. Conclusion .................................................................................................314 References..............................................................................................................315
I. INTRODUCTION The development of type 2 diabetes is usually associated with a combination of insulin resistance in skeletal muscle, fat, and liver and relative impairment of insulin production in pancreatic β-cells [1, 2]. Normal β-cells can compensate for insulin resistance by increasing insulin secretion, but insufficient compensation leads to the onset of glucose intolerance. For this reason, a decreased ability to secrete insulin is one of the major features of the pathophysiology of type 2 diabetes [1–3]. However, despite tremendous advances from molecular biology and the continued identification of molecules involved in insulin production in β-cells, the molecular mechanisms that underlie the development of β-cell dysfunction still remain elusive. There is good reason to believe that insulin-secreting β-cells are subject to injury from oxidative stress during development of type 2 diabetes [4–7]. Formation of reactive oxygen species (ROS), such as superoxide anion, hydrogen peroxide, hydroxyl radicals, and the concomitant generation of nitric oxide have been implicated in β-cell dysfunction or cell death caused by autoimmune attack and actions 303
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of cytokines in type 1 diabetes mellitus [4, 8]. ROS has also been associated with the impairment of β-cell function in type 2 diabetes [4–8]. Compared to many other cell types, the β-cell may be at high risk for oxidative damage and has an increased sensitivity for apoptosis [5, 6, 9]. Investigations implicating ROS in β-cell death or damage have, for the most part, relied on the protective effect of antioxidants, scavengers, and overexpression of antioxidant enzymes in islets or transgenic mice to reduce the destructive influence of some oxyradicals [4–6, 10]. However, elevated glucose concentrations are thought to alter metabolism, create oxidative stress, and to induce apoptosis in many cell types in addition to glucose-responsive β-cells [5, 9]. Why should ROS generation in β-cells be more dangerous than in other cell types? To resolve this problem, we have analyzed the existing data on mechanisms of glucose-stimulated insulin secretion (GSIS) in β-cells, ROS production, oxidative stress, and apoptosis, and have proposed that the same pathways can dramatically influence oxidative stress, apoptosis, and insulin production [11].
II. GLUCOSE UPTAKE AND ATP/ADP REGULATION According to the most widely accepted hypothesis, glucose induces insulin release as follows [1, 5, 12–15] (Figure 17.1): glucose rapidly equilibrates across the plasma membrane and is phosphorylated by glucokinase, which determines metabolic flux through glycolysis. The Km of glucokinase for glucose is ~ 8 mM, a value that is almost two orders of magnitude higher than any other hexokinase. These characteristics of glucokinase enable β-cells to increase glucose metabolism in proportion to elevations in extracellular glucose, underlying the dependence of the β-cell insulin secretory response to glucose in the physiological range. Glucose is converted by glycolysis to pyruvate, which enters the mitochondria via a pyruvate carrier, providing tricarboxylic acid (TCA) cycle substrates. Reducing equivalents are recovered by the TCA cycle from carbohydrates and from fats (after prior β-oxidation). Synthesized reducing equivalents (NAD(P)H and reduced flavins) are transferred to the electron transport chain (ETC). The energy released by the ETC is used to pump protons out of the mitochondrial inner membrane, creating the transmembrane electrochemical gradient. This gradient is used to make ATP from ADP and Pi, driven by proton movement back through the ATP-synthase complex. These events result in increased ATP production in mitochondria and in an enhanced ratio of ATP to ADP in the cytoplasm. In the presence of glucose, the increase in intracellular ATP to ADP ratio closes the KATP channels. This, in turn, results in depolarization of the plasma membrane, influx of extracellular Ca2+, a sharp increase in intracellular Ca2+, and activation of protein kinases, which then mediate exocytosis of insulin. However, our current understanding of adenine nucleotide regulation in β-cells is incomplete [14, 15], in particular, the effect of substrates that markedly enhance insulin secretion, including glucose, on ATP concentration is small, but the ratio of total ATP to total ADP increases considerably in most studies [16–18]. In contrast to ATP, only a small fraction of total cellular ADP is free [16, 19]. Several measurements of free ADP have been performed in β-cells. Ghosh et al. [19] found in β-cell rich rat pancreatic islet cores that an increase of glucose from
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FIGURE 17.1 The various components discussed in the text are illustrated in the cartoon of a β-cell and a mitochondrion within it. Glucose and fatty-acid metabolism leads to an increase in NAD(P)H and Ca2+, and to a decrease in ADP. In turn, decreased ADP leads to increased mitochondrial membrane potential (ΔΨ) and a corresponding increase in ROS production. Increased glycolytic flux, decreased ADP concentration, and increased intracellular Ca2+ concentration could all contribute both to increased GSIS and ROS generation in the electrontransport chain. Solid lines indicate flux of substrates, and dashed lines indicate regulating effects, where (+) represents activation and (–) represents repression.
4 to 8 mmol/l led to a decrease of free ADP from ~ 44 to ~ 31 μM (pooled data from Table 5 in [19]). ATP concentration increased only insignificantly following glucose challenge in these experiments. Ronner et al. [17] found (in clonal βHC9 insulin-secreting cells) that increased glucose concentration was associated with an exponential decline of the concentration of free ADP from about 50 μM at 0 mM glucose to about 5 μM at 30 mM glucose, while the concentration of ATP remained nearly constant. Recently, Sweet et al. [18], using measurement of cytochrome c redox state and oxygen consumption in perifused isolated rat islets, have evaluated ([ATP]/[ADP])/[Pi] in response to glucose. According to their Figure 7, this ratio can increase up to tenfold following a glucose step increase from 3 mM to 20 mM [18]. These data suggest that a sharp decrease of free ADP with only a relatively small change in ATP concentrations is the characteristic feature of the response of β-cells to glucose stimulation. The functional necessity of this change in the ATP/ADP ratio can be understood from a consideration of KATP regulation [14]. The activity of KATP channels decreases when pancreatic β-cells are exposed to increasing concentrations of glucose. However, as discussed above, only small changes in ATP concentrations were found following exposure to increased glucose concentrations. This cannot by itself induce closure of KATP channels. However,
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decreased free ADP concentrations in the physiological range can close KATP channels at constant ATP concentration [12, 20]. This means that a considerable increase in glycolytic flux and a sharp decrease in free ADP levels could be the necessary conditions leading to closure of KATP channels and to insulin secretion following glucose challenge.
III. CONNECTION OF ROS PRODUCTION IN β-CELLS WITH GSIS MECHANISM Several sources of ROS production exist in cells, for example, the intracellular nonenzymatic glycosylation reaction [21] and the hexosamine pathway [5]. However, the principal source of ROS in most mammalian tissues is the mitochondrial ETC itself [22–25]. Recently, we reported that real-time estimations of superoxide production indicated that O2– generation is coupled to mitochondrial metabolism in pancreatic β-cells [26]. A similar conclusion was reached by Sakai et al. [27]. The superoxide anions are generated by single-electron reduction of molecular oxygen in complexes of the mitochondrial ETC. Particularly, ROS production depends upon the concentration of the intermediate metabolites of these complexes, since the ETC carriers in a more reduced state have the property of donating electrons to oxygen [22, 24]. The reduced state of the ETC carriers can be achieved by increased production of reducing equivalents in mitochondria or by decreased electron transfer capability on (or after) these carriers [22, 24]. β-cells have a sensitive system, starting with glucokinase, for initiating the response to physiological changes in glucose concentration. Therefore, in contrast to most other mammalian cell types, increased glucose concentration stimulates a steeply increased glycolytic flux in β-cells followed by a steep stimulation in the production of reducing equivalents [12, 28]. This means that this part of the GSIS mechanism could lead itself to an enhancement of ROS production in pancreatic βcells following glucose challenge. High glucose increases intracellular ROS production from the mitochondria in pancreatic β-cells [26, 27]. Increased fatty-acid oxidation and the addition of some intermediate metabolites could also lead to additional production of reducing equivalents. However, downstream regulation of electron-transfer capability in the ETC can also be an important mechanism affecting ROS production. Since ETC is coupled to ATP synthesis through membrane potential (ΔΨm), the electron-transport rate, and, consequently, the rate of superoxide production will also depend on ΔΨm. The increased ΔΨm decreases electron-transport capability in ETC, leading to a reduced state of the carriers and increased ROS production [22, 24]. It was shown experimentally [29, 30] and confirmed by simulation with the corresponding mathematical model [31] that the rate of superoxide production increases dramatically with increased ΔΨm above 140 mV, when the rate of electron transport is restricted by increased ΔΨm. Since ΔΨm is used to make ATP from ADP and Pi, driven by proton movement back through the ATP synthase complex, its value also depends on the ATP production rate, and, in particular, on free ADP concentration. The mitochondrial oxidative
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↑ Glucose ↑ Fatty Acids
Cytokines
↑ Cytoplasmic Ca2+
Cell Surface Receptors
↑ Mitochondrial ROS
↑ Oxidative Stress
↑ Macromolecule Damage
↑ Mitochondrial Damage ↑ NF- κB, others ↑ Dysfunction
↑ Apoptosis
Deterioration of insulin secretion
FIGURE 17.2 Proposed causative link between elevated mitochondrial ROS generation, increased cytoplasmic Ca2+, oxidative stress, β-cell dysfunction, apoptosis, and deterioration of insulin secretion (explanations are in text).
phosphorylation rate increases with increased free ADP concentration, with an apparent half-saturated concentration of about 20–45 μM [32, 33]. Therefore, a decrease in free ADP concentration leads to decreased ATP production, that in turn increases ΔΨm and, correspondingly, ROS production. For example, results of mathematical modeling of coupled mitochondria show that ΔΨm can increase from 120 to about 200 mV as ADP decreases from 40 to 15 μM (Figure 17.3a from [31]), and that this can lead to a steep increase in ROS production (Figure 17.2 from [11]). Supporting the results of mathematical modeling, Korshunov et al. [29] have found that a 15 percent decrease in ΔΨm under resting conditions caused by a respiratory inhibitor or by the oxidative phosphorylation substrates ADP and Pi, resulted in a tenfold decrease in H2O2 production by heart mitochondria [29]. In the opposite situation, there is a steep increase in ROS production with decreased ADP concentration. These data lead to the conclusion that decreased ADP concentration can cause a considerable increase in ROS production [22, 31]. This idea was recently confirmed for β-cells by the demonstration that ADP inhibited ROS generation in permeabilized MIN6 cells [34]. After the addition of glucose, there is a decrease in free ADP concentration in β-cells (see Glucose Uptake and ATP/ADP Regulation). Hence, the specific stage in the GSIS mechanism leading to a decrease in free ADP can also be directly responsible for an overproduction of ROS. This decrease in ADP concentration is a specific property of β-cell stimulus-secretion coupling, possibly shared with other
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cell types that have a fuel-sensing function. In contrast, muscle work during aerobic exercise leads to increased ADP concentrations [33]. To make matters worse, β-cells have relatively low levels of free-radical detoxifying and redox-regulating enzymes, such as superoxide dismutase, glutathione peroxidase, catalase [5, 6, 35], and thioredoxin [4]. The reasons for this are unclear. Since ROS are involved in different physiological processes as mediators in signal-transduction pathways [25], it was hypothesized that ROS are involved in some signaling pathways that take part in the insulin-secretion mechanism [26]. In any case, the limited scavenging systems suggest that enhanced ROS concentrations in β-cells may occur due to both decreased scavenging systems and ROS overproduction. In support of this hypothesis we recently reported an estimation of ROS using an optical method. We found that stimulation with 10 mM glucose (from initial 2 mM) increased nearly twofold the O2– production rate in pancreatic β-cells from Zucker lean rats, confirming the possibility of abrupt increases in O2– production with increased glucose [26]. A similar increased ROS production rate was obtained by Sakai et al. [27] at increased glucose concentrations in a pancreatic β-cell line (MIN6) and in human islets. These studies are the first to measure the production of ROS in response to glucose in the β-cell.
IV. MANIFESTATIONS OF OXIDATIVE STRESS AND APOPTOSIS Protective effects of antioxidants, scavengers, and overexpression of antioxidant enzymes in transgenic mouse islets suggest that ROS overproduction can lead to manifestations of oxidative stress and apoptosis in β-cells [4–7, 10]. Several reviews have recently considered how increased ROS production (or decreased ROS consumption) can lead to oxidative stress and apoptosis in different cell types, including β-cells [5, 6, 9, 25, 33]. We present in Figure 17.2 the most common steps for these connections. Free radicals in cells (including the β-cell) may directly damage proteins, lipids, and nucleic acids [22, 24, 25, 36]. Because ROS are produced mainly in β-cell mitochondria, it appears that mitochondria are a primary target for the destructive action of ROS, leading to mitochondria damage, including decreased mitochondrial ATP synthesis, dysregulation of intracellular calcium homeostasis, and induction of the mitochondrial permeability transition pores [22, 37]. These processes are associated with the concept of programmed death of the mitochondrion (mitoptosis) in conditions of oxidative stress [22]. This can potentially decrease the quantity of mitochondria in cells and lead to necrosis and apoptosis in cells [22, 25, 37]. Altered mitochondria function plays a prominent role in the induction of apoptosis in several cellular models [22, 25], as well as in the β-cell line Ins-1 [38]. In our experiments the mitochondria were generally short and swollen in islets with the highest ROS production from the Zucker diabetic fatty (ZDF) rat, in contrast to Zucker lean control (ZLC) rat islets [26]. In addition to their ability to directly damage cellular macromolecules, ROS may also activate intracellular signaling pathways that lead to cell dysfunction and
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apoptosis [7–9, 25, 36, 39]. Two principal apoptotic pathways exist in β-cells: the intrinsic pathway initiated by the mitochondria and the extrinsic pathway initiated by cell surface receptors. The intrinsic pathway includes the activation of NF-κB and additional stresssensitive targets [9, 36]. There is some evidence that activation of NF-κB is mostly a proapoptotic event in β-cells [39]. However, in vascular endothelial cells, normalizing mitochondrial superoxide production blocks several major pathways, leading to hyperglycemic damage, including NF-κB activation, and it was suggested that ROS production in mitochondria is a causal link between elevated glucose and the main pathways responsible for hyperglycemic damage [40]. It would appear reasonable to infer that these pathways are also activated by ROS in the β-cell [5], but this has not been directly confirmed. The extrinsic pathway includes cytokine signaling and is considered in detail in a recent review by Donath et al. [8]. However, the question, “What makes the βcell so sensitive to proinflammatory cytokines?” remains open [8]. It has been suggested that glucose-induced β-cell apoptosis involves the induction of both free oxygen radicals and the synthesis of proinflammatory cytokines, especially Interleukin-1, activating proapoptotic pathways [9]. Consequently, although the death of β-cells that underlies type 1 diabetes is probably due to the autoimmune response, the particular susceptibility of β-cells to oxidative damage from ROS produced during inflammation may be a predisposing factor [7, 23]. Supporting this notion are the observations that the streptozotocinand alloxan-induced models of diabetes involve increased ROS production to kill β-cells [41, 42], and that overexpression of antioxidative enzymes protect β-cells against these agents [42–44]. An elevation of intracellular Ca2+ through voltage-gated Ca2+ channels is an integral part of the GSIS mechanism (see GSIS and Adenine Nucleotide Regulation). However, increased intracellular Ca2+ is also believed to stimulate mitochondrial generation of ROS [30]. Voltage-gated Ca2+ channels are also likely to play an activating role in β-cell apoptosis, although the molecular mechanisms remain to be described [8]. Hence, an increase in cytoplasmic Ca2+ concentration and an activation of voltage-gated Ca2+ channels are additional stages in GSIS, which may share responsibility for an increase of oxidative stress and for a mediation of apoptosis. We can conclude that at least three stages of the GSIS mechanism (increased glycolytic flux, decreased ADP concentration, and increased intracellular Ca2+ concentration) could lead to a dramatic increase in the development of oxidative stress and apoptosis in pancreatic β-cells. We can name this connection the GSIS→ROS hypothesis [11]. This GSIS→ROS hypothesis provides a testable framework to explain how β-cells may be uniquely at high risk for oxidative damage and apoptosis.
V. DUAL ROLE OF THE GSIS MECHANISM The consequences of the GSIS→ROS hypothesis can be further evaluated in light of the existing experimental data. According to this hypothesis, the metabolic secretagogues leading to GSIS activation play a dual role: The increase in metabolic
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secretagogue concentrations causing increased insulin secretion can also lead to increased oxidative stress as a result of elevated ROS production. This dual role of the GSIS mechanism might hinder investigations since an initial increase in the insulin-secretion rate can at first mask eventual detrimental effects of oxidative stress on insulin production. However, there is an essential difference in the temporal development of these processes. Insulin secretion changes relatively quickly, and oxidative stress seems to develop more gradually and may be revealed only after several days of exposure to metabolic secretagogues [5, 45]. Therefore, progressive injury of β-cell function by the same effectors that increase GSIS quickly could be considered a characteristic feature of oxidative stress activated by the GSIS mechanism itself. For example, chronic exposure to elevated glucose concentrations may cause damage to β-cells and ultimately β-cell death (glucose toxicity). Although multiple mechanisms have been proposed, emerging evidence suggests oxidative stress contributes to β-cell glucose toxicity [5, 6, 36, 45, 46]. This reinforces the idea that glucose initially activating insulin secretion can also injure β-cell function with time. Acute exposure to elevated concentration of free fatty acids leads to enhanced insulin secretion from the pancreatic β-cells [47]. On a short-term basis (< 24 h), fatty acids can stimulate insulin secretion, in part by causing an increase in the production of reducing equivalents due to β-oxidation and additional acyl-CoA mitochondrial oxidation [12]. Indeed, it was demonstrated in a series of studies by Randle et al. [48] that fatty acids can compete with glucose for substrate oxidation, and increased oxidation of fatty acids would cause an increase in the intramitochondrial NADH/NAD+ ratio. Fatty acids may also increase Ca2+ mobilization from the endoplasmic reticulum [49]. All these events can lead to decreased ADP level, increased cytoplasmic Ca2+, and increased insulin production. Chronic exposure to elevated levels of plasma FFAs, such as that observed in obesity, has been implicated in the development of type 2 diabetes in part by contributing to β-cell dysfunction. Lipotoxicity can develop in β-cells in a similar fashion to oxidative stress at elevated glucose concentration, and chronic exposure (> 24 h) of β-cells to fatty acids leads to a reduction in GSIS [5, 45]. While the mechanism of lipotoxicity in β-cells is not well-understood, current explanations of this lipid-induced toxicity in β-cells certainly involve the effects of oxidative stress [5, 50, 51]. Indeed, if administration of fatty acids caused an increase in the intramitochondrial NADH/NAD+ ratio, then increased FFAs may also lead to increased ROS production. Hence, lipotoxicity appears to be at least partly a manifestation of supplementary ROS production induced by additional production of reducing equivalents in mitochondria pari pasu with fatty-acid metabolism. Direct data on mitochondrial O2-production rates obtained in our laboratory also confirms the possibility that β-cells are subject to oxidative stress at increased concentrations of fatty acids. Superoxide production in ZDF rat islets was significantly higher than in Zucker lean control rat islets under resting conditions (with 2mM glucose), and the overproduction of superoxide was associated with perturbed mitochondrial morphology in ZDF rat islets [26]. Abnormal mitochondrial morphology in ZDF rat islets was also observed by Higa et al. [52]. Since ZDF rat islets
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accumulate triglyceride [52], these changes can be explained by increased ROS production as a result of increased content of free fatty acids in these β-cells.
VI. DUAL ROLE OF β-CELL MITOCHONDRIA UNCOUPLING Another consequence resulting from the GSIS→ROS hypothesis relates to uncoupling of β-cell mitochondria. Any active or passive transport of cations or anions across the mitochondrial inner membrane will change ΔΨm. Multiple uncoupling agents could degrade the proton gradient across the mitochondrial inner membrane and decrease the ΔΨm level, causing a corresponding decreased ATP secretion, increased ADP concentration, and diminished ROS production rates. However, this should be accompanied by a decrease in the ATP/ADP ratio and, consequently, by decreased insulin production, since plasma membrane KATP channels will be insufficiently closed (see Glucose Uptake and ATP/ADP Regulation). This dual role of uncoupling can be illustrated by considering the principal β–cell uncoupling protein 2 (UCP2), which catalyzes a regulated proton leak across the mitochondrial inner membrane (Figure 17.1) (see Chan et al. [53] for review). Indeed, islets from UCP2-deficient mice have an increased ATP level and an enhanced glucose-stimulated insulin secretion compared with controls [54]. On the other hand, overexpression of UCP2 in isolated pancreatic islets results in decreased ATP content, reduced ΔΨ, and blunted glucose-stimulated insulin secretion [55]. However, in line with the suggested dual role of mitochondrial-membrane uncoupling, overexpression of UCP2 enhanced resistance of β-cells towards H2O2 toxicity [56]. This indicated that while uncoupling and activation of UCPs can reduce ROS production, it might disrupt GSIS in β-cells. It also seems likely that β-cells can increase UCP2 expression to decrease oxidative stress. For example, superoxide increases proton conductance in mitochondria from pancreatic β-cells, probably via activation of UCP2 [57, 58]. Increased glucose induces expression of UCP2 in isolated human islets [59]. These mechanisms of protection from oxidative stress would decrease the rate of ATP production and the corresponding ATP/ADP ratio, leading to impaired β-cell sensitivity to glucose simulation [58], a characteristic feature of type 2 diabetes.
VII. THE GSIS-ROS HYPOTHESES AND REPAIR PROBLEMS Resent research has demonstrated a direct link between the imbalance of oxidative stress, impaired glucose uptake, and antioxidants for both diabetic animal models and in human disease. This leads to the hypothesis that the imbalance between ROS production and their removal is one important factor in the etiology of diabetes [5, 11, 60]. However, ROS-induced damage is the main factor mediating their effects on β-cells (see Manifestations of Oxidative Stress and Apoptosis). Consequently, this hypothesis also suggests that ROS imbalance in β-cells is only part of the process leading to the development of dysfunction of insulin secretion. A failure in the repair
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of intracellular systems or in β-cell regeneration could also be involved in β-cell dysfunction and decreased mass, along with or due to the ROS imbalance. Although the mechanisms responsible for the decline of β-cell function in type 2 diabetes are still being debated, it has been recognized that preservation of β-cell function through decreased apoptosis can be critical for slowing or halting the progression of disease [3]. There are a range of mechanisms to repair damaged lipid, protein, and DNA [23], and oxidative stress inside of cells can arise only when the endogenous antioxidant network and repair system fails to provide a sufficient compensatory response to survival or to restore a cellular function [5, 22]. For example, one important repair factor could be accelerated mitochondrial DNA synthesis in the β-cell, because it has been shown that depleting pancreatic β-cell lines of their mitochondrial DNA by culture in the presence of ethidium bromide abolished GSIS [61]. Expression of mitochondrial DNA is controlled by the mitochondrial transcription factor A (Tfam), and it is therefore of interest that the β-cell-specific deletion of the Tfam gene caused a diabetic phenotype [62]. Recent data have shown that adult pancreatic β-cells are formed by self-duplication and stem-cell differentiation [63, 64]. This process must also include replication of mitochondria. For this reason the mechanisms of β-cell proliferation and duplications must be critical in the progression of type 1 and type 2 diabetes. It should be pointed out that increased ROS levels also could lead to irreversible decrease in the level of the transcription factor PDX-1, a critical regulator for insulingene expression, and for β-cell neogenesis [6]. PDX-1 is also involved in mitochondrial function in β-cells [65]. Insulin receptor substrate 2 (IRS2) in β-cells is also essential for cell growth, function, and survival, and mediates the effects of glucagons, such as peptide 1 (GLP-1), on β-cell expansion [66]. Regulating pathways of IRS2 in β-cells may be also sensitive to ROS damage [67]. These data suggest that increased content of ROS can damage signaling pathways leading to gene expression in β-cells and their regeneration, as well as lipids, protein, and DNA.
VIII. PRESERVATION OF β-CELL FUNCTION AND ISLET MASS VERSUS ENHANCEMENT OF GSIS: MUTUALLY EXCLUSIVE GOALS? If our hypothesis is true, then reversal of the imbalance between ROS and antioxidant capacity should improve β-cell GSIS. However, direct and indirect actions should be recognized. Any decrease in circulating glucose or lipid concentrations can lead to decreased ROS production in β-cells that can be considered an indirect effect of improving ROS imbalance. Several pharmaceutical agents that decrease glucose and lipid concentration in blood, such as metformin, thiazolidinediones, and statins, are in considerable use in treatment of type 2 diabetes. Direct actions that may have therapeutic potential include strategies to decrease mitochondrial radical production and to increase antioxidant capacity. This could be achieved, for example, by the use of antioxidants or by decreasing the mitochondrial membrane potential [22, 23]. In studies with animal models of diabetes, antioxidants
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can preserve β-cell function and mass and can decrease the manifestations of oxidative stress [5, 7]. However, effective therapeutic strategies to prevent or delay the development of ROS damage remain limited. Clinical trials are needed that employ high concentrations of conventional antioxidants as vitamin C, lipoic acid, vitamin E, and their combinations, as well as much stronger antioxidants, such as N-acetylcysteine. Further work is also required for the development of special antioxidants targeted to mitochondria [6, 23]. Since activation of the initial stages of GSIS or increased ΔΨ leads immediately to increased insulin secretion, it is not surprising that these stages are targets for therapeutic intervention. For example, glucokinase plays a key role in initial GSIS stages by catalyzing the phosphorylation of glucose in β-cells. A new class of antidiabetic agents, mixed-type glucokinase activators that increased both the affinity for glucose and the Vmax, was shown to stimulate GSIS [13, 68]. A reduction in UCP2 activity was also suggested as a mechanism for significant improvement in insulin secretion [69]. However, such therapeutic strategies should be used with caution, since, according to our proposal, an increase in insulin secretion achieved by these approaches could also considerably increase ROS production, leading to oxidative stress. At first glance, prevention of apoptosis could have a beneficial effect on insulin secretion. Antiinflammatory therapeutic approaches designed to block signaling pathways for β-cell apoptosis were proposed to treat both type 1 and 2 diabetes [8]. However, apoptosis is essential for removal of damaged cells [22]. Increased sensitivity of β-cells to oxidative stress can lead to increased mitochondrial damage and corresponding loss of GSIS. Prevention of apoptosis allows damaged cells to survive. For example, β-cells overexpressing BcL-XL, which inhibits apoptosis via multiple effects in mitochondria, have impaired mitochondrial signals for insulin secretion [70]. For this reason, a therapeutic strategy that prevents apoptosis by blocking death pathways should also be used with caution, since, according to our proposal, an increase in β-cell mass achieved by these approaches might not be accompanied by increased glucose sensitivity and insulin secretion, if damaged cells are preserved. Activation of intracellular repair and β-cell proliferation systems can also be considered among mechanisms rescuing oxidative damage of insulin secretion (see The GSIS-ROS Hypothesis and Repair Problems). Such agents are proposed for treatment of both type 1 and type 2 diabetes [71]. For example, Glucagon-like peptide1 (GLP-1) agonists exert multiple effects on pancreatic β-cells [72]. Mounting evidence suggests that GLP-1 signaling stimulates β-cell proliferation acting through an activation of the homeodomain protein PDX-1 and IRS2 pathway [66, 71]. Recently, it was also found that thiazolidinediones (agonists of nuclear peroxisome proliferator-activated receptor-γ [PPAR-γ] used to treat insulin resistance) could take part in activation of β-cell proliferation. Long-term administration of troglitazone or rosiglitazone prevents the loss of β-cell mass in ZDF rats by maintaining β-cell proliferation and preventing increased net β-cell death [52, 73, 74]. Long-term treatment with pioglitazone prevents loss of β-cell mass and preserves pancreatic islet structure and insulin-secretory function in murine models of type 2 diabetes [75, 76].
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The concept of β-cell rest as originally developed, perhaps more for amelioration of type 1 than type 2 diabetes, argued that decreased demand on β-cell function can lead to improvements in insulin secretion and β-cell viability [5, 77, 78]. Such agents as diazoxide and calcium channel blockers, which reversibly inhibit insulin secretion, have improved β-cell function both in rodent models of diabetes [79, 80] and in humans [81]. This beneficial effect could be explained by the decreased ROS production during β-cell rest associated with decreased GSIS activity. Inhibition of the early stages of GSIS or decreased ΔΨ should also lead to decreased ROS production. Any inhibitor of glycolytic flux, the TCA cycle, fattyacid oxidation, or mitochondrial-membrane uncoupling could result in decreased ROS production. For example, this could be accomplished by specific inhibitors of β-cell glucokinase or by an increase in UCP2 expression. However, a decreased insulin-secretion rate is the necessary price to pay for these approaches to increasing β-cell function and survival. For this reason, such methods can predominantly be used when the GSIS mechanism is not the main source of insulin production. This, of course, can occur following treatment with plasma membrane KATP channel blockers, such as sulfonylureas and meglitinides, which can compensate for the inadequate closure of these KATP channels at reduced ATP/ADP levels, or simply by insulin therapy. However, plasma membrane KATP channel blockade is accompanied by increased Ca2+ levels in β-cells that can itself increase oxidative stress (see above, Dependence of ROS Production in β -Cells on the GSIS Mechanism). For this reason, the simplest, and potentially most beneficial, method to decrease oxidative stress in β-cells may be that of early use of the above-mentioned GSIS inhibitors with insulin as necessary, perhaps in combination with GLP-1 agonists. This approach would decrease both glucose levels and corresponding ROS production. Although this approach has not always been used to advantage [77], recent studies [78, 82, 83] have suggested that early insulin treatment in type 2 diabetes, indeed, preserves endogenous insulin secretion. Additional intervention with GSIS inhibitors, perhaps in combination with GLP-1 agonists, could improve the β-cell rest approach to treatment.
IX. CONCLUSION We have compared metabolic pathways of GSIS and ROS production, and suggest that secretagogues causing increased insulin secretion by the activation of initial steps of the GSIS mechanism can also lead to increased ROS production. This should lead to activation of oxidative stress concomitantly with stimulation of the GSIS mechanism. By this reasoning, the main function of a β-cell, regulated insulin secretion, can be connected with the seeds of its own destruction. This paradoxical feature of pancreatic β-cells suggests some specific therapeutic strategies such as a reexamination of the β-cell rest concept in type 2 diabetes and using specific agents promoting β-cell repair and regeneration.
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43. Kubisch, HM, et al., Targeted overexpression of Cu/Zn superoxide dismutase protects pancreatic beta-cells against oxidative stress, Diabetes, 46, 1563, 1997. 44. Xu, B, Moritz, JT, and Epstein, PN, Overexpression of catalase provides partial protection to transgenic mouse beta cells, Free Radic. Biol. Med., 27, 830, 1999. 45. Piro, S, et al., Chronic exposure to free fatty acids or high glucose induces apoptosis in rat pancreatic islets: possible role of oxidative stress, Metabolism, 51, 1340, 2002. 46. Wu, L, et al., Oxidative stress is a mediator of glucose toxicity in insulin-secreting pancreatic islet cell lines, J. Biol. Chem., 279, 12126, 2004. 47. Seyffert, WA, Jr. and Madison, LL, Physiologic effects of metabolic fuels on carbohydrate metabolism. I. Acute effect of elevation of plasma free fatty acids on hepatic glucose output, peripheral glucose utilization, serum insulin, and plasma glucagon levels, Diabetes, 16, 765, 1967. 48. Randle, PJ, et al., The glucose fatty acid cycle: its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus, Lancet, I, 785, 1963. 49. Rutter, GA, Insulin secretion: fatty acid signalling via serpentine receptors, Curr. Biol., 13, R403, 2003. 50. Carlsson, C, Borg, LA, and Welsh, N, Sodium palmitate induces partial mitochondrial uncoupling and reactive oxygen species in rat pancreatic islets in vitro, Endocrinology, 140, 3422, 1999. 51. Wang, X, et al., Gene and protein kinase expression profiling of reactive oxygen species-associated lipotoxicity in the pancreatic beta-cell line MIN6, Diabetes, 53, 129, 2004. 52. Higa, M, et al., Troglitazone prevents mitochondrial alterations, beta cell destruction, and diabetes in obese prediabetic rats, Proc. Natl. Acad. Sci. U.S.A., 96, 11513, 1999. 53. Chan, CB, et al., Uncoupling protein 2 and islet function, Diabetes, 53, S136, 2004. 54. Zhang, CY, et al., Uncoupling protein-2 negatively regulates insulin secretion and is a major link between obesity, beta cell dysfunction, and type 2 diabetes, Cell, 105, 745, 2001. 55. Chan, CB, et al., Increased uncoupling protein-2 levels in beta-cells are associated with impaired glucose-stimulated insulin secretion: mechanism of action, Diabetes, 50, 1302, 2001. 56. Li, LX, et al., Uncoupling protein-2 participates in cellular defense against oxidative stress in clonal beta-cells, Biochem. Biophys. Res. Commun., 282, 273, 2001. 57. Echtay, KS, et al., Superoxide activates mitochondrial uncoupling proteins, Nature, 415, 96, 2002. 58. Krauss, S, et al., Superoxide-mediated activation of uncoupling protein 2 causes pancreatic beta cell dysfunction, J. Clin. Invest., 112, 1831, 2003. 59. Brown, JE, et al., Glucose induces and leptin decreases expression of uncoupling protein-2 mRNA in human islets, F.E.B.S. Lett., 513, 189, 2002. 60. Rosen, P, et al., The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCOMCBN, the American Diabetes Association and the German Diabetes Society, Diab. Metab. Res. Rev., 17, 189, 2001. 61. Maassen, JA, et al., Mitochondrial diabetes: molecular mechanisms and clinical presentation, Diabetes, 53, S103, 2004. 62. Silva, JP, et al., Impaired insulin secretion and beta-cell loss in tissue-specific knockout mice with mitochondrial diabetes, Nat. Genet., 26, 336, 2000. 63. Dor, Y, et al., Adult pancreatic beta-cells are formed by self-duplication rather than stem-cell differentiation, Nature, 429(6987), 41, 2004.
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64. Holland, AM, Gonez, LJ, and Harrison, LC, Progenitor cells in the adult pancreas, Diabetes. Metab. Res. Rev., 20, 13, 2004. 65. Gauthier, BR, et al., Oligonucleotide microarray analysis reveals PDX1 as an essential regulator of mitochondrial metabolism in rat islets, J. Biol. Chem., 2004 (E-pub ahead of print). 66. Hennige, AM, et al., Upregulation of insulin receptor substrate-2 in pancreatic beta cells prevents diabetes, J. Clin. Invest., 112, 1521, 2003. 67. Maeda, H, et al., Epidermal growth factor and insulin inhibit cell death in pancreatic beta cells by activation of PI3-kinase/AKT signaling pathway under oxidative stress, Transpl. Proc., 36, 1163, 2004. 68. Grimsby, J, et al., Allosteric activators of glucokinase: potential role in diabetes therapy, Science, 301, 370–373, 2003. 69. Polonsky, KS and Semenkovich, CF, The pancreatic beta cell heats up: UCP2 and insulin secretion in diabetes, Cell, 105, 705, 2001. 70. Zhou, YP, et al., Overexpression of Bcl-x(L) in beta-cells prevents cell death but impairs mitochondrial signal for insulin secretion, Am. J. Physiol. Endocr. Metab., 278, E340, 2000. 71. List, JF and Habener, JF, Glucagon-like peptide 1 agonists and the development and growth of pancreatic beta-cells, Am. J. Physiol. Endocr. Metab., 286, E875, 2004. 72. Holz, GG and Chepurny, OG, Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus, Curr. Med. Chem., 10, 2471, 2003. 73. Sreenan, S, et al., Prevention of hyperglycemia in the Zucker diabetic fatty rat by treatment with metformin or troglitazone, Am. J. Physiol., 271, E742, 1996. 74. Finegood, DT and Topp, BG, Beta-cell deterioration — prospects for reversal or prevention, Diabet. Obes. Metab., 1, S20, 2001. 75. Diani, AR, et al., Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes, Am. J. Physiol. Endocrinol. Metab., 286, E116, 2004. 76. Ishida, H, et al., Pioglitazone improves insulin secretory capacity and prevents the loss of beta-cell mass in obese diabetic db/db mice: Possible protection of beta cells from oxidative stress, Metabolism, 53, 488, 2004. 77. Palmer, JP, Beta cell rest and recovery — does it bring patients with latent autoimmune diabetes in adults to euglycemia?, Ann. N.Y. Acad. Sci, 958, 89, 2002. 78. Alvarsson, M, et al., Beneficial effects of insulin versus sulphonylurea on insulin secretion and metabolic control in recently diagnosed type 2 diabetic patients, Diabet. Care, 26, 2231, 2003. 79. Alemzadeh, R, et al., Modification of insulin resistance by diazoxide in obese Zucker rats, Endocrinology, 133, 705, 1993. 80. Aizawa, T, et al., Prophylaxis of genetically determined diabetes by diazoxide: a study in a rat model of naturally occurring obese diabetes, J. Pharmacol. Exp. Ther., 275, 194, 1995. 81. Alemzadeh, R, et al., Beneficial effect of diazoxide in obese hyperinsulinemic adults, J. Clin. Endocrinol. Metab., 83, 1911, 1998. 82. Westphal, SA and Palumbo, PJ, Insulin and oral hypoglycemic agents should not be used in combination in the treatment of type 2 diabetes, Arch. Intern. Med., 163, 1783, 2003. 83. Ryan, EA, Imes, S, and Wallace, C, Short-term intensive insulin therapy in newly diagnosed type 2 diabetes, Diabet. Care, 27, 1028, 2004.
18
Oxidative Stress in Type 1 Diabetes: A Clinical Perspective Robert D. Hoeldtke, M.D., Ph.D.
CONTENTS I. Introduction................................................................................................319 II. Oxidative Stress in Early Type 1 Diabetes ...............................................320 III. Research Design and Methods ..................................................................321 A. Patients ..............................................................................................321 B. Peripheral-Nerve Testing...................................................................322 C. Biochemical Measures of Oxidative Stress ......................................322 D. Statistical Analysis ............................................................................322 E. Early Changes in Peripheral-Nerve Function in Type 1 Diabetes.................................................................................322 F. Oxidative Stress in Early Diabetes ...................................................324 G. Oxidative Stress and Peripheral-Nerve Function in Early Diabetes ...................................................................................326 H. Effects of Diabetes on Nitric Oxide .................................................328 I. Hemodynamic Consequences of Nitrosative Stress .........................330 J. Uric Acid and Autonomic Function in Type 1 Diabetes..................331 K. Oxidative Stress Versus Nitrosative Stress .......................................332 IV. Oxidative Stress and β-Cell Function .......................................................333 V. Oxidative Stress in Chronic Diabetes .......................................................335 VI. Antioxidant Defenses in Chronic Diabetes...............................................336 VII. Antioxidant Trials in Diabetes ..................................................................337 VIII. Summary ....................................................................................................337 References..............................................................................................................338
I. INTRODUCTION The excessive production of reactive-oxygen species has been demonstrated in experimental diabetes and been linked to both peripheral-nerve dysfunction (64, 76) and microvascular disease (28). It has been postulated that this is the mechanism
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for many diabetic complications (31). This theory has attracted a great deal of attention recently, because several adverse consequences of chronic hyperglycemia — the formation of advanced glycation end products (74), activation of the aldose reductase pathway (37), endothelial dysfunction (94), peroxynitrite formation (28), lipid peroxidation (64), activation of vascular NADPH oxidases (37), mitochondrial dysfunction (74), and programmed cell death (85) — have been linked to oxidative stress in animal models. Possible interactions between these biochemical mechanisms have been reviewed in depth elsewhere (31, 74). The present review pertains mainly to oxidative stress in human diabetes and will focus on peripheral nerve and beta-cell dysfunction. There are a number of indications that oxidative stress takes place in human diabetes. Clinical studies have documented increased 8-hydroxydeoxyguanosine, an index of oxidative damage to DNA in diabetic patients (33), increased lipid peroxidation (34, 55), and decreased antioxidant defenses (69). Although this and other evidence we will review supports the theory, it would be premature to conclude that oxidative stress has the same significance in human diabetes as it does experimentally. There are a number of problems with extrapolating the animal data to man (11). First of all, animals with experimental diabetes are typically severely hyperglycemic, catabolic, and often inadequately treated with insulin. Thus, multiple metabolic changes, in addition to hyperglycemia and oxidative stress, may be taking place in animals, but not taking place clinically. In animal models, nerve damage develops in a few months, whereas in man, neuropathy typically develops only after years or decades of chronic hyperglycemia. Finally, and most importantly, there is currently little physiological evidence that oxidative stress in human diabetes has deleterious consequences. The present review will focus on this question, and we will begin by describing our own efforts to address this issue in recent onset type 1 diabetes. We will then compare our data to those gathered in patients with longstanding diabetes. Finally, we will review some clinical trials of antioxidant therapy for diabetic neuropathy.
II. OXIDATIVE STRESS IN EARLY TYPE 1 DIABETES Multiple cardiovascular risk factors are prevalent in long-standing diabetes, including hypertension, hyperlipidemia, and insulin resistance. Oxidative stress has been linked to each of these conditions even in nondiabetic patients (71). Thus, in chronic diabetes, these confounding factors make it difficult to assess the significance of oxidative stress and document its relationship with hyperglycemia. In order to minimize the impact of these covariables, we have recently studied oxidative stress in patients with recently diagnosed (less than two years) type 1 diabetes. These patients had variable degrees of hyperglycemia, but were otherwise healthy and still minimally affected by the other above-mentioned cardiovascular risk factors that have been linked to oxidative stress in patients with long-standing disease. Our patient population, therefore, provided a unique opportunity to focus on the relationship between hyperglycemia, oxidative stress, and peripheral-nerve function. Our study focused on interactions between oxidative stress and nitric-oxide metabolism. This is of interest, since hyperglycemia and oxidative stress activate nuclear
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factor kappa beta (NFκβ), which mediates the gene expression of inducible nitricoxide synthase (iNOS), the major source of nitric-oxide production in the setting of diabetes (16). Moreover, reactive-oxygen species, particularly the superoxide anion, react with nitric oxide to form peroxynitrite, a cytotoxic compound (12) that damages the endothelium and perineurium in animal models (28). NO is unstable and cannot be directly measured, but its abundance can be estimated from its stable breakdown products, nitrite and nitrate (collectively NOx) (89). Peroxynitrite is also unstable and difficult to measure directly, but its rate of formation can be estimated from the nitrotyrosine content of protein (88) (although we have had technical difficulties with this, as will be described subsequently). In addition, we measured 8-isoprostaglandin F2 alpha, (8-iso-PGF2α), an isoprostane reflective of lipid peroxidation and the activity of iNOS (68, 73). Finally, we measured uric acid, an endogenous antioxidant and scavenger of peroxynitrite (84).
III. RESEARCH DESIGN AND METHODS A. PATIENTS Thirty-seven patients (10 males, 27 females) with type 1 diabetes were enrolled in a longitudinal study of peripheral nerve function (Table 18.1) 2–22 months after diagnosis. Patients with symptoms of neuropathy, other systemic illnesses, or excessive alcohol consumption (an average of more than two drinks per day) were excluded. All patients were taught to monitor their glucose levels at home and to adjust their insulin doses as necessary to maintain optimal glycemic control. HgbA1 was measured one to four times a year for three years. Twenty of the 37 patients maintained glycemic control within American Diabetes Association guidelines (HbA1c < 1 percent above the upper limit of normal for the nondiabetic population). Thirty-six patients underwent three annual evaluations; one patient withdrew after the second year. The diabetic patients were admitted to beds designated for research at West Virginia University Hospital to control their dietary intake, activity, and glucose before and during the annual autonomic function testing. Glucose was
TABLE 18.1 Clinical Characteristics of the Patients Diabetic Patients n(M/F) Age (years) Disease duration at initial evaluation (months)
37 (10/27) 20.3 (10–40)a 10.4 (2–22)
Note: Data are means (ranges) unless noted otherwise. a b
Age at diagnosis. Age at testing.
Healthy Control Subjects 41 (14/27) 21.0 (10–42)b
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monitored before each meal and snack and at 3 a.m., and insulin adjustments were made as needed. The daily insulin requirements were recorded. All patients were administered a standard weight-maintaining diet containing 130mEq sodium daily for three days before the collection of blood and urine; the diet did not include foods with high nitrite content (celery, lettuce, or spinach). Blood pressure was measured electronically with an Accutorr III (Datscope, Paramus, New Jersey) in the morning after the patients had been resting in the supine posture for 10 minutes prior to the peripheral-nerve testing. Autonomic function tests were also performed in 41 age- and gender-matched healthy control subjects to provide a basis of comparison with the diabetic patients. The control subjects were also admitted to the hospital, administered the same diet, and subjected to the same restrictions.
B. PERIPHERAL-NERVE TESTING Large fiber somatosensory testing was performed with a TD-20 TECCA electromograph (46, 49). Small fiber somatosensory function was assessed by quantitative sensory testing, using a microprocessor-controlled forced-choice technique (54). Cardiovascular autonomic reflexes (36), power-spectral analysis of heart rate variability (3), and sudomotor function (63) were tested, as previously described (46, 49). We also measured the renin/prorenin ratio, an index of the sympathetic innervation of the kidneys (48), and vanillylmandelic acid, an index of norepinephrine production (51).
C. BIOCHEMICAL MEASURES
OF
OXIDATIVE STRESS
Serum NOx was converted to nitrite by nitrate reductase, which was quantitated by the Gries reaction (89). 3- nitrotyrosine (NTY) and tyrosine (TY) were separated by High Pressusre Liquid Chromatography (HPLC) and measured electrochemically (88). 8Isoprostaglandin F2 alpha (8-iso-PGF2α) was measured by an Enzyme-Linked Immunosorbent Assay (ELISA) method (34), and uric acid was oxidized in the presence of uricase to form hydrogen peroxide, which was measured photometrically (56).
D. STATISTICAL ANALYSIS Analysis of Variance (ANOVA) was used to test differences between diabetic patients and control subjects and differences between years in the longitudinal study. Patients were also stratified each year as to whether their glycemic control was good or poor by determining whether their average HbA1c was below or above, respectively, the median of the average HbA1c determinations for all patients at that evaluation. Association between biochemical parameters and peripheral-nerve function was assessed using regression analysis (87).
E. EARLY CHANGES DIABETES
IN
PERIPHERAL-NERVE FUNCTION
IN
TYPE 1
None of the patients developed signs or symptoms of neuropathy during the course of the study. Only one patient had definitely abnormal results (less than two standard
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deviations below the mean) on multiple peripheral-nerve tests. Several measures of sympathetic function, however, including the renin/prorenin ratios, vanillymandelic acid, and the post Valsalva R-R interval ratios were significantly decreased in the poorly controlled diabetic patients. Moreover, the poorly controlled patients had relatively increased sudomotor responses above the waist and relatively decreased sudomotor responses below the waist, a pattern typical of sympathetic nerve injury (Figure 18.1) (47). These findings, taken together, indicate that the sympathetic nervous system is especially vulnerable to the adverse effects of chronic hyperglycemia in early diabetes.
FIGURE 18.1 Effect of glycemic control on sympathetic function in early diabetes. Mean results ± SE are presented for patients whose HgbA1 values were below (open bars) or above (closed bar) the median for the group, respectively, versus the control subjects (hatched bars). *Different from controls, p<.05; **p<.01; †Different from patients with low HgbA1 p < .01; †† p < .01; ‡ Diabetic patients with high versus low HgbA1 across all years were different, p < .01.
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F. OXIDATIVE STRESS
IN
EARLY DIABETES
NOx concentrations were higher in the diabetic patients at the first (52.4 + 5.1 μmol/l), second (50.0 + 5.1 μmol/l), and third (49.0 + 5.2μ mol/l) evaluations than in the control subjects (34.0 + 4.9μ mol/l) (P < 0.025). NOx was elevated in the diabetic patients with high HbA1 compared with control subjects (P < 0.01 at each evaluation), but nearly normal in the well-controlled diabetic patients (Figure 18.2). NOx was higher in the female diabetic patients than in the female control subjects (P < 0.01) or the male diabetic patients (P < 0.025) (Table 18.2). NOx was no different in the male diabetic versus control subjects. 8-Iso-PGF2α was not increased in the diabetic patients compared with control subjects. Nevertheless, 8-iso-PGF2α was higher in the poorly controlled versus the well-controlled diabetic patients (Figure 18.2). There was a strong correlation between 8-iso-PGF2α and NOx in the diabetic patients at the first (P < 0.05), second (P < 0.001), and third (P < 0.001) evaluations. Gender-specific Z scores for the NOx and 8-iso-PGF2α (see below) were similarly correlated. The diabetes-related genderdifference described for NOx was also seen for 8-iso-PGF2α (Table 18.2). Serum uric acid was suppressed in the diabetic patients, and the differences from the control subjects were highly significant at each time point (P < 0.001) (Table 18.3). Serum uric acid was decreased in males and females and in wellcontrolled, as well as poorly controlled, patients (Figure 18.2). Nevertheless, there was a negative association between HbA1 and serum uric acid that approached significance at the second evaluation (P = 0.065) and was significant at the third evaluation (P < 0.025). The fractional excretion of uric acid was increased in the diabetic patients at all evaluations, and total excretion was increased at the time of the third evaluation.
FIGURE 18.2 Effects of glycemic control on oxidative stress and serum uric acid (open bars, well-controlled patients; closed bars, poorly controlled patients). *p < 0.05 versus control subjects; **p < 0.01, † < 0.05 versus patients in good control; ‡ < 0.01, for patients in good control across all years versus patients in poor control.
93.2 ± 13
d
c
b
a
46.5 ± 14
88.7 ± 13
57.7 ± 8.2c
Males different from females < .025. Diabetic males different from diabetic females, p < .025. Diabetic females different from control females p < .01. Diabetic males different from diabetic females across all years, p < .05.
Note: Data represents mean ± SE.
91.1 ± 19
α 8-iso-PGF2α (pmol/L)
36.6 ± 5.3c
29.7 ± 2.8a
42.1 ± 4.7
NOx(μmol/L)
F
M
F
First Evaluation M
Control Subjects
TABLE 18.2 α Effect of Gender on NOx and 8-iso-PGF2α
59.0 ± 10
F
105 ± 18
54.2 ± 6.7c
Second
38.6 ± 5.2b
M
Diabetic Patients
75.4 ± 14
F
90 ± 9.6d
53.3 ± 7.2c
Third
36.3 ± 5.5b
M
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We have previously reported that protein-bound nitrotyrosine was increased in early type 1 diabetes and showed a negative correlation with motor-nerve conduction velocity. We analyzed nitrotyrosine and tyrosine by HPLC followed by electrochemical detection and expressed our results as the ratio of nitrotyrosine to tyrosine, which we found to be .34 ± .12 × 10–3 in the control subjects and .778 + .04 in diabetic patients. Since our data was published, others have analyzed protein-bound nitrotyrosine/tyrosine by mass spectrometry and observed ratios much lower than those we reported. Frost et al. performed alkaline hydrolysis of the plasma protein and reported a nitrotyrosine/tyrosine ratio of .044 × 10–3. Shishehbor et al. performed acid hydrolysis of serum protein and reported a nitrotyrosine-to-tyrosine ratio in nondiabetic patients of 5.2 × 10–6, much lower (100-fold) than we observed. After these reports became available, we have reassessed our HPLC method and performed a more in-depth analysis of the electrical properties of the peaks we have previously identified as nitrotyrosine using a multichannel CoulArray liquid chromatograph (ESA, Chelmsford Massachusetts). We observed that the electrical properties of the compound we identified as nitrotyrosine on the basis of HPLC retention time differed from the authentic compound in many samples. We concluded that interfering substances were obscuring the true nitrotyrosine peaks. We have used a second HPLC column and eliminated the interferences from some of our samples, and this decreased the estimated ratio of nitrotyrosine/tyrosine by approximately a factor of 100. On the basis of these considerations, we have concluded that our previously published nitrotyrosine data (49) are invalid, and are being formally retracted in this and other publications. Increased nitrotyrosine has been documented in other laboratories in clinical diabetes using other methods (23a, 86).
G. OXIDATIVE STRESS AND PERIPHERAL-NERVE FUNCTION IN EARLY DIABETES NOx and 8-iso-PGF2α both showed a negative correlation with sudomotor function. To assess the effects of NOx we categorized patients each year as to whether their NOx was above or below the median for the group at that time point. We observed that patients with high NOx had decreased total sweating, had decreased sweating below the waist, and had an increase in the ratio of sweating above the waist to below the waist, a typical profile in patients with sympathetic nerve injury (47). The diabetes-related gender differences in NOx cannot explain the decreased sudomotor function in the patients with high NOx versus low NOx. We observed no gender differences in sudomotor function in patients with diabetes (even though nondiabetic males sweat more than nondiabetic females). Gender specific Z scores for NOx correlated with sudomotor function (p < .025 at the second and third evaluations) (Figure 18.3). There were similar but weaker associations between 8-iso-PGF2α Z scores and sweating (Figure 18.3). Neither NOx nor 8-iso-PGF2α correlated with somatosensory or cardiovascular autonomic function. Performance on some of the cardiovascular and other autonomic-function tests, however, correlated with the suppression of uric acid. To assess this, we categorized each diabetic patient according to whether their uric acid was above or below the gender-specific median uric acid at that evaluation. We observed
Foot Sweat
4
0
2
4
6
8
10
12
14
0
0.5
1
1.5
2
2.5
3
–2 0 2 4 6 8 10 –1.5 –1–0.5 0 0.5 1 1.5 2 2.5 NOx Index 8-iso-PGF2α Index Third Evaluation
0
2
4
6
8
10
12
0
0.5
1
1.5
2
2.5
3
3.5
–1 0 1 2 3 4 5 6 7 8 9 –1.5 –1–0.5 0 0.5 1 1.5 2 2.5 Mean NOx Index Mean 8-iso-PGF2α Index Mean of ThreeEvaluations
FIGURE 18.3 Associations between the NOx index and the 8-iso-PGF2α index plotted against sweating. The sudomotor data are not corrected for sex because there were no sex-related differences in sweating in the diabetic patients (even though there were sex differences in control subjects). The averages of the NOx indexes and the 8-iso-PGF2α indexes were plotted against the averages of the sudomotor responses from the three evaluations. The association between the 8iso-PGF2α index and total sweat at the third evaluation approached statistical significance (P = 0.06). The association between mean 8-iso-PGF2α and mean foot sweat for all evaluations approached significance (P = 0.065).
Total Sweat
Mean Foot Sweat Mean Total Sweat
3.5
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that the diabetic patients with suppressed uric acid had decreased active renin to inactive renin (prorenin) ratios (p < .01) and decreased vanillylmandelic-acid excretion (p < .025) (Figure 18.4). The ratio of sweating above the waist to sweating below the waist, which increases with sympathetic nerve injury (47, 49) was accordingly elevated in the diabetic patients with suppressed uric acid (p < .025). Highfrequency power spectral analysis, a test of cardiac parasympathetic activity, was decreased in the patients with suppressed versus normal uric acid (p < .0025) (Figure 18.4). A similar pattern was observed for the beat-to-beat variation with deep breathing (p < .025). The heart-rate response to the Valsalva maneuver was the only test of autonomic function that did not correlate with the uric-acid status of the patient. In summary, NOx and 8-iso-PGF2α showed negative correlations with sudomotor function in early diabetes. The suppression of uric acid correlated negatively with multiple tests of autonomic function. None of these biochemical measures correlated with somatosensory function.
H. EFFECTS
OF
DIABETES
ON
NITRIC OXIDE
Abundant experimental data indicate that NO has physiologically beneficial effects on vascular tone, gastrointestinal motility, and erectile function and that these desirable actions may be compromised by diabetes, which has been believed to cause a deficiency in NO (26, 82). This appears contradictory to several recent animal (8) and clinical studies (27, 75), including our own (49), indicating that there is NO overproduction. Most of the evidence for NO deficiency in diabetes has derived from studies of the endothelium where NO synthesis is regulated by eNOS, which may respond differently to chronic hyperglycemia than does NO produced elsewhere. NO production in macrophages, monocytes, epithelial cells, vascular smooth muscle, hepatocytes, and many other tissues of the body are synthesized by iNOS (35). The gene expression of iNOS is mediated by NFκβ (43), which, in turn, is activated by hyperglycemia and oxidative stress (16). Neuronal NOS is similarly activated by hyperglycemia (72). Pitre et al. have reported immunochemical evidence of increased perineural iNOS in the diabetic rat (79). iNOS is a quantitatively more important source of nitric-oxide production in the whole patient than is eNOS, and this may explain the discrepancy between the physiological studies of endothelial function (which indicate NO is deficient) and the biochemical studies of the whole patient (which indicate NO is excessive). It is difficult to biochemically assess NO bioavailability in the setting of diabetes, because chronic hyperglycemia promotes overproduction of the superoxide anion, which inactivates NO by converting it to peroxynitrite (Figure 18.5). Animal models have been developed in which there is simultaneous evidence of both peroxynitrite excess (nitrotyrosine staining of the endothelium) and NO deficiency (failure of acetylcholine-induced nitric-oxide release) (28). The same perturbations probably take place clinically. Studies of endothelial function (94) and skin blood flow (97) have indicated that NO release is decreased in diabetes, and the nitrotyrosine content of plasma proteins is increased (86). Stimulation of iNOS and nitric-oxide overproduction also enhances lipid peroxidation. The formation of lipid peroxides in nerve membranes has adverse effects on fluidity, electrical conductivity, and function. The synthesis of 8-iso-PGF2α is
Oxidative Stress in Type 1 Diabetes: A Clinical Perspective
1 0.8 0.6 0.4 0.2 0
14 12 10 8 6 4 2 0
Valsalva Ratio
Sweating
Suppressed Uric Acid
0.6 0.5 0.4 0.3 0.2 0.1 0
Beat to Beat Variation High Frequency Vanillylmandelic with Deep Breathing Acid Excretion (mg/g Power Spectral (Maximum–Minimum) Analysis (.15–.4 Hz) creatinine)
Above Waist Below Waist
Active Renin/ Inactive
Normal Uric Acid
329
2.5 2 1.5 1 0.5 0
4 3 2 1 0
28 21 14 7 0
Controls
First Evaluation Second Evaluation Third Evaluation Diabetic Patients
FIGURE 18.4 Uric acid and autonomic function. Mean results ± SE are illustrated for patients categorized according to whether their uric acid was below the sex-specific median uric acid level at the evaluation. Open bars, normal uric acid; closed bars, suppressed uric acid. *p < 0.05, **p < 0.01 versus control subjects; † p < 0.025, diabetic patients with suppressed uric acid were different across all years from those with normal uric acid and different from control subjects; †† p < 0.025; ††† p < 0.0025, diabetic patients with suppressed versus normal uric acid were different across all years; ‡ p < 0.025, ‡ p < 0.01 versus patients with normal uric acid.
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FIGURE 18.5 Relationship between nitrosative stress and neuropathy. [.O2]- superoxide anion; [.NO] nitric oxide; [OONO]-, peroxynitrite.
a measure of oxidative stress and lipid peroxidation and is linked to iNOS activity. iNOS-deficient mice, for example, have decreased nitric-oxide production and decreased 8-iso-PGF2α (68). The strong correlation we observed between NOx and 8-iso-PGF2α (p < .001 at the time of the second and third evaluations) is consistent with these experimental data. The similar diabetes-related gender differences for NOx and 8-iso-PGF2α (Table 18.2), which we and others (27) have observed, further supports this concept. The negative associations between NOx and sudomotor function may signify that increased NO stimulates lipid peroxidation, which, in turn, has adverse effects on sudomotor nerves. The similarity between the negative associations between NOx and sudomotor function and the 8-iso-PGF2α-related negative associations with sweating is consistent with this (Figure 18.3).
I.
HEMODYNAMIC CONSEQUENCES
OF
NITROSATIVE STRESS
Patients with high NOx had lower blood pressures than those with low NOx at the first (p < .01) and second (p < .05) evaluations (Figure 18.6). The blood pressure correlated negatively with NOx at the second evaluation (p < .005) and third evaluation (p < .05). When the data for the second and third evaluations were combined, the correlation was –.41 (p < .01). Correcting for the gender effects of NOx did not affect the negative correlations with blood pressure. Why should NOx show a negative correlation with blood pressure? NO is a locally active vasodilator, which has been thought to bind to oxyhemoglobin and albumin and, therefore, be inactivated almost immediately upon entry into the circulation. This view has been recently challenged (81). Although nitrosylhemoglobin, nitrite, and nitrate have no hemodynamic effects, plasma S-nitrosoalbumin and related compounds may act as reservoirs for biologically active NO (59). The entry of NO into the circulation has recently been shown to lead to parallel increases in nitrite and S-nitrosothiols in healthy subjects, and the formation of the latter is accompanied by systemic hemodynamic effects and vasodilation (59, 81). The presently documented negative association between NOx and blood pressure in type 1
Oxidative Stress in Type 1 Diabetes: A Clinical Perspective
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FIGURE 18.6 Mean blood pressure in patients with low versus high NOx. All data represent mean ± SE.
diabetes is consistent with this observation. Alternatively, the inverse associations between NOx and blood pressure may reflect the diversion of NO away from peroxynitrite. Peroxynitrite’s pressor response has been validated in vitro (7) and in whole animals (14). Analysis of the metabolic and hemodynamic response to an acute glucose challenge in nondiabetic patients has indicated that peroxynitrite might also have a pressor effect in man (65, 66).
J.
URIC ACID
AND
AUTONOMIC FUNCTION
IN
TYPE 1 DIABETES
Our data indicate that type 1 diabetes is associated with decreased uric acid, and the latter was associated with decreased autonomic function (Figure 18.4). Uric acid correlated negatively with glycosylated hemoglobin (p < .025 at the third evaluation), so its suppression probably reflects a compensatory response to hyperglycemiamediated oxidative stress. We believe this explains why the suppression of uric acid was associated with multiple changes in autonomic function, as discussed previously. This implies that uric acid is functioning as an antioxidant in vivo. The antioxidant properties of uric acid have been demonstrated in vitro (4) and documented in birds (60). Pathological analyses of brain tissue of patients with Alzheimer’s disease have revealed reciprocal relationships between uric acid and nitrotyrosine, which has been interpreted to mean uric acid acts as a peroxynitrite scavenger and is neuroprotective (44). Our data, gathered in vivo, are consistent with this concept. Why should diabetes lead to suppression of uric acid? Multiple mechanisms need to be considered, and nitric-oxide overproduction probably plays a central role, either directly or by indirect renal mechanisms (Figure 18.5). It is likely that uric acid is degraded or metabolized when it scavenges peroxynitrite and other reactiveoxygen species (84). Accordingly, the suppression of serum uric acid occurred early, at the first patient evaluation, when there was minimal uricosuria (Table 18.3). This indicates that oxidative stress is the most important cause of uric-acid suppression,
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TABLE 18.3 Effect of Diabetes on Uric-Acid Excretion Diabetic Patients Controls Serum Uric Acid μmol/L Uric-Acid Excretion mmol/day mmol/g creatinine Fractional Excretion of Uric Acid (percent) Creatinine Clearance (ml/min)
First Evaluation
Second
Third
280 ± 9.9
218 ± 7.2a
215 ± 9.5 a
214 ± 8.0 a
2.35 ± 0.14 2.03 ± 0.09 5.93 ±.33
2.45 ± 0.16 2.14 ± 0.10 8.08 ±.56 c
2.64 ± 0.11 2.38 ± 0.11 b 9.60 ± 0.56 c
103 ± 5.6
101± 5.5
98.7 ± 4.6
2.73 ± 0.14 b 2.06 ± 0.10 7.68 ± 0.45 c 0 127 ± 6.5 b
Note: Data are means ± SE. a b c
p < 0.001. p < 0.005. p < 0.001 vs. control subjects.
at least initially. Indirect renal effects appear to play a contributory role. At the time of the third evaluation, uricosuria was documented that would be expected to aggravate the uric acid deficit, limit the scavenging of peroxynitrite, and increase the latter, which should further suppress uric acid, thus completing a vicious cycle (Figure 18.5). Nitric oxide overproduction is a critical component in this indirect mechanism, since it mediates hyperfiltration. This was initially reported by Chiarelli et al. (27) and confirmed by us (NOx correlated with creatinine clearance, p < .01, at the time of the third evaluation). The increase in glomerular filtration, coupled with an increase in filtration fraction for uric acid, eventually leads to uricosuria (Table 18.3). The loss of this endogenous antioxidant and peroxynitrite scavenger is disadvantageous and could, in theory, exacerbate multiple diabetic complications.
K. OXIDATIVE STRESS VERSUS NITROSATIVE STRESS Chronic hyperglycemia leads to the formation of advanced glycosylated end products, which activate widely distributed tissue receptors that promote the formation of reactive-oxygen intermediates. The latter may also be formed from the autooxidation of glucose or from enhanced mitochondrial respiration. The sorbital pathway, the hexosamine pathway, and ischemia, may also play a role (37). These and other potential mechanisms are not depicted in Figure 18.5, which is designed to illustrate possible interactions between oxidative stress and nitrosative stress, particularly the role of NFκβ, hyperfiltration, and the suppression of uric acid. This theoretical scheme will be difficult to test since the major end product of interest, peroxynitrite, cannot be directly measured in vivo. Moreover, our formulation (Figure 18.5) does not take into account the multiple potential mechanisms for reactiveoxygen species formation in patients with diabetes, nor did we address the possibility that eNOS may generate both superoxide anions and nitric oxide (and therefore
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peroxynitrite) (98). Similarly, we did not take into account the possibility that nitricoxide overproduction represents a response (rather than a stimulus, as we depicted) to oxidative stress and lipid peroxidation. None of these considerations should obscure the central hypothesis suggested by our data, namely that nitrosative stress and the suppression of uric acid synergistically affect autonomic function in early type 1 diabetes. There are no previous clinical data to suggest this, but the theory is plausible, since nitrosative stress is linked to oxidative stress, and there are multiple animal studies implicating the latter in experimental diabetic neuropathy. Although our sudomotor and cardiovascular autonomic nerve-function data supported this hypothesis, our somatosensory data did not.
IV. OXIDATIVE STRESS AND β-CELL FUNCTION Chronic hyperglycemia has an adverse effect on β-cell function, which eventually leads to worse hyperglycemia (99). This vicious cycle has led to the adage hyperglycemia begets hyperglycemia; the phenomenon has been designated glucose toxicity. Although autoimmune factors are the major cause of the loss of β-cell function in early diabetes, glucose toxicity plays a contributory role. The maintenance of normoglycemia during the first few years of type 1 diabetes helps preserve β-cell integrity, and this has a long-lasting benefit with respect to the prevention of complications (92). Although the mechanism of glucose toxicity is unknown, recent in vitro (17, 70, 90) and whole-animal studies have implicated reactive-oxygen species (35, 52, 98), which promote the formation of cytotoxic lipid peroxides (80) and damage the βcell by a variety of mechanisms (35, 57, 80). In order to determine whether these factors might play a role in human diabetes, we analyzed the biochemical measures of oxidative stress and nitrosative stress with respect to the insulin requirements of patients with early type 1 diabetes who were being followed longitudinally, as previously described. The study was designed to assess peripheral-nerve function (49), not insulin secretion, so blood samples from fasting patients, unfortunately, were not saved for C-peptide analysis. The insulin doses of the patients were recorded, however, which are known to vary inversely with β-cell function in early diabetes. Some of the biochemical measures of oxidative stress correlated with the insulin doses of the patients. NOx correlated with insulin dose at the first (p < .05), second (p < .025), and third (p < .05) evaluations. 8-iso-PGF2α correlated with insulin dose at the first (p < .01) and third (p < .0025) evaluations. Gender-specific Z scores for NOx correlated with insulin dose year two (p < .025) and year three (p < .05). Gender-specific Z scores for 8-iso-PGF2α correlated with insulin dose at the first (p < .025) and third (p < .005) evaluations (Figure 18.7). The mean NOx for the three evaluations correlated with the mean insulin dose (p < .05) and the mean 8-iso-PGF2α for each patient correlated with their mean insulin dose (p < .0025). Previous in vitro (17, 70, 90) and whole-animal (35, 52) studies have suggested that hyperglycemia has detrimental effects on the β-cell, which are linked to oxidative stress and similar to its effects on endothelial cells and nerves. The validity of this conclusion is based on the assumption that insulin requirements provide a mirror
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FIGURE 18.7 8-Iso-PGF2α versus insulin requirement. These data were gathered at the third evaluation. 8-iso-PGF-F2α correlated with insulin dose (r = .48, p < .0025). The 8-iso-PGF2α index also correlated with the insulin dose (r = .44, p < .005).
image of β-cell function throughout the course of this study. Inverse correlations between β-cell function and insulin requirements were reported by Marner et al. for the first three years of type 1 diabetes (67), and analysis of data from the Diabetes Control and Complications Trial (32) has indicated this correlation was maintained throughout the fourth year of diabetes and is thus perfectly maintained throughout the duration of the present study (50). A number of mechanisms have been proposed for the adverse effects of oxidative stress on the β-cell. Reactive-oxygen species interfere with the transcription of insulin-promoter genes and cause protein glycation and cross-linking, pancreatic fibrosis, and lipid peroxidation (35, 58). Reactive-oxygen intermediates also stimulate NFκβ, which, in turn, enhances the transcription of inducible nitric-oxide synthase (iNOS), a major source of nitric-oxide production, in patients with diabetes (35). iNOS is present in the β-cell, where its chemical properties and physiological regulation are similar to that in macrophages and smooth muscle (10, 35). Thus, it
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is reasonable to assume that the systemic nitrosative stress we have documented in plasma samples is also taking place in the pancreas, even within the β-cell itself. iNOS activity in the β-cells has been linked in animals to their susceptibility to injury. iNOS-deficient mice, for example, are resistant to the diabetogenic effects of streptozotocin (21). By contrast, animals that overexpress iNOS develop insulindependent diabetes (90). Nitric oxide has many adverse effects on the β-cell, where it inhibits insulin secretion, disrupts electron transport, promotes apotosis, and causes lipid peroxidation (35, 62). Our data indicate these considerations may be clinically relevant. The correlations between NOx and 8-iso-PGF2α suggest that these parameters are responding to a common stimulus or are otherwise physiologically linked. iNOS-deficient mice, for example, have dramatically decreased NOx and 8-isoPGF2α (58). We therefore postulate that oxidative-stress-induced iNOS activation is the source of NO overproduction in diabetes, and the latter has a quantitatively significant impact on NOx in hyperglycemic patients. The correlations between these parameters and insulin requirements suggest that activation of iNOS may be one of the mechanisms by which hyperglycemia and oxidative stress damage the β-cell. In summary, we have documented that some of the systemic measures of oxidative stress correlated with the insulin requirements of the patients with early type 1 diabetes (50). This suggests that oxidative stress is taking place in the pancreas and causing β-cell damage. These results are consistent with experimental studies, which have indicated that oxidative stress is the cause of glucose toxicity (53, 58).
V. OXIDATIVE STRESS IN CHRONIC DIABETES The early studies of oxidative stress in human diabetes focused on the measurement of malondialdehyde (MDA), a byproduct of lipid peroxidation known to be increased in the peripheral nerves of diabetic animals (64). This compound reacts with thiobarbituric acid to form a pink derivative that can be measured photometrically in blood and urine (TBARS, or thiobarbituric acid reactive substances) (1, 5, 61). The specificity of this method has been improved by performing HPLC analyses of the MDA thiobarbituric acid complex (2). Many studies have shown that TBARS are increased in chronic diabetes, but there is no consensus as to whether TBARS correlate with metabolic control or the presence of complications (1). Unfortunately, many of the early studies included patients with heterogeneous diabetic complications, frequently combining microvascular and macrovascular disorders. One study revealed that TBARS were increased in patients with neuropathy (42). It is possible that the increased TBARS in chronic diabetes is secondary to insulin resistance, dyslipidemia, hypertension, or endothelial dysfunction and not specifically related to hyperglycemia (41, 71). Other markers of lipid peroxidation are increased in patients with chronic diabetes, including total plasma hydroperoxides and conjugated dienes (41, 77). More recent studies of lipid peroxidation have focused on 8-iso-PGF2α, whose formation has been thought to specifically reflect the effects of reactive-oxygen species on membrane-bound phsopholipids (73). This compound is also a renal vasoconstrictor and may promote ischemia in other tissues as well, including peripheral nerves (73). Davi et al. have reported the 8-iso-PGF2α excretion is increased in diabetes,
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correlated with glycemic control, and suppressed by the administration of vitamin E (34). In our study of recent onset diabetes we found 8-iso-PGF2α to be increased only in females in poor control. Other groups, however, have failed to confirm an increase in 8-iso-PGF2α in patients with diabetes (96). Enhanced oxidation of DNA has been studied in experimental as well as clinical diabetes. Increased 8-hydroxy-2-deoxyguanosine (8-OH2′dG), a marker of oxidative damage to DNA, has been reported in white blood cells and urine of diabetic patients (33). In animal studies, oxidative damage to DNA leads to mutations and gene mutations. Some (34a), but not all (6), human studies have indicated that diabetes has similar effects on DNA in white blood cells. We have been unable, however, to confirm increased urinary excretion of 8-OH2’dG in patients with recent onset type 1 diabetes (45). Chronic hyperglycemia also enhances the oxidation of amino acids and proteins in animal models, and some clinical studies have indicated this also occurs in man (11). This observation has been of interest, because many studies have shown that glycoxidized proteins promote the formation of advanced glycosylated end products in animals. The relevance of this to human diabetes has been questioned, however, since glycoxidized proteins are not increased in diabetic patients at the time of autopsy (11). Recent studies have focused on methylglyoxal, a highly reactive dicarbonyl compound that forms readily in fibroblasts of patients with type 1 diabetes (13). Methylglyoxal has been detected in the plasma of diabetic patients, and the related advanced glycosylation end products, imidazolone and argpyrimidine, have been detected in the human tissues, including the arterial walls of the kidney (18). Protein nitration has also been linked to oxidative stress and endothelial dysfunction. The key intermediate is peroxynitrite, the product of NO and the superoxide anion, as detailed previously. The nitrotyrosine content of protein provides a measure of peroxynitrite formation, although the peroxynitrite pathway is not the only source of nitrotyrosine (20). Several laboratories have shown that the nitrotyrosine content of plasma protein is increased in patients with diabetes (23a, 86).
VI. ANTIOXIDANT DEFENSES IN CHRONIC DIABETES Several laboratories have established that antioxidant defenses, as measured in serum, are decreased in patients with diabetes. The traditional test is to measure the capacity of serum to delay lipid peroxidation by the total radical trapping antioxidant parameter (TRAP) assay. The standard approach is to stimulate the peroxidation of linoleic acid by 2, 2′azo-bis (2-amidinopropane) – hydrochloride and then measure the extent to which peroxyl radical formation increases oxygen formation (69). In type 1 diabetes, TRAP activity is decreased, and this largely reflects their suppressed uric acid (69). TRAP activity is also decreased in type 2 diabetic patients and related to both decreased uric acid and decreased protein-bound sulfhydryl groups (23). There are other indications that antioxidant defense mechanisms are decreased in chronic diabetes. Glutathione is decreased in white blood cells (25) and blood
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(1) of diabetic patients. The plasma concentration of the antioxidant enzymes superoxide dismutase and catalase are decreased in patients with diabetes (1). Moreover the messenger RNA for superoxide dismutase, glutathione peroxidase, and catalase are all decreased in skin fibroblasts of type 1 diabetic patients with nephropathy (24).
VII. ANTIOXIDANT TRIALS IN DIABETES In experimental animals, a wide variety of antioxidants, including vitamin E (95), probucol (21), α-lipoic acid (76), butylated hydroxytoluene (22), carvedilol (29), glutathione (19), desferroxamine (30), and N-acetylcysteine (83), slow the progression of neuropathy. Vitamin E (53) and a combination of vitamin E and N-acetylcysteine (58) protect the pancreas from the effects of chronic hyperglycemia in experimental animals. The vast majority of human studies have involved α-lipoic acid. This interesting and versatile antioxidant is well-tolerated clinically and has been extensively studied, as discussed by Russell and Kamisnsky in chapter 21. αLipoic acid is reduced in vivo to dihydrolipoate, which is able to regenerate multiple other antioxidants, including reduced glutathione, vitamin C, and vitamin E (76). This enhances nitric-oxide bioavailability, suppresses peroxynitrite-induced endothelial damage, and dramatically improves peripheral-nerve function in diabetic rats (28). Clinical trials, however, have revealed that α-lipoic acid leads to only a modest improvement in symptoms (100), and the benefits are marginal unless the drug is given intravenously (93). The drug leads to only minor improvements in objective measures of somatosensory (93, 100) and autonomic function (101). These disappointing results may stem from the fact that the trials have been performed in patients with long-standing diabetes who have irreversible nerve damage. Alternatively, it is possible that oxidative stress is less important clinically than it is in experimental animals.
VIII. SUMMARY Oxidative stress has been proven to cause neuropathy in experimental animals, and treatment with antioxidants is physiologically beneficial. Clinical studies have confirmed that oxidative stress, particularly lipid peroxidation, is increased, and antioxidant defenses are compromised. We have documented that increased lipid peroxidation in recent onset type 1 diabetes is associated with decreased sudomotor function, and the suppression of uric acid is associated with multiple abnormalities in autonomic function. We have been unable to confirm, however, an association between biochemical measures of oxidative stress and somatosensory function. Accordingly, clinical efforts to suppress oxidative stress have improved symptoms slightly, but shown little or no effect on objective measures of nerve function. In summary, abundant data have proven that oxidative stress is an important feature of experimental diabetes, but the physiological significance of this mechanism remains to be established in man.
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47. Hoeldtke, RD, Bryner, KD, Horvath, GG, Phares, RW, Broy, LF, and Hobbs, GR, Redistribution of sudomotor responses is an early sign of sympathetic dysfunction in type 1 diabetes, Diabetes, 50:436–443, 2001. 48. Hoeldtke, RD, Bryner, KD, Komanduri, P, Christie, I, Ganser, G, and Hobbs, GR, Decreased prorenin processing develops before autonomic dysfunction in type 1 diabetes, J. Clin. Endo. Metab., 85:585–589, 2000. 49. Hoeldtke, RD, Bryner, KD, McNeill, DR, Hobbs, GR, Riggs, JE, Warehime, SS, Christie, I, Ganser, G, and Van Dyke, K, Nitrosative stress, uric acid, and peripheral nerve function in early type 1 diabetes, Diabetes, 51:2817–2825, 2002. 50. Hoeldtke, RD, Bryner, KD, McNeill, DR, Warehime, SS, Van Dyke, K, and Hobbs, G, Oxidative stress and insulin requirements in patients with recent-onset type 1 diabetes, J. Clin. Endocrinol. Metab., 88:1624–1628, 2003. 51. Hoeldtke, RD and Cilmi, KM, Norepinephrine secretion and production in diabetic autonomic neuropathy, J. Clin. Endocrinol. Metab., 59:246–252, 1984. 52. Ihara, Y, Toyokuni, S, Uchida, K, Odaka, H, Tanaka, T, Ikeda, H, Hiai, H, Seino, Y, and Yamada, Y, Hyperglycemia causes oxidative stress in pancreatic β-cells of GK rats, a model of type 2 diabetes, Diabetes, 48:927–932, 1999. 53. Ihara, Y, Yamada, Y, Toyokuni, S, Miyawaki, K, Ban, N, Adachi, T, Kuroe, A, Iwakura, T, Kubota, A, Hiai, H, and Scino, Y, Antioxidant α-tocopherol ameliorates glycemic control of GK rats, a model of type 2 diabetes, F.E.B.S. Lett., 473:24–26, 2000. 54. Jamal, GA, Hansen, S, Weir, AL, and Ballantyne, JP, The neurophysiologic investigation of small fiber neuropathies, Musc. Nerve, 10:537–545, 1987. 55. Janero, DR, Malondialdehyde and thiobarbituric acid-reactivity as diagnostic indices of lipid peroxidation and peroxidative tissue injury, Free Radic. Biol. Med., 9:515–540, 1990. 56. Kageyama, N, A direct colorometric determination of uric acid in serum and urine with uricase-catalase system, Clin. Chem. Acta., 31:421–426, 1971. 57. Kaneto, H, Fujii, J, Myint, T, Miyazawa, N, Islam, KN, Kawasaki, Y, Suzuki, K, Nakamura, M, Tatsumi, H, Yamasaki, Y, and Taniguchi, N, Reducing sugars trigger oxidative modification and apoptosis in pancreatic β-cells by provoking oxidative stress through the glycation reaction, Biochem. J., 320:855–863, 1996. 58. Kaneto, H, Kajimato, Y, Miyagawa, J, Matsuoka, T, Fujitani, Y, Umayahara, Y, Hanafusa, T, Matsuzawa, Y, Yamasaki, Y, and Hori, M, Beneficial effects of antioxidants in diabetes. Possible protection of pancreatic β-cells against glucose toxicity, Diabetes, 48:2398–2406, 1999. 59. Keaney, JF, Simon, DI, Stamler, JS, Jaraki, O, Scharfstein, J, Vita, JA, and Loscalzo, J, NO forms an adduct with serum albumin that has endothelium-derived relaxing factor-like properties, J. Clin. Invest., 91:1582–1589, 1993. 60. Klandorf, H, Rathore, DS, Iqbal, M, Shi, X, and Van Dyke, K, Accelerated tissue aging and increased oxidative stress in broiler chickens fed allopurinol, Comp. Biochem. Physiol. C. Toxicol. Pharmacol., 129:93–104, 2001. 61. Kosugi, H, Kojima, T, and Kikugawa, K, Characteristics of the thiobarbituric acid reactivity of human urine as a possible consequence of lipid peroxidation, Lipids, 28:337–343, 1993. 62. Laybutt, DR, Kaneto, H, Hasenkamp, W, Grey, S, Jonas, JC, Sgroi, DC, Groff, A, Ferran, C, Bonner-Weir, S, Sharma, A, and Weir, GC, Increased expression of antioxidant and antiapoptotic genes in islets that may contribute to β-cell survival during chronic hyperglycemia, Diabetes, 51:413–423, 2002. 63. Low, PA, Caskey, PE, Tuck, RR, Fealey, RD, and Dyck, PJ, Quantitative sudomotor axon reflex test in normal and neuropathic subjects, Ann. Neurol., 14:573–580, 1983.
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64. Low, PA, Nickander, KK, and Tritschler, HJ, The roles of oxidative stress and antioxidant treatment in experimental diabetic neuropathy, Diabetes, 46(Suppl. 2):S38–42, 1997. 65. Marfella, R, Quagliaro, L, Nappo, F, Ceriello, A, and Giugliano, D, Acute hyperglycemia induces an oxidative stress in healthy subjects, J. Clin. Invest., 108:635–636, 2001. 66. Marfella, R, Verrazzo, G, Acampora, R, La Marca, C, Giunta, R, Lucarelli, C, Paolisso, G, Ceriello, and A, Giugliano, D, Glutathione reverses systemic hemodynamic changes induced by acute hyperglycemia in healthy subjects, Am. J. Physiol., 268:E1167–E1173, 1995. 67. Marner, B, Agner, T, Binder, C, Lernmark, A, Nerup, J, Mandrup-Poulsen, T, and Walldorff, S, Increased reduction of fasting C peptide is associated with islet cell antibodies in type 1 (insulin dependent) diabetic patients, Diabetologia, 28:875–880, 1984. 68. Marnett, LJ, Wright, TL, Crews, BC, Tannenbaum, SR, and Morrow, JD, Regulation of prostaglandin biosynthesis by nitric oxide is revealed by targeted deletion of inducible nitric-oxide synthase, J. Biol. Chem., 275:13427–13430, 2000. 69. Marra, G, Cotroneo, P, Pitocco, D, Manto, A, Di Leo, MAS, Ruotolo, V, Caputo, S, Giardina, B, Ghirlanda, G, and Santini, SA, Early increase of oxidative stress and reduced antioxidant defenses in patients with uncomplicated Type 1 diabetes, Diabet., Care, 25:370–375, 2002. 70. Matsuoka, T, Kajimot, Y, Watada, H, Kaneto, H, Kishimoto, M, Umayahara, Y, Fujitani, Y, Kamada, T, Kawamori, R, and Yamasaki, Y, Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells, J. Clin. Invest., 99:144–150, 1997. 71. McIntyre, M, Bohr, DF, and Dominiczak, AF, Endothelial function in hypertension. The role of superoxide anion, Hypertension, 34:539–545, 1999. 72. Ming-Chia, H, Chin-Han, W, Chia-Lin, C, Hung-Chun, C, Chun-Chang, C, and ShyiJang, S, High blood glucose and osmolality, but not high urinary glucose and osmolality, affect neuronal nitric oxide synthase expression in diabetic rat kidney, J. Lab. Clin. Med., 151:200–209, 2003. 73. Morrow, JD, Hill, KE, Burk, RF, Nammour, TM, Badr, KF, and Roberts, LJ, A series of prostaglandin F2-like compounds are produced in vivo in humans by a noncyclooxygenase, free radical-catalyzed mechanism, Proc. Natl. Acad. Sci. U.S.A., 87:9383–9387, 1990. 74. Nishikawa, T, Edelstein, D, and Brownlee, M, The missing link: A single unifying mechanism for diabetic complications, Kidney Int., 58(Suppl. 77):S26–S30, 2000. 75. O’Byrne, S, Forte, P, Roberts, LJ, II Morrow, JD, Johnston, A, Anggard, E, Leslie, RDG, and Benjamin, N, Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion, Diabetes, 49:857–862, 2000. 76. Packer, L, Tritschler, JH, and Wessel, K, Neuroprotection by the metabolic antioxidant alpha-lipoic acid, Free Radic. Biol. Med., 22:359–378, 1997. 77. Peuchant, E, Delmas-Beauvieux, MC, Couchouron, A, Dubourg, L, Thomas, MJ, Perromat, A, Clerc, M, and Gin, H, Short-term insulin therapy and normoglycemia. Effects on erythrocyte lipid peroxidation in NIDDM patients, Diabet. Care, 20:202–207, 1997.
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19
Oxidative Stress and Glycemic Control in Type 2 Diabetes Emmanuel C. Opara, Ph.D.
CONTENTS I. II. III. IV.
Introduction................................................................................................345 Association between Oxidative Stress and Type 2 Diabetes....................346 Role of Oxidative Stress in the Pathogenesis of Type 2 Diabetes ...........348 Studies of Antioxidant Supplementation for Glycemic Control in Type 2 Diabetes .......................................................................349 A. Vitamin E...........................................................................................350 B. Vitamin C ..........................................................................................350 C. Beta-Carotene ....................................................................................351 D. Glutathione ........................................................................................351 E. α-Lipoic Acid ....................................................................................352 F. Coenzyme Q10 ...................................................................................352 G. Trace Elements ..................................................................................353 V. Innovative Antioxidant Formulation..........................................................354 VI. Conclusion .................................................................................................354 References ............................................................................................................356
I. INTRODUCTION Oxidative stress can be defined as a situation of imbalance in which the levels of prooxidants, referred to as reactive-oxygen species (ROS), present in tissues by far outweigh the amounts of neutralizing substances, otherwise known as antioxidants, as illustrated in Figure 19.1. There is overwhelming evidence in the literature to show that this phenomenon is associated with both type 1 and type 2 diabetes (1–7). Many experimental approaches have been used to demonstrate the association of oxidative stress with diabetes. Some investigators have examined levels of reactiveoxygen species or their degradation products, while others have assessed tissue and blood levels of micronutrient antioxidants or the levels and activities of antioxidant enzymes in experimental animals and in individuals afflicted with diabetes. While
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Antioxidants
Pro-oxidants (ROS)
FIGURE 19.1 Illustration of oxidative stress: Oxidative stress can be defined as a situation of imbalance in which the levels of prooxidants, referred to as reactive-oxygen species (ROS) present in tissues, outweigh the amounts of neutralizing substances, otherwise known as antioxidants. Opara, EC, J. Invest. Med., 52:19–23, 2004. Reprinted with permission.
it has been fairly accepted that oxidative stress may play a role in the etiology of type 1 diabetes (4, 8, 9), it is presently not clear that it plays any role in the pathogenesis of type 2 diabetes. Previous studies had suggested that oxidative stress is a consequence of type 2 diabetes, which is involved in the development of secondary complications of the disease (10–15). However, there is a growing body of evidence to show that it may actually play a role, even if secondary, in the pathogenesis of the disease (1–3, 6, 7, 16–20). In this chapter, we will review the literature to determine the relationship between oxidative stress and type 2 diabetes, with particular attention to the role played by oxidative stress in the pathogenesis of the disease. We will then be able to determine if there is a valid scientific basis for a beneficial role of antioxidant supplementation in the prevention of, and as adjunct therapy in, type 2 diabetes, as reported in some studies.
II. ASSOCIATION BETWEEN OXIDATIVE STRESS AND TYPE 2 DIABETES As indicated earlier, it has been shown in numerous studies that oxidative stress is present in type 2 diabetes. The strong association between oxidative stress and type 2 diabetes can be illustrated by a study that we reported several years ago (21). In that study, we distinguished between two groups of type 2 diabetic patients on the basis of the absence or presence of microalbuminuria. We showed that those patients who had diabetes for longer duration presented with microalbuminuria and had higher incidence of diabetic complications. The diabetic patients typically presented with hyperglycemia, hyperinsulinemia, and hyperlipidemia. We assessed oxidative stress in these patients by measurements of plasma lipid-peroxide levels and total antioxidant capacity. We found that the diabetic patients had increased plasma levels of lipid peroxides and decreased levels of plasma total antioxidant capacity compared to control nondiabetic subjects. The degree of oxidative stress was more pronounced in the group of diabetic patients with microalbuminuria and a higher incidence of diabetic complications (21). Using total antioxidant capacity assay as an index of oxidative stress, other investigators have also found that patients with type 2 diabetes have reduced antioxidant status (13–15, 22–24). However, using the total peroxyl
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radical-trapping potential (TRAP) assay to assess antioxidant status, it has also been reported that there is no major defect in the antioxidant potential in the plasma of patients suffering from type 2 diabetes (25). The reason for this discrepancy is unclear, since other investigators have used the same assay to report a deficiency of antioxidant status in type 2 diabetes (13, 22–24). Many studies have found deficiencies in the levels of individual antioxidant substances in type 2 diabetes. Thus, reduced blood levels of α-Tocopherol (vitamin E), ascorbic acid (vitamin C), carotenoids, zinc, chromium, and reduced glutathione (GSH) have been reported in individuals afflicted with type 2 diabetes (3, 26–32). Since patients with the metabolic syndrome and type 2 diabetes present with hyperinsulinemia, it is of interest that it has been observed that insulin infusion acutely depletes circulating vitamin E levels in humans (33). Complementary to these reports are also data showing that high blood levels of certain antioxidant substances, including α-Tocopherol, β-carotene, and lycopene, are associated with decreased risk of type 2 diabetes (34, 35). Another approach used by some investigators to demonstrate the presence of oxidative stress in type 2 diabetes is the measurement of lipid-peroxide levels and their degradation products. Using a validated technique for measuring authentic plasma lipid-peroxide levels, it has been shown that individuals with type 2 diabetes have higher levels of thiobarbituric acid reactive substances (TBARS) compared to nondiabetic subjects (21, 29, 30, 36–40). In one study, lipid peroxides expressed as malondialdehyde (MDA) was measured along with certain hemostatic variables: fibrinogen, von Willebrand factor (vWf), plasminogen activator inhibitor (PAI-1), tissue plasminogen activator (t-PA), and plasmin activity in type 2 diabetic patients. It was found that MDA was elevated in the patients with microalbuminuria compared with patients without microalbuminuria and control nondiabetic patients. All the hemostatic parameters were also increased in the diabetic patients compared to the control subjects (41). Isoprostanes are widely recognized products of lipid peroxidation, whose measurement provides a reliable index of oxidant injury (42). Hence, it has also been used to assess the presence of oxidative stress in diabetes. In one study, plasma F2 isoprostane levels were measured at baseline and 90 minutes after a glucose load in diabetic patients. It was found that the isoprostane levels increased during acute hyperglycemia in type 2 diabetes, thus providing direct evidence of free-radical-mediated oxidative damage in the disease (43). In other studies, investigators have also measured antioxidant enzyme levels and activities in the assessment of oxidative stress in type 2 diabetes. In two reports from the same group of investigators, Cu-Zn superoxide dismutase (SOD) and glutathione peroxidase (GPX) activities in red blood cells were measured and found to be normal in diabetic patients (30, 36). In another study, serum SOD levels and the activities of serum SOD and GPX were reported to be lower in diabetic patients compared to control nondiabetic individuals (37). However, it also has been reported that diabetic patients have increased serum SOD activity when compared to healthy subjects (29, 44). The reason for the discrepancies in these reports is unclear. However, in an in vitro study designed to link hyperglycemia to oxidative stress, it has been shown that high glucose levels induced an overexpression of the antioxidant enzymes, SOD, catalase, and GPX in human endothelial cells in culture (45). This
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observation is consistent with the findings in the reports by Seghrouchni et al. (29) and Sozmen et al. (44).
III. ROLE OF OXIDATIVE STRESS IN THE PATHOGENESIS OF TYPE 2 DIABETES It is clear that oxidative stress is strongly associated with type 2 diabetes, as shown by various studies using different approaches, as outlined in the preceding section. The crucial question from these studies showing association between oxidative stress and type 2 diabetes is the role, if any, that oxidative stress may play in the pathogenesis of type 2 diabetes. To address this question, it is pertinent to review the metabolic pathways of glucose disposal. The primary pathway of glucose metabolism is glycolysis, through which pyruvate is generated and enters the second pathway known as the Krebs cycle for complete oxidation (46). The complete oxidation of glucose to yield Adenosine Triphosphate (ATP) is achieved by oxidative phosphorylation that is coupled to an electron-transport chain. In the glycolytic pathway, glyceraldehyde-3phosphate dehydrogenase enzyme catalyzes the degradation of glyceraldehyde-3-phosphate to 1,3-bisphosphoglycerate. This enzyme is a heme-containing protein that can be inhibited when oxidized severely by a burden of oxidants (47, 48). Also, the cytochrome enzymes of the electron-transport chain contain the transition metal copper (Cu++), which can also be inhibited when oxidized by the abundance of ROS. The consequence of these blockages to glucose metabolism by oxidative stress would contribute to an elevation of blood glucose or hyperglycemia. There are several mechanisms by which oxidative stress may be involved in the pathogenesis of type 2 diabetes. First, it could impair glucose metabolism at the level of the major tissues responsible for glucose disposal. The site of major glucose utilization in the body is the skeletal muscle. It is therefore not surprising that it has been reported that the pathogenesis of type 2 diabetes involves perturbations to the antioxidant defense systems within the skeletal muscle (17). In the study, muscle samples were obtained from seven patients with type 2 diabetes and five agematched, as well as nine young, nondiabetic, subjects, before and after a euglycemichyperinsulinemic clamp for 120 minutes. The samples were analyzed for heat-shock protein (HSP)-72 and heme oxygenase (HO)-1 mRNA, intramuscular triglyceride content, and the maximal activities of β-hydroxyacyl-CoA dehydrogenase (β-HAD) and citrate synthase (CS). Basal expression of both HSP72 and HO-1 mRNA were lower by 33 percent and 55 percent, respectively, when comparing diabetic patients with age-matched and young control subjects, with no differences between the latter groups. Both basal HSP72 and HO-1 mRNA correlated with glucose-infusion rate during the clamp. Significant correlations were also observed between HSP72 mRNA and both β-HAD and CS. HSP72 mRNA was induced by the clamp in all groups. The data thus provided evidence that the genes involved in providing cellular protection against oxidative stress are defective in individuals afflicted with type 2 diabetes (17). In an experimental model of diabetes, it has also been reported that oxidative stress may impair muscle repair (16), which probably would diminish the capacity of skeletal muscle to dispose of glucose.
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Second, oxidative stress activates certain signaling pathways, such as nuclear factor-κΒ, p38 MAPK, and NH2-terminal Jun kinases, which underlie the development of diabetic complications. It has recently been proposed that the activation of these same stress pathways by glucose and fatty acids may lead to both insulin resistance and impaired insulin secretion (6). Third, the progressive decline in βcell function frequently seen in patients with type 2 diabetes has been attributed to glucose toxicity and lipotoxicity, which are associated with oxidative stress (2). This subject is discussed in detail in another chapter written by Dr. Philipson and his associate. Of interest, it has also been shown that oxidative stress causes depolarization and Ca2+ uptake in a β-cell line (49), a phenomenon that stimulates insulin secretion that may contribute to hyperinsulinemia seen in type 2 diabetes. Also, as illustrated in our study (21) described earlier, type 2 diabetes generally presents with a triangular relationship of hyperlipidemia, hyperglycemia, and hyperinsulinemia, and it is a matter of debate which of these factors is a cause or consequence of the other. The scenario that I would propose is that the problem starts with hyperilipidemia, in which increased fatty-acid oxidation would stimulate insulin secretion (50), resulting in increased plasma levels of insulin, or hyperinsulinemia. Hyperinsulinemia would down-regulate insulin-receptor numbers and insulin action (51, 52), leading to diminished insulin sensitivity and an increase in blood-glucose levels. Simultaneously, products of the fatty oxidation would cause inhibition of glucose metabolism while enhancing hepatic glucose synthesis (53, 54), thereby exacerbating the hyperglycemia. Among these products of fatty-acid metabolism are increased levels of ROS that would inhibit glucose metabolism and further enhance the elevation of glucose in the blood, as outlined earlier. Bloodglucose overload in the face of impediments to its oxidation would activate minor pathways of glucose metabolism, such as glucose auto-oxidation, which generate more ROS and exacerbate oxidative stress and type 2 diabetes, as illustrated in Figure 19.2.
IV. STUDIES OF ANTIOXIDANT SUPPLEMENTATION FOR GLYCEMIC CONTROL IN TYPE 2 DIABETES The abundance of evidence in support of the association between oxidative stress and type 2 diabetes has led to numerous studies that have examined the effects of various antioxidant supplements as adjunct therapy in type 2 diabetic patients (1, 19, 27). Also, it is fairly established that the incidence of type 2 diabetes increases with age, which has been associated with increased oxidative stress in many studies (5, 19, 31). It is therefore necessary to explore the potential of antioxidant supplementation as preventive strategy and in the management of type 2 diabetes, which increases with age. Various studies have examined the use of certain antioxidants, either as single supplements or in combination, as disease-prevention strategy in high-risk subjects, and as adjunct therapy in type 2 diabetes. In this section, we will review the literature for the effects on glycemic control of the various antioxidant-supplementation regimens that have been employed in these studies in human subjects.
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Type 2 Diabetes
Hyperinsulinemia
Hyperglycemia
Glucose autoxidation Hyperlipidemia
Fatty acid metabolism
ROS
FIGURE 19.2 A hypothesis on the pathogenesis of type 2 diabetes: It is possible that the pathogenesis of type 2 diabetes starts with hyperlipidemia in which increased fatty-acid oxidation would stimulate insulin secretion, resulting in increased plasma levels of insulin or hyperinsulinemia. Hyperinsulinemia would down-regulate insulin-receptor numbers and insulin action, leading to diminished insulin sensitivity and an increase in blood-glucose levels. Simultaneously, products of fatty-acid oxidation would cause inhibition of glucose metabolism while enhancing de novo glucose synthesis, thereby exacerbating hyperglycemia. Among the byproducts of fatty-acid metabolism are increased levels of reactive-oxygen species (ROS), which would cause further elevation of blood-glucose levels. Opara, EC, J. Invest. Med., 52:19–23, 2004. Reprinted with permission.
A. VITAMIN E Epidemiological studies indicate that low vitamin E intake is a risk factor for the development of type 2 diabetes. The use of vitamin E for the prevention and, as adjunct therapy, in the management of the disease is of significant interest (5, 18, 19). As illustrated in Table 19.1, one of three studies in humans failed to show any beneficial effect of vitamin E supplementation on glycemic control (55–57). However, it is noteworthy that the study by Sharma et al., which was only for a short duration of four weeks, used a vitamin E dose that is less than half of the dose used in the other studies whose duration was three months or more. Furthermore, the effect of this low-dose vitamin E supplementation on blood glucose was examined only after normal blood-glucose control had been achieved. In other words, the patients enrolled in the study had reduced oxidative stress and normal blood-glucose levels (55), therefore leaving no room for additional improvement.
B. VITAMIN C A few groups of investigators have also examined the effect of vitamin C supplementation on insulin secretion and insulin action. In some studies, vitamin C supplementation was provided by systemic infusion in the dose range of 500–2000 mg, and it was observed that this vitamin enhanced glucose disposal by enhancing insulin sensitivity without affecting insulin secretion (58–60). Another study was performed
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TABLE 19.1 Effect of Vitamin E Supplementation on Blood Glucose Reference #
Study Design
Dose
55
30 diabetic patients 15 healthy controls Placebo controlled, double-blind cross over study with 35 elderly patients
400 IU/day
4 weeks
No effect
900 IU/day
3 months
Reduction in plasma glucose
Placebo controlled, 15 patients and 10 healthy controls
900 IU/day
4 months
Reduction of glucose AUC in glucose tolerance tests of healthy and diabetic patients
56
57
Duration
Result
using a randomized, double-blind crossover design, and supplementation was done by oral ingestion of vitamin C (2000 mg/day), which was compared to magnesium supplementation (600 mg/day) for three months. It was found that vitamin C caused a reduction in fasting plasma glucose and HbA1c levels, which were not affected by magnesium supplementation (61).
C. ΒETA-CAROTENE A large-scale, long-term study has been performed with β-carotene (62). In the study, a total of 22,071 healthy U.S. male physicians aged 40–84 years were enrolled in a randomized, double-blind, placebo-controlled trial from 1982–1995. A total of 10,756 subjects were randomly assigned to receive β-carotene (50 mg on alternate days), and another 10,712 received a placebo. At the end of the follow-up period (mean duration, 12 years), the incidence of type 2 diabetes did not differ between the two groups. Thus, in this study of apparently healthy men, supplementation with β-carotene had no effect on the risk of development of type 2 diabetes (62). Perhaps it is pertinent to point out that the dose of β-carotene used in this trial is significantly below the revised recommended upper intake for this supplement (63). Therefore, it is probably advisable to exercise caution in using this observation to determine whether β-carotene has any role in the prevention and treatment of type 2 diabetes.
D. GLUTATHIONE Glutathione (GSH), a tri-peptide molecule that plays an important role in cellular metabolism and protects against oxidative stress (64, 65) has been studied as an antioxidant supplement in type 2 diabetes. In two studies by the same group of investigators, GSH supplementation was performed by systemic infusion in the dose range of 10–15 mg/min for 120 minutes, using normal saline infusion for control.
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In one study, it was found that GSH enhanced glucose-stimulated insulin secretion in aged individuals with impaired glucose tolerance, but not in normal control subjects (66). In the other study, the investigators observed that, while GSH only enhanced insulin secretion in diabetic patients, it increased nonoxidative glucose disposal in both healthy and diabetic individuals (67). In another study by a different group of investigators, GSH was infused at the rate of 1.35 g/m2/h for one hour in 10 healthy and 10 diabetic individuals, and the data were compared to saline infusion in the same experimental subjects. It was found that GSH enhanced glucose uptake assessed by the euglycemic clamp technique (68), consistent with the observations by Paolisso et al. (67).
E. α-LIPOIC ACID α-Lipoic acid is a disulfide compound that is produced in small quantities in cells. It normally functions as a coenzyme in the pyruvate dehydrogenase and α-ketoglutarate dehydrogenase enzyme complexes of the tri-carboxylic-acid cycle but has antioxidant properties in pharmacological doses (69). In patients with type 2 diabetes, it has been reported that, while intravenous infusion of α-Lipoic acid significantly enhanced insulin-mediated glucose disposal, oral supplementation had only marginal effects (69), thus suggesting that the contention here may be bioavailability through the oral route. Some investigators have suggested that bioavailability of oral supplements may be enhanced if taken with meals.
F. COENZYME Q10 Coenzyme Q10 (CoQ10), also called ubiquinone, is an isoprenoid derivative, which is involved in mitochondrial electron-transport chain, where it accepts and donates electrons, thereby functioning as an antioxidant. Based on observations that CoQ10 deficiency is associated with type 2 diabetes, two groups of investigators have examined the effect of CoQ10 supplementation on metabolic control in individuals afflicted with the disease. In one small study, 23 patients were enrolled in a randomized six-month, double-blind, placebo-controlled trial in which one group received 100 mg CoQ10 twice/daily and another received a placebo. CoQ10 supplementation caused > threefold rise in serum concentrations, but did not affect glycemic control in the diabetic patients (70). In the other study, using a randomized placebo-controlled 2 × 2 factorial design, 74 individuals with uncomplicated type 2 diabetes and dyslipidemia were assigned to receive either an oral dose of 100 mg twice/day or a placebo for 12 weeks. The CoQ10 supplementation also resulted in a threefold increase of the supplement in plasma concentrations, which was accompanied by an improvement in glycemic control, as apparent in significant reductions in plasma HbA1c levels (71). The reason for the discrepancy between these two observations on the effect of the same dose of CoQ10 supplementation on glycemic control is unclear. Additional studies are therefore required to determine the effect of CoQ10 supplementation on blood-glucose regulation in diabetic patients.
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G. TRACE ELEMENTS Blood-glucose regulation is dependent upon normal glucose metabolism, which, in turn, is regulated by chains of reactions catalyzed by enzymes. Some enzymes require no chemical groups for activity other than their amino residues, and others require an additional chemical component referred to as a cofactor. The cofactor may be either one or more inorganic ions or a complex organic or metallorganic molecule called a coenzyme. Certain enzymes require both a coenzyme and one or more metal ions for activity. These metal ions are usually transition metals, which are obtained from the diet in small (micrograms and milligrams) amounts, hence the term trace elements. As already mentioned, some of these elements are present in the cells and tissues as cofactors of certain antioxidant enzymes, such as zinc in superoxide dismutase (SOD) and selenium in glutathione peroxidase (GPx). As transition metals, the trace elements have antioxidant potential, and the effect of supplementation with certain trace elements on glycemic control has been examined in diabetic patients. A number of investigators have examined the effect of chromium (Cr) supplementation on glycemic control in type 2 diabetes. In one study, 180 individuals being treated for type 2 diabetes were randomly assigned to receive either a placebo, 100 μg as chromium picolinate twice/day, or 500 μg Cr twice/day. During the period of supplementation, the patients continued to take their normal medications and were instructed not to change their dietary patterns and lifestyle. It was found that HbA1c levels improved significantly after two months in the group receiving 1000 μg Cr/day and were lower in both Cr-supplemented groups after four months when compared to the placebo group. There was also significant improvement in fasting plasmaglucose levels in the Cr-supplemented groups (72). In another study, Anderson et al. examined the effects of Cr and zinc (Zn) supplementation in adult Tunisian subjects with type 2 diabetes whose plasma HbA1c levels were > 7.5 percent. The subjects were supplemented for six months with either 30 mg/day of Zn as zinc gluconate, 400μg/day Cr as chromium pidolate, a combination of both Zn and Cr supplements, or a placebo. In this study, supplementation had no effect on HbA1c levels or glucose homeostasis, although it reduced lipid-peroxide levels in each of the supplementation groups (30). It is not clear why these two studies by the same group of investigators produced different results in terms of the effect of Cr supplementation on glycemic control. The observation of a lack of effect of Zn supplementation on glycemic control is consistent with that made in another study that examined the effects of Zn supplementation in Tunisians with type 2 diabetes (36). More recently, another group has examined the effects of Cr supplementation in euglycemic subjects and in those with type 2 diabetes. The study subjects consisted of a group with plasma HbA1c levels < 6.0 percent, a mildly hyperglycemic group with HbA1c levels in the range of 6.8 percent to 8.5 percent, and a severely hyperglycemic group with HbA1c levels > 8.5 percent. Each group was divided into two random subgroups, which were supplemented daily with either 1000 μg Cr as yeast Cr (III) or a placebo. The investigators found that although supplementation reduced oxidative stress, it had no effect of on glycemic control in any of the three groups when compared to a placebo (26).
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V. INNOVATIVE ANTIOXIDANT FORMULATION There is an urgent need to determine the best approach to designing an optimum antioxidant-supplementation regimen for glycemic control in diabetic patients. In the body, there are two systems of antioxidants, micronutrients and enzymes, and both systems are linked together in a biochemical chain that destroys ROS (64). The network system of antioxidant action against oxidative stress needs to be taken into consideration in the use of antioxidant supplements in order to avoid alteration in the antioxidant–prooxidant balance. When an antioxidant donates an electron to an invading ROS, it becomes a prooxidant and needs a replenishment of the electron to revert to its antioxidant status. This phenomenon occurs readily in a balanced system of micronutrients, as illustrated by Machlin and Bendich (64). The lesson from this natural system is that antioxidant supplements may actually work better when provided as a formula that incorporates vitamins and trace elements, in order to provide for the optimum environment for the networking required in their action (5, 64). Indeed, it had previously been suggested that some degree of supplementation with certain vitamins and minerals would be worthwhile for the regulation of blood-glucose levels in diabetic patients (73). Based on this rationale, investigators have started designing antioxidant formulas, comprising multiple vitamins and trace elements, to be used for supplementation instead of individual vitamins or trace elements. One such formula that is commercially available is the Akesis formula, which we had used in an open-label study (5). Diabetic patients received supplementation of this balanced formula as adjunct therapy while they remained on their usual treatment regimen of oral agents. We found a mean +/– SEM 1.89 percent reduction in HbA1c levels after three months of supplementation (5). Although these data need to be confirmed in a well-designed placebo-controlled study, the original formula used in the open-label study has actually been recently improved. The improvement has been made by the removal of pantothenic acid, calcium, phosphorus, and iodine, which play no role in reducing oxidative stress, while α-lipoic acid has been added, and the doses of zinc and selenium in the formula have been augmented. The revised formula has now been renamed as InResponse (Response Scientific Inc., Cleveland, Oklahoma). The composition of the revised formula, to be used in an upcoming double-blind placebo-controlled trial, is provided in Table 19.2. For the individual constituents of the formula, the doses exceed the RDA levels but are within the dietary-reference intakes (DRI) approved in 2000 by the National Academy of Sciences (63).
VI. CONCLUSION In summary, the occurrence of redox reactions in both the glycolytic and electron-transport of during oxidative phosphorylation during glucose metabolism, if not adequately regulated by antioxidants, as well as the increased production of ROS in diabetes, will cause oxidative stress that is capable of inhibiting glucose metabolism. It is therefore reasonable to suggest that oxidative stress may actually play a role, even if it is only secondary, in the pathogenesis of type 2 diabetes. This putative role constitutes a biochemical basis for the need to use antioxidants, as
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TABLE 19.2 Composition of the In Response Formula Compared to RDA Values Compound
Supplement Dose
Percent RDA
Vanadyl (vanadium) sulfate hydrate Elemental Chromium Vitamin E Beta-carotene (pre-vitamin A) Elemental Magnesium α-Lipoic acid Vitamin C (L-ascorbic acid) Vitamin B6 Vitamin B12 Thiamine Riboflavin Nicotinamide (B3) Folate Biotin Zinc Selenium Copper Manganese
102 mg 360 μg 420 IU 10,000 IU 48 mg 102 mg 100 mg 24 mg 60 μg 3 mg 3.6 mg 30 mg 600 μg 300 μg 30 mg 90 μg 2 mg 12 mg
N/A 300 percent 1400 percent 200 percent 12 percent N/A 100 percent 1200 percent 1000 percent 200 percent 212 percent 150 percent 150 percent 100 percent 200 percent 129 percent 100 percent 600 percent
N/A = not available
adjunct therapy in type 2 diabetes, in order to diminish oxidative stress and thus help to control blood-glucose levels in diabetic patients. The review of the literature in this chapter clearly shows that a good number of antioxidant-supplementation regimens can have a positive outcome for glycemic control in diabetic patients. However, there is currently no standardized antioxidant regimen for this purpose. Based on the natural, biochemical chain of interactions of micronutrient and enzymatic antioxidants in the defense against oxidative stress (64), for future studies, it is prudent to suggest that an appropriate approach to designing a regimen is to use a formula consisting of relevant trace elements and vitamins. It is noteworthy that, for therapeutic use, individual doses of the constituents of such a formula must exceed the RDA levels for any efficacy to be observed. Using this approach, appropriate studies are required to determine effective antioxidant regimens to be used as adjunct therapy for glycemic control in type 2 diabetes. Another issue of critical importance is the bioavailability of the supplemental substance (s), and this should be of utmost consideration when compounding antioxidant-supplementation formulas. It is also necessary to determine the optimum duration of any antioxidant supplement for beneficial outcome on glycemic control. It is conceivable that long-term use of an optimum antioxidant regimen involving effective doses of relevant vitamins and trace elements, with careful formulation as adjunct therapy, may help to regulate blood glucose in type 2 diabetes.
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Oxidative Stress and Vascular Complications of Diabetes Mellitus Fateh Entabi, M.D. and Michael T. Watkins, M.D.
CONTENTS I . Introduction................................................................................................361 II. Oxidative Stress and Diabetes...................................................................362 III. The Pathophysiology of Oxidative Stress, Diabetes, and Vascular Injury...........................................................................................362 A. Hyperglycemia...................................................................................363 B. Dyslipidemia......................................................................................365 C. Insulin Resistance..............................................................................366 IV. Diabetic Vascular Injury — Prothrombotic Environment.........................367 V. Clinical Manifestations of Diabetic Angiopathy.......................................368 A. Microvascular Complications............................................................368 1. Retinopathy..................................................................................368 2. Nephropathy ................................................................................368 B. Macrovascular Complications ...........................................................369 1. Coronary Disease ........................................................................369 2. Cerebrovascular ...........................................................................369 3. Peripheral Vascular......................................................................369 VI. Treatment: Oxidative Stress and Diabetes ................................................370 VII. Summary ....................................................................................................371 Acknowledgments..................................................................................................371 References..............................................................................................................372
I. INTRODUCTION In 1997, approximately 124 million people worldwide were affected by diabetes mellitus. The number is expected to reach 221 million by 2010. With the improvement in treatment, diabetic patients are living longer lives, which consequently reflects an increase in the prevalence of diabetes and its complications, including vascular complications [1]. There is a fourfold increased risk of developing coronary,
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cerebrovascular, and peripheral arterial disease in diabetic patients [2]. Clinical studies have shown that diabetic patients with no history of myocardial infarction have a risk of myocardial infarction, which is equivalent to nondiabetic patients with previous myocardial infarction. [3]. Moreover, after myocardial infarction, diabetic patients have a 58 percent increase in first-month mortality [4], and 100 percent increase in five-years mortality compared to nondiabetic patients [5]. Patients with diabetes suffer a fourfold increase in cerebrovascular mortality at all ages [6, 7]. This is especially obvious in the younger age groups, where there is more than tenfold increased risk for strokes in patients younger than 44 years old [8]. In addition, diabetes doubles the rate of recurrent stroke [9], and trebles the frequency of stroke-related dementia [10]. Studies to explore the pathology of vascular complications in diabetes suggest oxidative stress may have a key role in the pathogenesis of vascular complications, both at the microvascular and macrovascular level [11, 12].
II. OXIDATIVE STRESS AND DIABETES Oxidative stress is defined as excessive production of reactive-oxygen species (ROS) or prooxidant factors in the presence of diminished antioxidants [13, 14]. Prooxidants and ROS may be atoms or molecules having one or more unpaired electron in their atomic structures and thus are highly reactive. Antioxidant factors include molecules, proteins, and enzymes that scavenge those free radicals and ROS. Antioxidant factors include vitamins, minerals, and enzymes that interact together in a special biochemical chain to scavenge free radicals [14]. An imbalance between prooxidant and antioxidant factors can be caused by depletion of endogenous antioxidants (e.g., glutathione), or low dietary intake of antioxidants (e.g., vitamin E, vitamin C, βcarotene, Mg) and increased formation of free radicals (e.g., O2, HO2, HO·, NO·) and other reactive species. There are numerous studies that show an increase in markers of increased oxidant production in patients with diabetes [15–18]. There is a clear relationship between oxidative stress and the development of medical complications in diabetes [11, 19, 20]. In fact, oxidative age (the abundance of volatile organic compounds measured in breath) has been recently proposed as a screening marker for increased risk of complications associated with diabetes mellitus [21].
III. THE PATHOPHYSIOLOGY OF OXIDATIVE STRESS, DIABETES, AND VASCULAR INJURY Clinical studies on hyperglycemic patients with early stage type 1 diabetes have shown endothelial dysfunction, increased oxidative stress, as well as a reduction of vascular compliance of both large and small arteries, even before any clinical complications from the diabetes are evident [22, 23]. Major clinical components of type 2 diabetes include hyperglycemia, dyslipidemia, and insulin resistance. While each component contributes to the overall morbidity and mortality associated with diabetes through different physiologic pathways, each component contributes to vascular disease by mechanisms that include oxidative stress.
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HYPERGLYCEMIA
↓GLUTATHIONE ↓NADPH/NADP ↑NADH/NAD
↑GLUTCOSE AUTOOXIDATION ↑PROTEIN GLYCOSYLATION
⇔ eNO S ↑ iNO S
↑NO ↑Advanced Glycation End Products
↑NAD(P)H OXIDASE
↑Superoxide Ion ↑Hydrogen Peroxide
↑Peroxynitrite Anion OONO-
Oxidative Stress
FIGURE 20.1 Hyperglycemia-induced oxidative stress:. Hyperglycemia causes oxidative stress by a variety of metabolic pathways, which include advanced glycation end products, reactive-oxygen, and nitrogen species.
A. HYPERGLYCEMIA Hyperglycemia associated with diabetes contributes to oxidative stress and vascular complications by a number of biochemically distinct pathways (Figure 20.1). Data to support the effects of hyperglycemia come from a variety of in vivo and in vitro studies. Hyperglycemia has been shown to induce superoxide production in isolated bovine aortic endothelial cells [24]. Inhibitors of mitochondria respiration (rotenone, a complex I inhibitor; thenoyltirfluoracetone, a complex II inhibitor; or carbonyl cyanide m-chlorophenylhydrazone, an uncoupler of oxidative phosphorylation that abolishes the mitochondrial membrane proton gradient) decreased superoxide ion production induced by hyperglycemia. These in vitro data suggest that hyperglycemia interferes with normal mitochondrial function in an isolated setting and may independently contribute to oxidative stress in vivo. Superoxide-induced activation of protein kinase C (PKC) exacerbates cellular oxidative stress by leading to activation of membrane-associated nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidases [25–28]. Normalizing levels of mitochondrial superoxide anions prevents glucose-induced activation of PKC, the formation of advanced glycation end products (AGE), accumulation of sorbitol, and activation of nuclear factor κ B (NF-κβ) in endothelial cells [29]. In a hyperglycemic environment, increased intracellular glucose results in its increased enzymatic conversion into the polyalcohol sorbitol, with concomitant decrease in NADPH. It has been proposed that reduction of glucose to sorbitol by NADPH consumes NADPH, which is required for generation of reduced glutathione, thereby exacerbating intracellular oxidative stress. Since sorbitol does not diffuse easily across cell membranes, it was originally thought to cause osmotic damage to microvascular endothelium. However,
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the concentrations of sorbitol measured in diabetic vessels and nerves are too low to cause osmotic damage. AGEs independently increase the production of oxygen-derived free radicals and also autoactivate the AGE receptor (RAGE). AGEs are found in increased amounts in diabetic retinal vessels and renal glomeruli, and, as such, likely play a role in the microvascular complications of diabetes. AGEs were originally thought to arise from nonenzymatic reactions between extracellular proteins and glucose, but it now seems likely that intracellular hyperglycemia is the primary initiating event in the formation of both intracellular and extracellular AGE. The importance of AGEs in the pathogenesis of diabetic complications is indicated by the observation in animal models that AGE inhibitors partially prevented various functional and structural manifestations of diabetic microvascular disease in the retinal, kidney, and nerve. In a multicenter trial, the AGE inhibitor aminoguanidine slowed the progression of nephropathy in type 1 diabetic patients [30]. RAGE activation also produces more free radicals by increasing intracellular enzymatic-superoxide production. Increased levels of superoxide may cause direct damage to intracellular proteins, extracellular matrix, and alter the physiologic milieu by interacting with endothelial autacoids, such as nitric oxide (NO). NO is the most potent vasodilator in the body, and one of the most important molecules synthesized by endothelial cells to maintain vascular homeostasis. NO is produced by endothelial NO synthase (eNOS) through a five-electron oxidation of the guanidine-nitrogen terminal of L-arginine [31]. NO prevents vascular injury by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and, consequently, inhibits excessive vascular smooth-muscle-cell proliferation and migration [32]. Eventually, monocytes and vascular smooth muscle cells migrate to the intima and form macrophage foam cells, which initiate the development of atherosclerosis [33]. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells [32, 34, 35]. Increased cellular levels of superoxide ion associated with hyperglycemia are believed to be responsible for decreased endothelialdependent vasodilation in ex vivo (aortic rings) experiments [36], and in vivo (healthy people during hyperglycemic clamping) studies [24, 37]. The decreased levels of NO, seen in diabetes, is coincident with increased activity of the proinflammatory transcription factor NF-κB [29, 38, 39]. The mechanism whereby oxidative stress is believed to contribute to decreased endothelial-dependent vasodilation involves quenching NO by superoxide ion, thereby leading to increased cellular levels of peroxynitrite ion [40, 41]. Peroxynitrite ion oxidizes tetrahydrobiopterin (BH4) [2, 11, 42–44], an important cofactor of eNOS. The oxidization of BH4 alters the activity of eNOS such that O2 production increases, leading to further increases in oxidative stress and decreased bioavailability of NO [45, 46]. This vicious circle results in ever-increasing levels of superoxide anion and inactivation of NO [24, 47, 48]. Hyperglycemia also stimulates release of xanthine oxidase from liver cells into plasma, where this enzyme further contributes to worsening oxidative stress through generation of superoxide ion [48]. There is evidence to suggest that increased superoxide-anion production also activates the hexosamine pathway, which inhibits eNOS activation by O-acetylglucsoaminylation at the Protein Kinase B, a serine threonine protein kinase (Akt) site of the eNOS protein [47]. Shunting of excess
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glucose into the hexosamine pathway is also believed to result in increased activity of the enzyme O-GlcNAc-β-N-acetylglucosaminidase [49]. This activation likely results in O-acetylglucoaminylation of the transcription factor Sp1 and other glucoseresponsive genes, thereby modulating both gene expression and protein function in the vascular wall to contribute to the pathogenesis of diabetic complications. Oxidative stress further inhibits biosynthesis of NO by reducing the activity of dimethylarginine dimethylaminohydrolase, an enzyme responsible for the inactivation of asymmetric dimethylarginine [50]. This leads to increased amounts of asymmetric dimethylarginine, an important competitive antagonist of NOS, which again results in reduction of NO synthesis. A rodent model of arterial infusion of ascorbic acid (vitamin C), a well-known antioxidant, results in restoring NO-dependent, endothelium-dependent vasodilation [37, 51, 52]. Furthermore, clinical studies on healthy humans (hyperglycemic clamp) and patients with type 1 and type 2 diabetes showed that ascorbic acid restored NOdependent, endothelium-dependent vasodilation [37]. Hyperglycemia also reduces the availability of NO by its action on the PKC pathway [53]. Clinical studies have shown that administering a PKC inhibitor to healthy humans prevents the abnormal endothelium-dependent vasodilation caused by hyperglycemia [37]. The cumulative biological consequences of decreased NO results in increased activity of the proinflammatory transcription factor NF-κB, increased expression of leukocyte-adhesion molecules, and production of chemokines and cytokines [29, 38, 39, 54–56]. This scenario leads to a chronic vascular injury, which is known to facilitate the development of hypertension [36, 57, 58], thrombosis [54, 59, 60], and atherosclerosis [56]. Recent data implicate a role for the nuclear enzyme poly (ADP-ribose) in the pathogenesis of vascular dysfunction associated with diabetes. Polymerase (PARP) activation is stimulated by a number of noxious stimuli, most prominently ROS, which are abundant in the hyperglycemic environment [61]. In a rodent model of diabetes, histologic evidence of increased PARP activity was demonstrated in the aorta and myocardium. Moreover, the PARP inhibitor PJ34 ameliorated indices of left-ventricular dysfunction and compromised aortic, endothelial-dependent vasodilation in diabetic animals [62]. These findings implicate yet another metabolic pathway in the pathogenesis of diabetic vascular dysfunction.
B. DYSLIPIDEMIA Elevated levels of circulating free fatty acids (Figure 20.2) that accompany diabetes can be ascribed to their release from adipose tissue and diminished uptake by skeletal muscle [63]. The increase in circulating free fatty acids stimulates the liver to increase the amount of very low-density lipoprotein (VLDL) [64]. This increase in VLDL, with diminished clearance by lipoprotein lipase, causes hypertriglyceridemia [65, 66], which results in decreased HDL and generation of small, dense LDL, which is more atherogenic [45, 67]. In the setting of noninsulin-dependent diabetes, LDL oxidation (by ambient ROS) is increased, which may then lead to increased foamcell formation and atherogenesis [66]. In addition, hypertriglyceridemia and low HDL have been associated with endothelial dysfunction [67]. One of the most important ways that free fatty acids impair endothelial function is through increased
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Increased Serum Free Fatty Acids
Reactive Oxygen Species
↑ Hepatic VLDL ↑ LDL
PKC activation Of NADPH Oxidases
↑ Oxidized LDL
Vascular Injury
Oxidative Stress
FIGURE 20.2 Contributions of dyslipidemia to oxidative stress: Increased levels of free fatty acids modulate increased hepatic levels of VLDL and reactive-oxygen species. VLDL can be converted to LDL and oxidized LDL. Reactive-oxygen species also cause oxidative stress through PKC-mediated increase in NADPH oxidases.
production of oxygen-derived free radicals, activation of PKC, and further exacerbation of dyslipidemia [27, 68]. Furthermore, oxidized LDL has been shown to decrease nitric-oxide levels by binding to LDL receptors [69]. Infusions of free fatty acids reduce endothelium-dependent vasodilation in healthy and type 2 diabetic patients [70]. NO-mediated vasodilation could be preserved by simultaneous infusion of free fatty acids with ascorbic acid, suggesting that fatty acids modulate vascular relaxation by pathways dependent on ROS [71]. In addition to promoting the development of foam cells and atherogenic lesions in the arterial wall, oxidized LDL induces tissue factor and plasminogen activator inhibitor 1 synthesis in endothelial cells, leading to a prothrombotic state [72]. Oxidized LDL may also have a role in inhibiting platelet NO synthase, thereby increasing platelet aggregation and thrombus formation [73]. Oxidized LDL is also involved in increasing the levels of endothelin [74–77], which is responsible for the disruption of the endothelial response in diabetic patients. Blockade of endothelin A receptors increases forearm blood flow in patients with type 2 diabetes mellitus, indicating increased activity of endogenous endothelin1 in resistance vessels of these patients [36, 78].
C. INSULIN RESISTANCE The role of insulin resistance in the vascular complications that accompany the metabolic syndrome has been both supported [79] and questioned [80] in the literature. Part of the controversy in understanding the role of oxidative stress in insulin resistance revolves around difficulties encountered in isolating the effects of insulin resistance using in vivo or in vitro experimental models. Oxidative stress has been implicated in the development of both endothelial dysfunction and insulin resistance. In fructose-induced, insulin-resistant rats, there is evidence of impaired endotheliumdependent vasodilation, associated with increased levels of the lipid-peroxidation marker Thiobarbituric Acid Reactive Substances (TBARS), and decreased Cu,
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Zn-Superoxide Dismutase activity [81]. In these same insulin resistant rats, vasomotor reactivity was restored by administering a scavenger of superoxide ion [82]. Although the scenario of blunted endothelial function is frequently observed in conditions associated with insulin-resistance and high concentrations of ROS, the underlying mechanisms have not been clarified [83]. Clinical studies do confirm a parallel with the experimental models in animals, i.e., correlation between insulin resistance and serum markers of oxidative stress in diabetic men [84, 85]. Data also suggest that insulin-mediated decreases in serum glucose levels correlates inversely with the severity of decreased endothelium-dependent vasodilation [86, 87]. In clinical settings, drug therapies that increase insulin sensitivity, such as metformin and the thiazolidinediones, improve endotheliumdependent vasodilation [86, 88]. Some clue to the mechanism(s) whereby these agents increase endothelial reactivity is provided by studies in rats, which show that metformin potentiates antioxidant defense and normalizes circulating insulin/glucose levels [89]. Insulin resistance often accompanies obesity. Obesity is associated with high levels of adipokines, such as leptin and tumor necrosis factor, which may play an important role in normal vascular homeostasis, atherogenesis, thrombosis, and the inflammatory response [90–92]. Leptin increases levels of ROS in human endothelium, providing an additional prooxidant stress which, over the long term, could play a significant role in the development of vascular pathology [93]. TNF-α stimulates NF-κB activation, and thus may increase oxidative stress through proinflammatory pathways [94], which exacerbate a variety of different pathological processes. Increased oxidative stress likely leads to increased oxidized low-density lipoprotein, endothelial dysfunction, hypertension and atherogenesis [95].
IV. DIABETIC VASCULAR INJURY — PROTHROMBOTIC ENVIRONMENT Clinical studies in pediatric patients with new onset type 1 diabetes (primarily hyperglycemic patients) reveal a direct correlation between markers of oxidative stress (urinary isoprostanes) with serum markers of platelet activation (thromboxane) in serum, thereby suggesting the existence of prothrombotic state in these young patients [96]. Recent studies in type 2 diabetic patients show that hyperglycemia induces thrombin activation, and that antioxidant administration may counterbalance this effect [97]. The effect of oxidative stress is apparent in studies of platelet function. Superoxide anion formation and the accompanying increase in PKC activity decreases platelet derived NO [59, 98]. Evidence to support the role of oxidative stress in promoting thrombosis in diabetes is provided by an animal study, which showed that treatment with antioxidants decreased the levels of von Willebrand factor and plasma-soluble thrombomodulin [99]. This result suggests that administration of antioxidants may ameliorate the risk of thromboembolism in diabetes.
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V. CLINICAL MANIFESTATIONS OF DIABETIC ANGIOPATHY While the risk of dying from acute complications of diabetes (sepsis, dehydration) has been reduced, the majority of patients with diabetes suffer from increased mortality and morbidity due to the vascular complications that develop within a variety of organ systems. Most vascular complications of diabetes mellitus are generally categorized as either microvascular or macrovascular problems; however, many patients with vascular disease have both kinds of vasculopathies, although to varying degrees [100]. Major risk factors for the progression of microangiopathy include poor glycemic control, a prolonged history of diabetes, and hypertension [101]. Those for macroangiopathy are aging, obesity, abnormal lipid metabolism, hypertension, and smoking [102].
A. MICROVASCULAR COMPLICATIONS Microvascular complications of diabetes are related to the age of onset and duration of diabetes and to metabolic control. Evidence to support a primary role of hyperglycemia in the development of microvascular complications is provided by a direct relationship between elevated levels of glycosylated hemoglobin (HbA1c) and microvascular complications in patients with both type 1 and type 2 diabetes [103]. Microvascular angiopathy includes nephropathy, which is the leading cause of kidney failure; diabetic microvascular retinopathy is responsible for the majority of new cases of adult blindness [103, 104]. 1. Retinopathy The retinal microangiopathy caused by diabetes leads to ischemic retinopathy with sight-threatening neovascularization when a critical number of capillaries become nonperfused and obliterated [105]. The clinical diagnosis is confirmed using flourescein angiograms, which demonstrate areas of retinal nonperfusion [106]. Histologic characterization of the affected retinas show capillary tubes of basement membranes, devoid of endothelial lining and mural pericytes [105]. Longitudinal studies have shown that this capillary closure is mostly irreversible, but a percentage of capillaries can be recanalized, suggesting the presence of reversible occlusive phenomena [107]. Recent analysis of postmortem tissue has documented significantly greater areas of microthrombosis, likely responsible for retinal hypoperfusion in diabetics versus nondiabetic individuals [108]. 2. Nephropathy Nephropathy, characterized by albuminuria, hypertension, and progressive decline in glomerular filtration rate, develops in 10 percent to 40 percent of diabetic patients [1]. An associated progressive loss of cardiovascular function, largely due to hypertension, leads to mortality in this population. The structural changes occurring in early diabetic nephropathy, characterized by renal hypertrophy and increased microvascular permeability, suggest a causal role for impairment of the distribution of growth factors within
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the renal parenchyma [109]. Microalbuminuria is thought to reflect a more generalized vascular process that affects the glomeruli, retina, and intimal of large vessels simultaneously. Patients with microalbuminuria show increased endothelial vasoconstrictor activity, [110] decreased vascular permeability to macromolecules [111], and loss of anticoagulant [112] and profibrinolytic properties [113].
B. MACROVASCULAR COMPLICATIONS Diabetic macrovascular disease is frequently manifest as coronary-artery disease, stroke, and atherosclerotic peripheral vascular-occlusive disease. 1. Coronary Disease Findings from the United Kingdom Prospective Diabetes Study suggest that the relative risk of cardiac mortality increases by 25 percent per percentage point of HbA1c [114]. Although only 6 percent to 8 percent of the population is diabetic, patients with diabetes account for 20 percent to 30 percent of acute coronary syndrome and more that 50 percent of cardiovascular deaths [115]. Despite similar infarct size, diabetic patients have a twofold to threefold greater rate of death after myocardial infarction than do nondiabetic individuals, and they are more likely to have congestive heart failure and stroke [116]. Recurrent myocardial ischemia is also more common, with a greater risk for postinfarction angina, and a fivefold greater risk for combined end points of death, myocardial infarction, or readmission for unstable angina at one year [117]. Diabetes eliminates the usual female advantage in risk for death from coronary-artery disease; these patients have a fivefold to eightfold higher death rate than do nondiabetic women [118]. 2. Cerebrovascular The Framingham study found a 2.5-fold incidence of ischemic stroke in diabetic men and a 3.6-fold increase in diabetic women [119]. It is difficult to determine the level of association between diabetes and ischemic stroke, as diabetes is also associated with a twofold higher incidence of hypertension and cardiac disease, along with an increased incidence of asymptomatic carotid artery disease and hyperlipidemia. In a recent analysis of the anatomic, clinical, and outcome of stroke in diabetics versus nondiabetics, investigators have recently determined that diabetic individuals have a lower relative prevalence of intracerebral hemorrhage [120]. Subcortical infarctions, including lacunar strokes, were more frequent in persons with diabetes. In diabetics, stroke was usually associated with large-artery versus small-vessel disease. The functional outcome and severity of stroke, whether hemorrhagic or ischemic in nature, were not significantly different between diabetic and nondiabetic patients. 3. Peripheral Vascular Fifty percent of all nontraumatic, lower-extremity amputation in the U.S. occurs in patients with diabetes, the amputation rate being 15 to 40 times higher than for those
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without diabetes. While the histologic appearance of atherosclerotic occlusive disease is not altered in diabetes, lower-extremity peripheral-vascular disease is more common and progressive in diabetic patients, particularly those who smoke [121]. The clinical pattern of peripheral-vascular disease in diabetic patients is different, in that 65 percent to 75 percent of the patients undergoing femorotibial bypasses have diabetes. Thus, it is not unusual for a diabetic patient to have no occlusive disease down to the popliteal artery, as demonstrated by a strong pulse behind the knee, yet to still have a severely ischemic foot. Even though the tibial arteries are occluded, the arteries in the foot are relatively spared. Controlled studies have failed to demonstrate any small-vessel occlusive disease in the foot associated with macrovascular tibial obstruction in the calf [122, 123]. Patients with diabetes do have a thickened capillary-basement membrane, but the capillary lumen is not narrowed. This may impair nutritional and blood-cell exchange, but does not impede oxygen diffusion [124, 125].
VI. TREATMENT: OXIDATIVE STRESS AND DIABETES While there is a plethora of data implicating a causal role for oxidative stress in the development of diabetic vascular complications, mainstream therapeutic interventions for diabetes have not directly attacked oxidative stress, per se. The primary pharmacologic attack adopted by most clinicians focuses on modulating one side of the equation, i.e., hyperglycemia, dyslipidemia, and insulin resistance[126]. While tight glycemic control clearly reduces the risk of microvascular complications, it does not modulate the incidence of macrovascular complications associated with diabetes [127]. In contrast to glycemic control, numerous studies consistently show that pharmacological interventions directed against dyslipidemia and hypertension can reduce risk of macrovascular complications [128, 129]. Surgical intervention for peripheral vascular complications of diabetes center on improvement in blood flow, using minimally invasive-endovascular and open-arterial bypass [130–132], without concomitant attention to oxidative stress [133]. Despite these aggressive drug and physiologically based therapy approaches to directly combat oxidative stress, they have not gained universal acceptance or implementation. It has been established that there is a direct relationship between antioxidant depletion, oxidative stress, glycemic control, and the development of complications in a controlled population of patients with type 2 diabetes [134]. There have been a number of human studies to address antioxidant treatment as it relates primarily to cardiovascular complications. Epidemiological studies have shown that high dietary intake of vitamin E, but not vitamin C or β-carotene, is associated with reduction in the risk of developing cardiovascular disease [135–137]. However, clinical trials with vitamin E failed to show consistent reduction in the risk of developing cardiovascular effects [14, 138] With regard to cardiovascular complications of diabetes, the only micronutrient antioxidants that have been studied in some detail are α-tocopherol (vitamin E) and ascorbic acid (vitamin C). Vitamin E supplementation reduces oxidative stress in vitro and in vivo by decreasing lipid peroxidation and LDL-oxidative susceptibility, and thus may slow the progression of atherosclerosis [139]. Four studies have shown that vitamin E
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significantly decreased LDL oxidation in type 2 diabetics [140–142]. In type 1 diabetic subjects, a high dose of vitamin E normalized retinal blood flow and hyperfiltration [143]. A combination of vitamins E and C resulted in a significant reduction in urinary albumin-excretion rates, thereby indicating a decrease in vascular nephropathy [144]. A placebo-controlled randomized study, where 42 percent of the patients were diabetic and had dialysis-dependent renal failure, demonstrated a 54 percent reduction in myocardial infarction (primary end point) associated with vitamin E therapy [145]. An eight-week course of vitamin E therapy in patients with type 2 diabetes was associated with a significant improvement in brachial-artery reactivity and decreased plasma markers of oxidative stress when compared to placebo [146]. Multifactorial therapies (antioxidants, low-fat diet, exercise, smoking cessation) for diabetes mellitus were recently compared to conventional treatments in a randomized controlled trial [147]. This target-driven, long-term trial aimed at multiple risk factors in patients with type 2 diabetes, and microalbuminuria reduced the risk of cardiovascular and microvascular events by about 50 percent. The success of this kind of clinical trial may be further improved if the approach to oxidative stress is expanded by the use of interconnected micronutrient- and enzymatic-defense systems [14]. Ascorbic acid is a potent, water-soluble antioxidant, which has not been extensively studied in diabetic patients. Several studies have documented that high doses of vitamin C are effective in improving vasodilation in smokers, nonsmokers, and hypertensive and diabetic patients [148]. Some of the conventional medications used to treat dyslipidemia, insulin resistance, and hypertension have antioxidant effects that were prominent in clinical experiments, such as ACE inhibitors, angiotensin II type 1 receptor blocker [149–151], and thiazolidinediones [152], which have been shown to have strong intracellular antioxidant activity. However, there is some controversy about the role of calcium channel blockers in reducing oxidative stress in a clinical setting [153]. Statins have been shown to have antioxidant properties in clinical studies [154], whereas there was no evidence to support its antioxidant potential in vitro [155]. This latter observation emphasizes the need to evaluate alternate explanations for the clinical efficacy of a number of drugs destined for clinical use in diabetic patients.
VII. SUMMARY As the incidence of diabetes reaches pandemic proportions, therapeutic interventions that target all components of this complex disease, particularly oxidative stress, will be needed to decrease the devastating impact of vascular complications on society.
ACKNOWLEDGMENTS The authors acknowledge support from the American Diabetes Association Research Council and the Department of Surgery, Division of Vascular and Endovascular Surgery, Massachusetts General Hospital, during the completion of this work.
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Oxidative Injury in Diabetic Neuropathy James W. Russell, M.D., M.Sc. and Alexander J. Kaminsky, M.D.
CONTENTS I. Introduction................................................................................................381 II. Overview of Mechanisms of Diabetic Injury in the Peripheral Nervous System (PNS)..............................................................................382 III. NO and Nitrosative Injury in the PNS......................................................384 IV. Glucose-Induced Oxidative Stress in DRG Neurons................................385 V. Uncoupling Proteins and Oxidative Injury ...............................................385 VI. Targeting of Oxidative Injury with Antioxidant Therapies ......................386 A. α-Lipoic Acid ....................................................................................386 B. Vitamins.............................................................................................387 C. Aldose Reductase Inhibitors (ARIs) .................................................387 D. Growth Factors ..................................................................................387 E. Other Potential Therapies that Reduce Oxidative Injury .................388 VII. Summary ....................................................................................................390 Acknowledgments..................................................................................................390 References..............................................................................................................391
I. INTRODUCTION Clinical studies in both type 1 and 2 diabetes indicate that chronic hyperglycemia is implicated in the pathogenesis of both somatic and autonomic diabetic neuropathy (1–6). The Diabetes Control and Complications Trial (DCCT) showed that improved glycemic control can reduce the rate of both somatic and autonomic neuropathy in type 1 diabetes (7, 8), while similar effects are observed in type 2 diabetes (9). Recent interest has focused on the association between early impaired glucose regulation (impaired glucose tolerance [IGT] and impaired fasting glucose [IFG]) and diabetic microvascular and macrovascular complications. However, even optimal glycemic control cannot completely prevent the development of neuropathy, so alternative forms of therapy are required. Recent evidence implicates induction of reactive-oxygen species (ROS) in neuronal cytotoxicity, both in vitro and in vivo (10–14). 381
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II. OVERVIEW OF MECHANISMS OF DIABETIC INJURY IN THE PERIPHERAL NERVOUS SYSTEM (PNS) Diabetic complications are hypothesized to result from alterations in four main signaling pathways: 1) the aldose reductase; 2) advanced glycation end product; 3) reactive-oxygen intermediates; and 4) the protein kinase C (15–18). These effects are believed to be due primarily to systemic hyperglycemia (19) caused either by reduced insulin secretion (type 1 diabetes) or insulin resistance (type 2). The interaction of these four important signaling pathways and effects of other critical cellular responses are outlined in Figure 21.1. This review of diabetic neuropathy will focus on the role of oxidative stress in neuronal-, axonal-, and Schwann-cell injury and the potential therapies that are currently being explored. Hyperglycemia-induced increases in the production of superoxides (O2-) via increased flux through the electron-transport chain may be responsible for most of the key features of oxidative stress (20). In cell culture models of hyperglycemia, inhibition of O2- formation prevents glucose-induced formation of advanced glycation end products (AGEs) and activation of protein kinase C (21). O2- can also react with nitric oxide (NO) to form peroxynitrite (ONOO-), which can damage intracellular lipids and proteins, resulting in lipid peroxidation, DNA fragmentation, and cell death. Hyperglycemia
Oxidative Phosphorylation
Glycoxidation
Reactive Oxygen Species
AGE’s
Activation of Signaling Molecules: Impaired Antioxidant Defense Oxidative Injury
Protein Kinase C Mitogen Activated Protein Kinase Nuclear Factor κ B
Reduced NADPH Oxidase Altered Gene Expression
Neuronal Cell Death
FIGURE 21.1 Known and putative mechanisms leading to cellular injury in the peripheral nervous system. In addition to direct induction of oxidative injury, diabetes can result in glycoxidation with formation of advanced glycation end products (AGEs). Formation of AGEs can further lead to oxidative injury and reduction of NADP oxidase. Although these oxidative pathways are important in nonneuronal complications, their role in the pathogenesis of diabetic neuropathy are still putative. Many of the pathways described in this model interact and can result in oxidative injury.
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The mechanisms of oxidative stress in neurons are reviewed in Figure 21.2. In diabetic patients, neurons and their peripheral processes are particularly sensitive to oxidative stress and cellular injury (3, 4). Dorsal-root ganglia (DRG) neurons undergo apoptosis in both in vivo and in vitro models of diabetic neuropathy (22–25), and apoptosis can be prevented by the inhibition of O2-. (23). Mechanisms of cellularprogrammed cell death (PCD) are reviewed in Figure 21.3.
FIGURE 21.2 Mechanisms for oxidative damage under diabetic conditions within the mitochondrion. Under diabetic conditions, incomplete electron transfer through complexes I, II, II, and IV generates superoxides. Superoxide (O2–) can facilitate the production of other radical species, for example, hydrogen peroxide (H202) or hydroxyl radicals (OH–). manganese superoxide Dismutase (MnSOD) converts superoxide to H202, which is then converted to water either though catalase or glutathione peroxidase (GPX). Reduced glutathione (GSH) is regenerated from glutathione disulfide (GSSG) through glutathione reductase (GR) and nicotinamide adeninedinucleotide phosphate (NADPH). Nitric oxide synthase (NOS) with its cofactor tetrahydrobiopterin (THB) generates nitric oxide (NO), which couples with superoxide to create peroxynitrite (ONOO–). Peroxynitrite, superoxide, and hydroxyl radicals lead to a destabilization of the inner mitochondrial membrane, with resultant release of cytochrome c (Cyt C) from the inner mitochondrial membrane space into the cytosol. Cytochrome c release leads to activation of the programmed cell death (PCD) pathway (see Figure 21.3). Uncoupling of oxidative phosphorylation in the neuronal mitochondrion by uncoupling proteins (UCP2 or UCP3) can restore the proton equilibrium under diabetic conditions and prevent the generation of reactive-oxygen species.
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FIGURE 21.3 Model for programmed cell death pathways in neurons. Following inner mitochondrial-membrane depolarization, cytochrome c (Cyt C) is released and combines with cell death pathway components to form the apoptosome complex, consisting of caspase-9 and apoptosis protease-activating factor 1 (Apaf-1). The formation of this complex leads to cleavage of caspase-9 and downstream activation of effector caspases 3, 6, and 7. The activation of the effector caspases is blocked by inhibitor of apoptosis proteins (IAPs). The IAPs in turn may be inhibited by second mitochondrial activator of caspase (SMAC/DIABLO) that is released by apoptotic stimulation of the mitochondria. The effector caspases damage structural proteins, inhibit the DNA repair cycle, DNA transcription and translation, and cleave poly-ADP-ribose-polymerase (PARP). Cleavage of PARP facilitates the degradation of DNA. apoptosis inducing factor (AIF) is released from the mitochondrion with induction of apoptosis. AIF translocates to the nucleus, causing DNA fragmentation. Genes that regulate apoptosis (both activators and inhibitors) are listed.
III. NO AND NITROSATIVE INJURY IN THE PNS NO is one potential stimulus for O2- generation (26), and evidence of increased production of reactive-nitrogen species (NO and ONOO-), coupled with evidence of PCD, implicate nitrosative injury in models of diabetic neuropathy (27–29). Therefore, diabetic DRG neuronal and PCO may involve the formation of ONOO- in the presence of increased concentrations of O2- and NO. NO is formed by activation of nitric-oxide synthase (NOS), which catalyzes the oxidation of L-arginine to NO and citrulline (30). Neuronal NOS (nNOS) is the primary constitutively active isoform in neurons. NO may have both neuroprotective and neurotoxic roles, depending on other modifying pathways. NO-induced toxicity
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depends in general on the degree of local generation of NO and O2- (31, 32). ONOOcan inactivate electron-transfer complexes I, II, and ATPase (33), reversibly nitrolylate- or irreversibly nitrate-critical proteins and enzymes, including manganese superoxide dismutase, cytochrome c, aconitase, and the voltage-dependent anion channel (34). In combination, these effects of NO increase oxidative stress and nitrosative stress through the overproduction of S-nitrosylated proteins (35).
IV. GLUCOSE-INDUCED OXIDATIVE STRESS IN DRG NEURONS Elevated levels of glucose are associated with generation of ROS and PCD, both in vitro and in vivo (4, 22, 23, 25). High glucose causes an acute rise in ROS production, a reduction in the ADP:ATP ratio, and rapid caspase 3 activation (22, 23). ROS production is accompanied by the swelling of mitochondria and a loss of the inner mitochondrial-membrane potential, which can be prevented by inhibitors of the mitochondrial electron-transport chain, e.g., Mt complex II or III inhibitors, for example, TTFA or myxothiazole (13, 23). Although inhibition of excess electron transfer between the complexes may reduce oxidative stress, another mechanism is to stabilize the inner mitochondrial-membrane potential. This may be achieved by preventing depolarization of the membrane by blocking the adenine nucleotide translocase/voltage-dependent anion channel with either bongkrekic acid or cyclosporine (23). However, a more physiological response is by regulating key mitochondrial proteins that control the membrane potential.
V. UNCOUPLING PROTEINS AND OXIDATIVE INJURY Changes in the Mt inner-membrane potential are associated with induction of ROS (16, 23, 36), opening of the adenine nucleotide translocase/voltage-dependent anion channel, and Mt swelling that disrupts the integrity of the outer membrane (22, 37, 38). Integral Mt proteins, the uncoupling proteins (UCPs), for example, UCP2 and UCP3, may regulate ROS generation during oxidative phosphorylation by facilitating proton leak across the Mt membrane, thus limiting a high Mt inner-membrane potential and reducing the generation of electron-rich intermediates capable of generating superoxide radicals (Figure 21.2). Because UCPs are associated with the regulation of energy metabolism, their role in diabetes has received considerable attention. Mapping of the UCP2 gene to loci associated with obesity and hyperinsulinemia led to investigations into the role of this UCP in weight regulation and energy balance (39, 40). It has been shown that UCP2 may be increased in pancreatic β-cells in the prediabetic state and that this relates to impaired glucose-induced insulin secretion (41). One mechanism for increased UCP2 in prediabetes is the presence of a polymorphism in the UCP2 promoter that leads to increased expression of the gene (42). Although UCP2 overexpression in β-cells results in hyperglycemia, reduced expression of UCP3 is observed in the muscle in type 2 diabetes (43) and in DRG from streptozotocin-induced diabetic rats (36), and UCP2 is decreased in
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ZDF diabetic rats (44). In contrast, overexpression of UCP1, 2, or 3 reduces oxidative stress and induction of downstream PCD pathways (Figure 21.3) in DRG neurons. Thus, tissue location of the UCPs is critical, UCPs in neurons are associated with a reduction in oxidative injury, and therapeutic regimens designed to up-regulate UCPs may prevent oxidative injury.
VI. TARGETING OF OXIDATIVE INJURY WITH ANTIOXIDANT THERAPIES Understanding specific mechanisms of oxidative injury as described above are important, because they permit targeting of individual or groups of oxidative-stress pathways that are important in diabetic oxidative-neuronal injury.
A. α-LIPOIC ACID α-Lipoic acid is one of the most extensively studied antioxidants (45, 46). α-Lipoic acid reduces oxidative stress in diabetic neuropathy (45), reduces pathological fluxes of NO production (47), decreases ONOO--mediated damage (48), and prevents reduced endothelial NO production induced by oxidative stress (49). As a result of each of these effects, α-lipoic acid ameliorates diabetic-induced reduction in peripheral nerve blood flow seen in microvascular peripheral-nerve injury and, therefore, improves diabetic neuropathy. α-Lipoic acid in vivo is reduced to active dihydrolipoate, which is able to regenerate other antioxidants, such as vitamin C, vitamin E, and reduced glutathione (GSH), through redox cycling. In rats, α-lipoic acid prevents the development of nerve-conduction deficits during six weeks of diabetes following streptozotocin (STZ) treatment (50), although it may be more effective at correcting deficits in the peripheral sensory-nerve action potential than in motor-nerve conduction responses (14, 45). In addition, α-lipoic acid improves endoneurial blood flow, increases NAD+:NADH ratios, reduces GSH depletion, and increases ATPase activity (14). There is also evidence that α-lipoic acid reduces oxidative injury in diabetic neurons by blocking activation of caspases (51) and maintaining normal nervegrowth factor levels in diabetic neuropathy (52). Multiple clinical trials with α-lipoic acid have been completed using a variety of study designs, routes of administration, and sample sizes (53, 54). In one of the larger, multicenter, randomized, double-blind, placebo-controlled studies, ALADIN III, there was a small but significant improvement in the Neuropathy Impairment Score in αlipoic-acid treated patients, but no significant improvement in the Total Symptom Score. Similar results were obtained in the Deutsche Kardiale Autonome Neuropathie (DEKAN) Study, where there were small improvements in components of the cardiac autonomic spectral analysis (55). Care must be taken in interpreting the results of these smaller studies. A larger phase III study (NATHAN I) is currently being completed. However, the following observations can be made: 1) both neuropathic symptoms and deficits are improved by α-lipoic-acid treatment; 2) oral therapy is effective in reducing the symptoms and deficits due to diabetic neuropathy in the short term (at six months); 3) there is a favorable adverse effect profile with α-lipoic acid; and 4) α-lipoic acid may be effective in treating both somatic and autonomic neuropathies.
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B. VITAMINS Dietary vitamins A, C, and E directly reduce systemic ROS levels. Vitamin C increases NO production by endothelial cells via the stabilization of tetrahydrobiopterin (56–58), decreases plasma free radicals, increases cellular GSH levels (59), and improves vasodilation (60). Reduced levels of vitamin E are associated with increased production of aldehydes and peroxides. Vitamin E is a component of the total peroxyl-radical-trapping antioxidant and protects lipid membranes against oxidative injury (61, 62). Vitamin E levels vary in diabetes, and may not correlate with the severity of the complication (63, 64). Although vitamin E may play a role in ameliorating other complications of diabetes, its role in diabetic neuropathy is unclear.
C. ALDOSE REDUCTASE INHIBITORS (ARIS) Aldose reductase (AR) acts on the first step of the polyol metabolic pathway to catalyze the reduction of glucose to sorbitol with reduced nicotinamide adenine dinucleotide phosphate (NADPH) as a coenzyme. Increased activity of polyol pathway in diabetic patients is closely related to the onset and progression of complications, and ARIs may be potential pharmacotherapeutic agents for the treatment of diabetic complications. AR inhibition reduces ROS-mediated endothelial injury caused by activation of the polyol pathway (65). In the diabetic AR overexpressing mouse model, there is an increase in sorbitol and fructose levels in peripheral nerve and evidence of neuropathy that is more severe than in diabetic wild type controls (66). Furthermore, the severity of nerve conduction abnormalities in the AR-overexpressing animals correlates with loss of large myelinated fibers, indicating the presence of a more severe neuropathy. These findings correspond to evidence that ARIs ameliorate experimental diabetic neuropathy (67–70). In animal and small-scale human studies, there is evidence that ARIs ameliorate experimental diabetic neuropathy (71, 72), however, the value of ARIs in large clinical studies is far less convincing. Most large phase III human trials have failed to show significant benefit or have been discontinued because of concern over unacceptable side effects (73).
D. GROWTH FACTORS In animal models of diabetes, levels of several growth factors may be reduced, and treatment with growth factors may improve neuropathy. These factors include nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and insulinlike growth factor-I (IGF-I). These factors have been observed in models of diabetes, and the administration of these factors protects against diabetic neuropathy in animals (22, 74, 75). Impaired trophic support increases oxidative injury (76), whereas NGF may prevent neuronal oxidative stress by increasing intracellular concentrations of GSH and catalase in neurons (77). Administration of NGF in experimental hyperglycemia regulates changes in the inner mitochondrial-membrane potential, blocks depolarization, and induction of apoptosis in Schwann cells, probably through regulation of the p75 neurotropin receptor (p75NTR) (4).
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IGF-I signaling, predominantly through the phosphatidylinositol 3-kinase-dependent pathway, may also prevent glucose-induced down-regulation of Bcl-2, inner mitochondrial-membrane depolarization, and mitochondrial swelling (78). Other growth factors, such as BDNF, may improve glycemic control and may have a potential role in the treatment and prevention of the complications of diabetes, including diabetic neuropathy (79). Despite promising results in experimental diabetic neuropathy, growth factors have not shown a significant benefit in a clinical setting. NGF primarily supports the survival of small fiber-sensory neurons that mediate pain and temperature sensation and would be expected to be of benefit for diabetic patients with early diabetic neuropathy. Although initial promising results were obtained in a phase II study of recombinant human NGF (rhNGF) in preventing progression of diabetic neuropathy (80), a larger phase III study showed no measurable benefit (81). Although NGF was well-tolerated at the doses selected for this study, it is likely that the study failed to achieve concentrations found to be therapeutic in prior animal studies. BDNF has significant neurotrophic effects (82, 83), enhances neurite outgrowth, and supports DRG neuronal survival. Systemic administration of BDNF also decreases nonfasted blood glucose in obese, noninsulin-dependent diabetic C57BLKS-Leprdb/leprdb (db/db) mice, and this effect can persist for weeks after cessation of BDNF treatment (79). These preclinical observations would suggest an important role in the treatment of diabetic neuropathy; however, a phase II trial of human recombinant BDNF showed only a small improvement in cold perception, but not in other quantitative electrophysiology or in intraepidermal nerve-fiber measurements (84). IGF-I activity is reduced in both clinical and experimental diabetes. Sensory neurons and supporting Schwann cells from diabetic rodents express lowered amounts of IGF-I and IGF-I receptor (85) and are susceptible to oxidative damage and apoptosis (22, 86, 87). Furthermore, there is a decrease in serum IGF-I content (85, 88, 89) and a reduction in IGF-I mRNA in sciatic nerve, liver, kidney, lung, and heart from diabetic animals (85, 90, 91), and IGF-I administration blocks the development of neuropathy in diabetic rats and promotes nerve regeneration (92, 93). In man, IGF-I and IGF-I receptor levels are decreased in diabetic patients with neuropathy, compared to those diabetic patients without neuropathy (94). Despite the potential for IGF-I treatment for human diabetic neuropathy, human clinical trials have not been completed because of a concern that IGF-I may worsen ocular findings in diabetic patients. There were similar concerns with intensive insulin therapy during the DCCT study. However, this study showed that the risk of increased retinopathy was far outweighed by the reduction in complication severity with intensive insulin therapy (7).
E. OTHER POTENTIAL THERAPIES
THAT
REDUCE OXIDATIVE INJURY
Angiotensin-converting enzyme (ACE) inhibitors have an established role in preventing renal microvascular disease, and may also ameliorate peripheral neuropathy by 1) regulating diabetic microvascular function and thus ischemia in the nerve; and 2) reducing endothelial or neuronal oxidative injury. In STZ-induced diabetic
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animals, the ACE inhibitor ramipril reduced renal AGE accumulation and nitrotyrosine levels (95, 96). With another ACE-inhibitor, trandolapril, there was significant improvement in human diabetic peripheral neuropathy (97). There is increasing evidence that the metabotropic glutamate receptors (mGluRs) modulate cellular injury (98–100), although the role of the mGluRs in diabetic neuropathy is presently unknown. The mGluRs are a subfamily of glutamate receptors that are G-protein coupled and linked to second-messenger systems (100, 101). In addition to strong mechanism-driven evidence that GCPII inhibitors and mGluR3 agonists are neuroprotective, there is preclinical data that GCPII inhibitors ameliorate diabetic neuropathy in animal models (102). GCPII inhibition has beneficial effects on hyperalgesia, nerve function, and structural degenerative changes in diabetic neuropathy. The Glutamate carboxypeptidase II (GCP II) inhibitor 2-(phosphonomethyl)pentanedioic acid (2-PMPA) is protective against glucose-induced programmed cell death (PCD) and neurite degeneration in DRG neurons in a cell-culture model of diabetic neuropathy (103). In this model, inhibition of neuronal PCD is mediated by the Group II metabotropic glutamate receptor, mGluR3. 2-PMPA neuroprotection is completely reversed by the mGluR3 antagonist, (S)-α-ethylglutamic acid (EGLU), but not by Group I and III mGluR inhibitors. Other mGluR3 agonists, for example, (2R, 4R)-4-aminopyrrolidine-2, 4-dicarboxylate (APDC), and Nacetyl-aspartyl-glutamate (NAAG), provide protection to neurons exposed to high glucose conditions, consistent with the concept that 2-PMPA neuroprotection is mediated by increased NAAG activity. Furthermore, the direct mGluR3 agonist, APDC, prevents induction of ROS (104). Together, these findings are consistent with an emerging concept that mGluRs may protect against cellular injury by regulating oxidative stress in the neuron and may represent a novel mechanism to prevent oxidative injury in diabetic neuropathy. Diabetes is also associated with glycation of proteins, for example, AGEs. AGEs may modify a wide variety of cellular proteins, and AGE formation augments ROS generation by a process known as auto-oxidative glycosylation (Figure 21.1). During the normal course of aging, AGEs irreversibly modify proteins in a process called the Maillard reaction, leading to tissue browning. One hypothesis is that diabetic neuropathy may be a form of premature aging of the nervous system. AGEs bind to a cell-surface receptor (RAGE) that activates several downstream signaling pathways, including protein kinase C (PKC) and the transcription factor NFκB. NFκB is associated with endothelial dysfunction, impaired nerve blood flow, and ischemia (16). PKC is a peripheral membrane protein through which many signal-transduction cascades are mediated. Activation of PKC isoforms (α, β, δ, ε, ξ) are reported in some, but not all, tissues prone to diabetic complications (105). PKC phosphorylates NADPH oxidase, stimulating translocation to the membrane and subsequent formation of superoxide radicals (106, 107) and induces oxidative stress. In addition, an increase in glycolytic or aldose reductase pathway activity promotes de novo formation of diacylglycerol (DAG) synthesis by glycerol-3-phosphate following increased levels of intracellular glyceraldehyde-3-phosphate. In turn, chronic elevation of DAG increases PKC activity. PKC promotes vasoconstriction and ischemia, increased permeability, nitric-oxide dysregulation, and increased leukocyte adhesion, further inducing diabetic neuropathy. High-affinity PKCβ
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inhibitors, such as ruboxistaurin mesylate, are being evaluated for treatment of human diabetic neuropathy.
VII. SUMMARY There is increasing evidence of oxidative stress within the PNS. Potentially, oxidative stress can directly injure both DRG neurons and also axons. Modulation of the NO system may have detrimental effects on endothelial function and neuronal survival, so O2- may be a good target for therapeutic intervention. ROS alter plasma and mitochondrial-membrane structure, alter protein function, and interfere with signaling pathways. There are several potential sources of ROS. An important ROS generator in the PNS is the mitochondrion, which produces superoxide from the partial reduction of oxygen. A result of this mitochondrial oxidative stress is loss of the normal mitochondrial-membrane potential, release of cytochrome c from the intermitochondrial membrane space, and activation of key neuronal and Schwann cell PCD pathways. ROS deplete antioxidant defenses, such as antioxidant vitamins, glutathione, and antioxidant enzyme activity, for example, GSH peroxidase, reductase, catalase, and superoxide dismutase. In addition, diabetes stimulates aldose reductase activity and depletes NADPH, an important cofactor of GSH reductase. NO formation by nNOS and the subsequent combination with O2- to form ONOOmay be responsible for widespread endothelial and neuronal cell damage, and reduction in vasoreactivity seen in patients with diabetic neuropathy. If oxidative buffering capacity is exceeded, cellular lipids and proteins are oxidized to form reactive molecules, such as malondialdehyde and 4-hydroxynonenal. These products react with protein and DNA, change their function, and may induce genetic mutations. AGE formation, ROS, and protein oxidation, can alter protein structure and activate signal-transduction pathways through PKC and NFκB. Currently, antioxidant approaches to the treatment of diabetic neuropathy offer promise, as they have the ability to inhibit the formation of mitochondrial and other sources of ROS, prevent oxidative cellular injury, maintain endoneurial vascular reactivity, prevent formation of AGEs, and prevent upregulation of neurotoxic signaling pathways. However, many compounds with antioxidant properties are not specific in their mechanism of action. Future studies should focus on developing approaches to more specifically target oxidation pathways and thus prevent diabetic neuropathy.
ACKNOWLEDGMENTS We would like to thank Ms. Denice Janus for secretarial support. This work was supported in part by NIH NS42056, The Juvenile Diabetes Research Foundation Center for the Study of Complications in Diabetes (JDRF), Office of Research Development (Medical Research Service), Department of Veterans Affairs.
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69. Sima, AAF, Stevens, MJ, Feldman, EL, Cherian, PV, and Greene, DA, Animal models as tools for the testing of preventive and therapeutic measures in diabetic neuropathy, in Lessons from Animal Diabetes IV, Shafrir, E, Ed., Smith-Gordon, London, 1993, p. 177–191. 70. Cameron, NE, Cotter, MA, Basso, M, and Hohman, TC, Comparison of the effects of inhibitors of aldose reductase and sorbitol dehydrogenase on neurovascular function, nerve conduction and tissue polyol pathway metabolites in streptozotocin-diabetic rats, Diabetologia, 40:271–281, 1997. 71. Greene, DA, Arezzo, JC, and Brown, MB, Effect of aldose reductase inhibition on nerve conduction and morphometry in diabetic neuropathy. Zenarestat Study Group, Neurology, 53:580–591 1999. 72. Hotta, N, Toyota, T, Matsuoka, K, Shigeta ,Y, Kikkawa, R, Kaneko, T, et al., Clinical efficacy of fidarestat, a novel aldose reductase inhibitor, for diabetic peripheral neuropathy: a 52-week multicenter placebo-controlled double-blind parallel group study, Diabet. Care, 24:1776–1782, 2001. 73. Feldman, EL, Stevens, MJ, Russel, JW, and Greene, DA, Diabetic neuropathy, in Principles and Practice of Endocrinology and Metabolism, Becker, KL, Ed., Lippincott Williams & Wilkins, Philadelphia, 2001, p. 1391–1399. 74. Hellweg, R and Hartung, H-D, Endogenous levels of nerve growth factor (NGF) are altered in experimental diabetes mellitus: A possible role for NGF in the pathogenesis of diabetic neuropathy, J. Neurosci. Res., 26:258–267, 1990. 75. Schmid, RE, Dorsey, DA, Beaudet, LN, Parvin, CA, and Escandon, E, Effect of NGF and neurotrophin-3 treatment on experimental diabetic autonomic neuropathy, J. Neuropathol. Exp. Neurol., 60:263–273, 2001. 76. Park, DS, Morris, EJ, Stefanis, L, Troy, CM, Shelanski, ML, Geller, HM, et al., Multiple pathways of neuronal death induced by DNA-damaging agents, NGF deprivation, and oxidative stress, J. Neurosci., 18:830–840, 1998. 77. Sampath, D, Jackson, GR, Werrbach-Perez, K, and Perez-Polo, JR, Effects of nerve growth factor on glutathione peroxidase and catalase in PC12 cells, J. Neurochem., 62:2476–2479, 1994. 78. Leinninger, GM, Russell, JW, van Golen, CM, Berent, A, and Feldman, EL, Insulinlike growth factor-I regulates glucose-induced mitochondrial depolarization and apoptosis in human neuroblastoma, Cell Death Differ., 11:885–896, 2004. 79. Tonra, JR, Ono, M, Liu, X, Garcia, K, Jackson, C, Yancopoulos, GD, et al., Brainderived neurotrophic factor improves blood glucose control and alleviates fasting hyperglycemia in C57BLKS-Lepr(db)/lepr(db) mice, Diabetes, 48:588–594, 1999. 80. Apfel, SC, Kessler, JA, Adornato, BT, Litchy, WJ, Sanders, C, and Rask, CA, Recombinant human nerve growth factor in the treatment of diabetic polyneuropathy. NGF Study Group, Neurology, 51:695–702, 1998. 81. Apfel, SC, Schwartz, S, Adornato, BT, Freeman, R, Biton, V, Rendell, M, et al., Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: A randomized controlled trial (in process citation), JAMA, 284:2215–2221, 2000. 82. Skup, MH, BDNF and NT-3 widen the scope of neurotrophin activity: pharmacological implications, Acta. Neurobiol. Exp., 54:81–94, 1994. 83. Wozniak, W, Brain-derived neurotrophic factor (BDNF): role in neuronal development and survival, Folia. Morphol., 52:173–181, 1993.
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84. Wellmer, A, Misra, VP, Sharief, MK, Kopelman, PG, and Anand, P, A double-blind placebo-controlled clinical trial of recombinant human brain-derived neurotrophic factor (rhBDNF) in diabetic polyneuropathy, J. Peripher. Nerv. Syst., 6(4):204–210, 2001. 85. Yang, H, Scheff, AJ, and Schalch, DS, Effects of streptozotocin-induced diabetes mellitus on growth and hepatic insulin-like growth factor I gene expression in the rat, Metabolism, 39(3):295–301, 1990. 86. Delaney, CL and Feldman, EL, Insulin-like growth factor-I and apoptosis in glial cell biology, The Neurosci., 6:39–47, 2000. 87. Delaney, CL, Cheng, H-L, and Feldman, EL, Insulin-like growth factor-I prevents caspase mediated apoptosis in Schwann cells, J. Neurobiol., 41:540–548, 1999. 88. Ekstrom, AR, Kanje, M, and Skottner, A, Nerve regeneration and serum levels of insulin-like growth factor-I in rats with streptozotocin-induced insulin deficiency, Brain Res., 496:141–147, 1989. 89. Graubert, MD, Goldstein, S, and Phillips, LS, Nutrition and somatomedin: XXVII. Total and free IGF-I and IGF binding proteins in rats with streptozocin-induced diabetes, Diabetes, 40:959–965, 1991. 90. Bornfeldt, KE, Arnqvist, HJ, Enberg, B, Mathews, LS, and Norstedt, G, Regulation of insulin-like growth factor-I and growth hormone receptor gene expression by diabetes and nutritional state in rat tissues, J. Endocrinol., 122:651–656, 1989. 91. Luo, J and Murphy, LJ, Differential expression of insulin-like growth factor-I and insulin-like growth factor binding protein-1 in the diabetic rat, Mol. Cell Biochem., 103:41–50, 1991. 92. Zhuang, HX, Synder, CK, Pu, SF, and Ishii, DN, Insulin-like growth factors reverse or arrest diabetic neuropathy: Effects on hyperalgesia and impaired nerve regeneration in rats, Exp. Neurol., 140:198–205, 1996. 93. Schmidt, RE, Dorsey, DA, Beaudet, LN, Plurad, SB, Parvin, CA, and Miller, MS, Insulin-like growth factor I reverses experimental diabetic autonomic neuropathy, Am. J. Pathol., 155:1651–1660, 1999. 94. Migdalis, IN, Kalogeropoulou, K, Kalantzis, L, Nounopoulos, C, Bouloukos, A, and Samartzis, M, Insulin-like growth factor-I and IGF-I receptors in diabetic patients with neuropathy, Diabet, Med., 12:823–827, 1995. 95. Forbes, JM, Cooper, ME, Thallas, V, Burns, WC, Thomas, MC, Brammar, GC, et al., Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy, Diabetes, (11):3274–3282, 2002. 96. De Cavanagh, EM, Inserra, F, Toblli, J, Stella, I, Fraga, CG, and Ferder, L, Enalapril attenuates oxidative stress in diabetic rats, Hypertension, 38(5):1130–1136, 2001. 97. Malik, RA, Williamson, S, Abbott, C, Carrington, AL, Iqbal, J, Schady, W, et al., Effect of angiotensin-converting-enzyme (ACE) inhibitor trandolapril on human diabetic neuropathy: randomised double-blind controlled trial, Lancet, 352(9145):1978–1981, 1998. 98. Flor, PJ, Battaglia, G, Nicoletti, F, Gasparini, F, and Bruno, V, Neuroprotective activity of metabotropic glutamate receptor ligands, Adv. Exp. Med. Biol., 513:197–223, 2002. 99. Vincent, AM and Maiese, K, The metabotropic glutamate system promotes neuronal survival through distinct pathways of programmed cell death, Exp. Neurol., 166:65–82, 2000. 100. De Blasi, A, Conn, PJ, Pin, J, and Nicoletti, F, Molecular determinants of metabotropic glutamate receptor signaling, Trends Pharmacol. Sci., 22(3):114–120, 2001.
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Diabetic Nephropathy Carlton J. Young, M.D.
CONTENTS I. II. III. IV.
Introduction................................................................................................399 Oxidative Stress and Hyperglycemia ........................................................401 Advanced Glycation End Products (AGE) ...............................................404 Medical Nutrition Therapy ........................................................................409 A. Sorbitol and Taurine..........................................................................410 B. Selenium, Thiamine, Vitamin C, Glutathione...................................412 V. Conclusions................................................................................................414 Acknowledgments..................................................................................................416 References..............................................................................................................416
I. INTRODUCTION Diabetic nephropathy (DN) is a significant complication of diabetes mellitus (DM). Unfortunately, the incidence and prevalence of DM has risen. In 1994, there were 120 million diabetics worldwide. By 2010, there will be upwards of 240 million diabetics (1). Diabetic Nephropathy is a leading cause of end-stage renal disease (ESRD) in Western societies. In American and European adults, diabetics constitute more than 33 percent of all patients entering renal support programs (2, 3). Of these, 50 percent to 60 percent with DN have type 2 DM. Of the two major types of diabetes, type 2 DM is more prevalent (90 percent of cases), but the frequency of developing DN is less than those with type 1 DM (approximately 30 percent to 40 percent of type 1 diabetics develop DN); however, the size of the type 2 population makes it just as important. Unlike type 1 diabetics who have a genetic predisposition to developing DN, the occurrence of type 2 DM appears to be influenced by ethnicity (4). African Americans have four times the risk, and Mexican Americans six times the risk, of Caucasians for developing DN (2, 5, 6). There are conflicting reports as to whether there has been a decline in the incidence of DN (7,8). Nevertheless, studies estimate the prevalence of DN is 5 percent to 10 percent at time of diagnosis for type 2 DM. This is in concert with a prevalence rate of 25 percent to 60 percent at 20 years being linked to racial background (9).
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Caucasians are significantly more likely to be affected by type 1 DM than underrepresented U.S racial minorities. The reasons for ethnic differences in the incidence of renal disease in type 2 are multifactorial, but may be related to a higher incidence of hypertension and DM among the Asian and Afro-Caribbean populations than in the Caucasian population (2). Hypertension in the Caucasian population does not uniformly signal an impending decline in renal function, whereas ethnic minorities have a varied and often more indolent response to hypertension (2). Initially, the glomerular filtration rate (GFR) of these patients is high, but it starts to decline after about five years, with 10–15 years from the onset of overt DN needed to develop ESRD (2). Once DM is manifested, there is an increase in kidney and glomerular volume, with hypertrophic glomeruli showing normal structure (4). After several years of DM, structural changes appear, such as thickening of the glomerular basement membrane and mesangial expansion. (4, 10, 11) One of the earliest manifestations of injury is microalbuminuria. Electron microscopic studies of type 1 and type 2 DM patients demonstrate that an increase in the glomerular extracellular matrix (ECM) correlates with the extent of microalbuminuria (12, 13). As DN progresses, alterations in collagen synthesis of the basement membrane, renal interstitium, and arterioles occur. In addition, there is a decrease in basement-membrane-associated heparin sulfate proteoglycan. This negatively charged molecule is an integral component of the glomerular filtration unit (1418). Eventually, GFR decreases and leads to ESRD. More disturbingly, the presence of microalbuminuria indicates a manifold increased risk of developing cardiovascular morbidity and mortality, in addition to being an indicator of extrarenal vasculopathies (19). Clinically, tight glucose and blood-pressure control remain paramount in thwarting the progression of diabetic nephropathy. New insights into the etiology of diabetic reno-vascular pathophysiology have been elucidated. The evolution of thought defining the mechanism of DN will one day lead to more directed therapies, of which dietary manipulation may be of particular value. Many theories have been posited to define the driving forces behind the development of DN. Currently, oxidative stress (OS) has been implicated as the primary causative mechanism that incites a variety of pathophysiologic processes. Reactiveoxygen species (ROS), naturally occurring antioxidant inactivation, lipid peroxidation, advanced glycation end products (AGE), TGF-ß, protein kinase C, and several other pathways have been implicated in the pathogenesis of DN. It appears that all of these perturbations of normal hemostasis begin with elevated glucose levels and the pathophysiologic responses that correct this abnormal state. This chapter will review and summarize the current state of thinking pertaining to DN, as well as discuss dietary and other measures to thwart the progression of this disease. It must be noted that research in this area is dynamic, and any compilation will necessarily be incomplete, given the vast complexity of the effects of hyperglycemia. Nevertheless, great strides have been made in elucidating the many aberrant pathways that make DN a pathophysiological condition of compelling interest to clinicians.
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II. OXIDATIVE STRESS AND HYPERGLYCEMIA Overwhelming evidence supports the contention that oxidative stress is the major mechanism behind the development of DN. Oxidative stress affects numerous pathways, rendering them either inoperative or inciting alternative pathologic pathways that result in the formation of unwanted byproducts. As these byproducts accumulate, they have a detrimental effect on tissues and organ systems. Elucidation of these pathophysiologic mechanisms may hold the key to thwarting the progression of DN through targeted therapies. By identifying aberrant pathways, directed therapies have been somewhat successful in reversing these detrimental effects. Oxidative stress causes cell injury and death. Excess production of oxygen free radicals overwhelms natural antioxidant cellular defense systems. The primary antioxidant enzymes are superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px)/oxidized glutathione reductase (GSSG-RD), and nonenzymatic (glutathione and vitamin E) scavengers (20, 21). In the diabetic state, hyperglycemia causes the normal physiologic milieu to be significantly altered. ROS are manufactured by glucose auto-oxidation, as well as by nonenzymatic protein glycation (22). Vascular endothelium is acutely affected by overlapping pathways that produce advanced glycation products (AGE), activation of protein kinase C (PKC), and the heretofore-mentioned ROS. While ROS have been implicated in the progression of DN, convincing clinical evidence for antioxidant therapy, while abundant in animal models, is still lacking in humans (23). Nevertheless, ROS and their production have become a focal point for numerous investigators. Nonphagocytic NADPH oxidase has been implicated as a major mechanism in the formation of ROS leading to DN. NADPH oxidase was first discovered in neutrophils. Within these cells, millimolar quantities of superoxide (O2-) are produced during phagocytosis (24). NADPH oxidase comprises a membrane-associated cytochrome b558 that is composed of one p22phox (phox = phagocyte oxidase), one gp91phox subunit, and at least four cytosolic subunits (p47phox, p67phox, p40phox, and the small GTPase rac1 or rac2) (24). Nonphagocytic cells, such as fibroblasts, endothelial cells, vascular smoothmuscle cells (VSMC), and renal mesangial, tubular, and other cells possess O2-producing enzymes similar to phagocytic NADPH oxidase. These oxidases are structurally related to, but functionally distinct from, neutrophil oxidase. Interestingly, the greatest proportion of ROS produced via nonphagocytic means appears to be intracellular, compared to extracellular expression, during phagocytosis. It is believed that even low amounts of ROS produced by nonphagocytic pathways may act as secondary messengers to influence redox-sensitive signal transduction, while high levels of intracellular ROS may contribute to oxidative stress (24). Currently, the role of NADPH oxidase in type 1 DM is unclear. However, ROS generation in rats after streptozotocin administration may contribute to islet cell death (25). In an attempt to find a clinical correlation between the diabetic state and OS, Wautier et al. (26) incubated human endothelial cells with red blood cells (RBCs) from type 1 diabetics and normals. He found that normal endothelial cells had their endogenous NADPH oxidase activated by the diabetic RBCs, but there was no
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activation seen in normal controls. He surmised that increased ROS generation was due to the formation of advanced glycation end products on the surface of diabetic RBCs. NADPH oxidase-dependent ROS generation associated with endothelial dysfunction has been shown in animal models as well as diabetic patients (27–29). It is well-known that the kidney is vulnerable to oxidative stress-induced cellular damage. ROS production in renal disease is multifactorial, but the kidney is known to express NADPH oxidase and generate ROS (30-32). Expression of p22phox, p47phox, and p67phox has been reported in renal mesangial cells, and Nox 4 was cloned from the kidney and found to be highly expressed in renal tubular cells (30, 33). Also, many of the NADPH oxidase subunits, in unstimulated cells, are preassembled, functional ROS-generating complexes (34). Normal kidneys produce small amounts of ROS that are easily handled by naturally occurring antioxidants. However, when hemodynamic changes occur, e.g., hypertension, excessive ROS may be produced by dysfunctional renal cells, causing further injury after the antioxidant system is overwhelmed (31). ROS in renal parenchyma are thought to regulate renal medullary blood flow by affecting arterial blood pressure (BP). Consequently, increased oxidative stress may lead to renovascular hypertension (35, 36). Oxidative stress has wide-ranging consequences in the kidney. The discovery of these nonphagocytic mechanisms leading to ROS production was a major step forward in elucidating the pathogenesis of DN. It is now known that glomerular mesangial cells are targeted in DN and that they possess NADPH oxidase. As a result, the endothelial lining of the glomerulus interfaces with the blood, the mesangium, and expresses a constitutively active NADPH oxidase (37). Exposure of mesangial cells and endothelial cells to a diabetic environment, i.e., high glucose or free fatty acid, leads to an activation of NADPH oxidase and increases ROS generation (38). Hyperglycemia induces free-radical stress by generating reactive α-dicarbonyl intermediates. These hydroxyl radicals, created during sugar autoxidation, degrade proteins by breaking down covalent bonds, and promote cell membrane lipid peroxidation (39). Elevated levels of oxidized LDL and hyperlipidemia are also potent NADPH oxidase activators and have been implicated as pathogenic factors in diabetic complications (40, 41). Also, the intra-renal concentration of Angiotension II (Ang II) is much higher than in serum, where Ang II can activate NADPH oxidase in both mesangial cells and endothelial cells (42, 43). Increased O2- within the glomerular microcirculation decreases Nitric Oxide (NO) bioactivity on mesangial contraction and arteriolar tone and therefore may contribute to vascular abnormalities seen in DN (24). Currently, it is postulated that oxidative stress may ultimately lead to glomerular cell apoptosis, endothelial dysfunction, leukocyte adherence, and impaired coagulation in the kidney (44, 45) (Figure 22.1). Oxidative stress affects the kidney in a myriad ways. Multiple pathways exist for development of ROS that make treatment difficult. Current belief supports a link between oxidative stress and the production of AGE, which, while still difficult to establish in vivo, nevertheless represents a significant and plausible mechanism of injury. AGE may generate ROS through the stimulation of membrane-bound NADPH
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FIGURE 22.1 NADPH-oxidase and the development of diabetic nephropathy.
oxidase via the AGE receptor (RAGE) (46). Also, AGE may augment formation of ROS through catalytic sites in their molecular structure (47). In addition, oxidative stress and ROS formation may represent a pathophysiological link between hyperglycemia and the other major pathways thought responsible for development of diabetic complications (1). Hyperglycemia has been shown, in vitro using aortic endothelial cells, to increase rapidly the intracellular generation of ROS and the lipid-peroxidation product MDA (48). Moreover, hyperhomocystinuria, a recognized contributor to endothelial dysfunction in diabetic patients, promotes oxidant injury to the vascular endothelium, impairs endothelium-derived vasodilator NO production, and may alter the coagulant properties of blood (49). In an effort to determine whether the progression of DN could be stymied though control of hyperglycemia, the Medical Nutrition Therapy (MNT), as coined by The Diabetes Control and Complications Trial (DCCT), was undertaken (50). The DCCT, a 29-center, randomized clinical trial that compared the effects of conventional and intensive diabetes therapies, was reported in the Journal of Renal Nutrition, 1998. This trial was designed to achieve glucose levels as close to normal as possible. Type I diabetics, ages 13–39, n = 1441, were studied over three to nine years. Patients were divided into two groups: 726 patients had no retinopathy with near-normal albuminuria (< 40 mg/24hr), and 715 patients had mild to moderate retinopathy with albuminuria (< 200 mg/24hr). Patients in each group received either conventional therapy or intensive diabetes management. Intensive treatment consisted of three or more insulin shots per day or an insulin pump, along with close blood-glucose monitoring of at least four times per day. Target glucose levels for the intensive group (70–120 mg/dl, preprandially, < 180 mg/dl postprandially and > 65 mg/dl at 3 a.m.) and HbA1c levels less than 6.05 were within two standard deviations of values for nondiabetics (50).
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In addition to tight glucose control, dietary education with a dietitian to achieve better cholesterol control and carbohydrate consistency was introduced. Contrarily, this led to a threefold increase in severe hypoglycemia and a 33 percent increase in the risk of becoming overweight. The latter was attributed to less calorie loss due to glycosuria, to extra food intake to treat more frequent bouts of hypoglycemia, and to more efficient patterns of energy expenditure with well-controlled diabetes (51). Strict hyperglycemic control did show a positive effect in terms of renal function. In the primary prevention cohort, there was a 15 percent decrease in the albuminexcretion rate (AER) by the end of the first year of therapy, with stabilization thereafter. In the secondary cohort, those with a prior history of retinopathy or albuminuria and who continued conventional therapy had a 6.5 percent per year increase in AER, whereas the intensive-therapy group had almost no change over time. Of note, the beneficial effect of intensive therapy in this group was less for women, where an 18 percent risk reduction was observed, versus a 57 percent reduction in men. While levels of albuminuria are highly variable within the microalbuminuria range, analyses using less-variable outcomes showed that intensive treatment reduced the risk of developing sustained microalbuminuria by 60 percent and the risk of developing advanced microalbuminuria (≥ 100 mg/24 hr) by 51 percent. Lastly, for each 10 percent higher mean HbA1c, the risk of developing microalbuminuria (≥ 40 mg/24hr) was 31 percent higher in the conventional treatment groups and 29 percent greater in the intensively treated groups. However, every 10 percent reduction in HbA1c showed a 25 percent risk reduction for microalbuminuria, a 39 percent risk reduction for sustained microalbuminuria, and a 44 percent risk reduction in the secondary cohort for albuminuria. This study unequivocally showed that strict control of glucose levels could lead to improvement in renal function, as well as implying that the postulated effects of hyperglycemia leading to OS are warranted. Nevertheless, regardless of its etiology, oxidative stress appears to play a central role in the development of DN. The resulting byproducts of metabolic injury are varied and complex, but new insights have sought to quantitate, as well as qualify, the effects of OS.
III. ADVANCED GLYCATION END PRODUCTS (AGE) Enzymatic activation of ROS plays a significant role in cellular injury. However, nonenzymatic reactions between sugars and free amino groups on proteins, lipids, and nucleic acids can also lead to cellular damage through the formation of advanced glycation end products (AGE) (52). AGE have been the focus of intense study. Their role in the development of diabetic complications has not been fully defined. AGE are biologically active species that can interact with specific receptors and bridge proteins that ultimately influence the expression of growth factors and cytokines, including TGF-β and CTGF. Consequently, the presence of AGE affecting the growth and proliferation of various renal cell types may be another causative factor that leads to the observed pathologic changes seen in DN (52). AGE have been implicated in the progression of atherosclerosis, hypertension, diabetic glomerular sclerosis, uremia, and aging. AGE represent a diverse group of
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TABLE 22.1 Age Effects 1. 2. 3. 4. 5. 6.
1. 2. 3. 4. 5. 6.
1. 2. 3. 4. 5.
1. 2. 3. 4.
Aging Glycation of lens protein = > cataract AGE in bone = > chemotaxis, IL-6, TNF-α = > osteoporosis Glycated tau protein, lipofusion, and beta-amyloid peptide = > GM-CSF, free radicals = > Alzheimer’s disease Abnormal gene expression = > increased incidence of cancer Cross-linking of collagen = > defective catabolism = > skin changes AGE in mesangium and GBM = > proteinuria = > glomerulosclerosis Atherosclerosis Modified LDL = > Uptake by macrophage = > atheroma Reactive oxygen intermediates = > altered gene expression of cytokines and proteins = > abnormal cell proliferation Mononuclear cell activation = > cytokine and growth factor release = > increased vascular matrix = > narrowing of lumen Quenching NO = > defective II-1, TNF-α, IGF-1, PDGF = > smooth muscle proliferation Increased endothelial cell permeability and procoagulant activity = > thrombosis Diabetic Glomerulosclerosis Glycation of proteins = > basement membrane thickening and increased vascular AGEs and hyperlipidemia = > microvascular changes in glomeruli and atherosclerosis IGF-1, IGF-2, TGF-β, PDGF = >increased ECM protein and type IV collagen synthesis = > mesangial expansion Trapping of proteins and lipids = > mesangial expansion Chemotaxis = > macrophage accumulation and complement activation = > immune-mediated damage Uremia AGE peptides = > AGE-Apo B and AGE-lipid = > defective clearance = > dyslipidemia AGE, oxidative stress, and dyslipidemia = > atherosclerosis Glycation of 2-microglobumin = > chemotaxis of monocytes, IL = 1, TNF-α, and IL-6 = > dialysis-related amyloidosis Glucose in PD fluid = > local AGE formation in peritoneum = > ultrafiltration failure
Note: Abbreviations: ECM, extracellular matrix; GBM, glomerular basement membrane; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-1, interleukin-1; IGF-1, insulin-like growth factor-1; PDGF, platelet-derived growth factor; TGF-β, transforming growth factor-; TNF-α, tumor necrosis factor-1.
molecules formed by the glycation of both soluble and structural proteins. The complexity of the effects from AGE is summarized in Table 22.1. While controversy still exists as to their exact structure, chemistry, and pathogenic capabilities, AGE have a vital role in the aging process, as well as the evolution of DN (53). The severity of DN is correlated with AGE accumulation in the glomerular and tubulointerstitial compartments and structural alterations of ECM proteins (52).
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FIGURE 22.2 Formation of AGE.
Hyperglycemia is the catalyst whereby diabetic changes occur. Glycation is a posttranslational modification of proteins that result from the condensation of reducing sugars with ε-amino groups of lysine in proteins. The subsequent Schiff base reaction leads to a rearrangement to form relatively stable ketoamines and Amadori products (53). These glycated proteins are susceptible to progressive dehydration, cyclization, oxidation, and rearrangement to form AGE (53, 54) (Figure 22.2). The formation of AGE is dependent upon the reaction between a free amino group and the sugar carbonyl group from either glucose or fructose forming a 1-amino-1-deoxyketose Amadori product. Oxidization of the Amadori product leads to a highly reactive dicarbonyl intermediate (55). Reactive AGE intermediates can arise from the oxidative reaction (glycooxidation) of free sugars or from initial Schiff base condensation products with a protein amino group, rather than just from classic Amadori products (56). Due to the ubiquitous nature of these reactions, AGE have been found in collagen, lens crystalline, hemoglobin, β2-microglobulin, myelin, and tau protein (53). In addition, AGE fragments have been identified in the urine, suggesting that the renal system is at least one mechanism by which AGE breakdown products are cleared. Moreover, it appears that other carbohydrates, such as ascorbate, pentoses, and other metabolic intermediates, may act as potent glycating agents (57, 58). Once formed, the reaction is irreversible, causing an accumulation over time. Patients with diabetes are awash in excess glucose, leading to ongoing formation and deposition of AGE whose receptors are ubiquitous on monocytes, macrophages, T lymphocytes, endothelial cells, platelets, fibroblasts, smooth-muscle cells, glial cells, and mesangial cells (47). Once these receptors are activated, a litany of responses follow (Table 22.2) that significantly alter the physiologic milieu of these patients, with resulting end-organ damage. Interestingly, restoration of normal renal function by kidney transplantation has been associated with a reduction in serum and tissue AGE levels (59, 60). Nevertheless, the structural changes that result from the presence of AGE are far ranging and may still exert effect even after renal function has been restored. A hallmark of DN is the accumulation of extracellular matrix (ECM) protein in the glomerular mesangium and tubulo-interstitium. It has been proposed that an imbalance between the synthesis and degradation of ECM components is a major factor leading to this pathologic state (52). ECM-accumulation products have been identified, but are not limited to, collagens, fibronectins, and laminins. AGE can affect all of these. ECM proteins are susceptible to AGE due to their slow turnover. Modifications of ECM by AGE can be seen in the formation of intermolecular and intramolecular cross-links after glycation of collagen. These structural alterations, including changes
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TABLE 22.2 Consequences of Age Receptor Activation Cell
Species
Response
Bone Endothelial cells
Mouse Increased IL-6, TNF-α, and recruit monocyte/macrophage Human, bovine, rat Increased ligand binding, transcytosis, degradation Increased permeability Increased VCAM and ICAM expression Increased tissue factor, thrombomodulin Fibroblast Human, rat Increased ligand binding, EGF Increased proliferation Glial cells, astrocytes Human, mouse Increased ligand binding, degradation Increased GM-CSF, free radicals Mesangial cells Human, rat, mouse Increased ligand binding, endocytosis, degradation Increased fibronectin, collagen IV, laminin, induction of growth factors (PDGF, TGF-β1) Monocyte/macrophage Human, rat, mouse Increased ligand binding, endocytosis, and degradation Increased chemotaxis Increased cytokine production (TNF-1, IL-1) Increased growth factor production (PDGF, IGF-1) Smooth muscle cells Human, rat Increased ligand binding, proliferation T lymphocytes Human, rat mouse Increased binding, interferon- production Note: Abbreviations: EGF, epidermal growth factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule-1; IGF-1, insulin-like growth factor-1; IL-1, Interleukin-1; PDGF, platelet-derived growth factor; TGF- β1, transforming growth factor- β1; TNFα, tumor necrosis factor-; VCAM-1, vascular cell adhesion molecule-1.
in packing density and surface charge, are manifested by increased stiffness, reduced thermal stability, and resistance to proteolytic digestion (52, 61–64). Of note, when these abnormally cross-linked proteins are exposed to N-phenacylthiazolium bromide and ALT-71, cleavage occurs that restores collagen solubility and reduces matrix accumulation within the kidney (65, 66). AGE also affects the affinity of laminin and fibronection for heparin sulfate proteoglycan in type IV collagen (67, 68). Also, glycation inhibits the homotypic interactions required for polymeric self-assembly of type IV collagen and laminin, especially in the glomerular basement membrane, where cross-linking between amines leads to an increase in protein permeability (63, 68). Excessive ECM production is also characterized by the influx of interstitial fibroblasts, myofibroblasts, and infiltrating macrophages. Even though chemokines released in response to injury have been implicated in the recruitment of these cells, they may also play a role in the development of DN (52). Intrarenal rennin-angiotensin system (RAS) overactivity has been implicated in the pathogenesis of DN, even though the source of this activation has not been elucidated (69). AGE interact with the RAS. This has been demonstrated by the reversal of AGE-induced collagen production by Captopril in vitro (70). Moreover,
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clinical evidence suggests that angiotensin-converting enzyme inhibition can attenuate formation and accumulation of AGE in experimental diabetes (71). A potential basis for this observation is linked to mechanisms that promote the formation of AGE. The addition of ACE inhibitors may act by preventing formation of AGE through metal chelation (72) and reducing formation of ROS by preventing glycooxidation (73). Expansion of the mesangial matrix and thickening of the capillary basement membrane leads to capillary narrowing and glomerular filtration diminution. It appears that growth factors, such as TGF-β, play a significant role in the expansion of the matrix. Also, external growth factors, hormones, and cytokines appear to work through the transduction of second messenger molecules, such as protein kinase (PKC) (74). Scivittaro et al. (74) demonstrated a link between AGE and PKC activation, leading to changes seen in DN. PKC activity is elevated in the glomeruli of animals with diabetes. PKC-β (βI and βII) are isoforms of PKC most frequently associated with alterations in mesangial cell phenotypic behavior, such as proliferation and matrix deposition (75). These observations are important, because they provide a possible therapeutic intervention strategy. Blocking PKC-β can decrease albuminuria in animal models of diabetes (76). Aminoguanidine, an inhibitor of AGE formation, has been shown to block mesangial expansion in streptozotocin-treated rats (77). A dose-response relationship between high content AGE, the induction of intracellular oxidative stress, and translocation of the specific isoform PKC-βII (associated with rapid mesangial-cell proliferation during early development) was found (74). These findings are important, since PKC activity is increased in the renal glomeruli of diabetic animals (78). PKC activation in the glomeruli isolated from streptozotocin-induced diabetic rats have elevated levels of mRNA encoding matrix components, as well as accelerated matrix synthesis. Aside from the activation of PKC, AGE also appear to activate other transcription factors that up-regulate nuclear factor NF-κB. Once again, their activation seems predicated upon both direct (through AGE receptors) and indirect (via generation of oxygen free radicals) pathways that lead to the production of cytokines, adhesion molecules, and chemokines (52). Moreover, it is possible that these pathways are interrelated, such that depletion of intracellular antioxidants reduces the AGE concentration needed for mesangial-cell activation of NF-κB (79). The promoter region of the RAGE receptor gene contains NF-κB binding sites that could represent a potential self-perpetuating pathway (80). There remains, however, more far-reaching effects of AGE that implicate them as a primary progenitor of DN. It is known that AGE contribute to the release of proinflammatory cytokines and the expression of growth factors and adhesion molecules (VEGF, CTGF, TGF-β, IGF-I, PDGF, TNF-α, IL-1β, and IL-6) (81-83). As mentioned previously, TGF-β plays a role in the expansion of the ECM, while inhibitors of AGE reduce the overproduction of TGF-β1 in diabetic animals, independent of glycemic status (81). PKC-dependent pathways appear to modulate transcriptional upregulation of TGF-ß1, for which AGE are potent stimuli. Also, inhibitors of AGE have been shown to be renoprotective by providing attenuation of renal PKC overexpression in diabetic rats (79).
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AGE appear to be pivotal in the development of diabetic complications. While they are ultimately the result of oxidative stress, they nonetheless exert their influence in a variety of ways. It must be remembered that the progression of diabetic complications is variable among individuals. This fact may reflect an individual’s ability to handle oxidative stress despite similar glycemic control. While overproduction of AGE has been postulated, Shimoike et al. (84) discovered another possible explanation for rising levels of AGE in diabetic and hemodialysis patients. After studying patients with normoalbuminuria, microalbuminuria, and overt proteinuria, along with hemodialysis dependent and nondiabetic patients with nephropathy, he determined that increased serum AGE in patients with nephropathy are primarily due to decreased clearance rather than increased production by glycation or oxidative stress. Serum AGE levels were increased in nondiabetic patients with renal failure and those undergoing dialysis to the same extent as in diabetic patients. He suggests that serum AGE may not be involved in the pathogensis of DN; however, it is possible that AGE formed directly within renal tissue will contribute to the development of DN. This is supported by the observation that aminoguanidine prevents glomerular lesions and albuminuria in several experimental models. Serum AGE levels may be a useful marker for the therapeutic effects of such agents. Regardless of whether serum AGE is pathogenic, within kidneys, the presence of AGE in renal tissue is pathogenic, and efforts to reduce renal AGE should be pursued as a means to provide renoprotection in the diabetic state. It must be remembered that AGE remains only one pathway producing renal injury. The combination and interaction of metabolic and hemodynamic factors contribute to the deleterious effects of hyperglycemia, making it unlikely that a single, common pathway will be identified (85). Therefore, current efforts should be directed toward targeting multiple pathways and further defining the mechanisms by which AGE contributes to the development of DN.
IV. MEDICAL NUTRITION THERAPY Current research into the etiology of DN has identified numerous mechanisms of potentiation. Therapeutic interventions in both the laboratory and clinical settings have suggested that alterations in the progression of DN can be achieved, at least to some degree, using dietary supplementation with vitamins and other compounds. While much of the data is experimental and definitive clinical trials lacking, the prospect of enhancing the antioxidant arsenal of diabetic patients appears promising. The assumption that such interventions may prove beneficial hinges on the observation that oxidative stress leads to a depletion of naturally occurring antioxidants. Whether or not exogenous supplementation can significantly thwart the progression of DN can only be determined through large clinical trials. Until then, based on current research, it is not unreasonable to assume that some type of intervention along these lines may prove beneficial in slowing the effects of OS within the renal parenchyma.
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TAURINE
As we have already discussed, tight glucose control is an essential step to slow the progression of DN. While intuitive, the DCCT showed that proof of principle; nevertheless, tight glucose control is not enough, because exogenous insulin therapy, even with a pump, cannot duplicate the native pancreas. Therefore, strategies to cope with the byproducts of OS must be devised to give the diabetic patient the best chance to preserve kidney function, as well as other organ systems. The pathophysiology of excess glucose metabolism results in the accumulation of sorbitol. While sorbitol is normally present in low amounts, its production is increased in the hyperglycemic state. Concomitant with the appearance of intracellular sorbitol is the depletion of intracellular compounds, including osmolytes, such as myo-inositol and taurine (86). Cellular physiologic homeostasis depends upon a cell’s ability to balance its intracellular environment with the extracellular. Increased extracellular levels of glucose causes osmotic stress on cells. To maintain osmotic balance across the cell membrane, production or transport of additional intracellular osmolytes are needed. Taurine, betaine, myo-inositol, sorbitol, and glycerophosphorylcholine (GPC) are considered the most important osmolytes (87, 88). Research has shown that all cells do not depend upon insulin for glucose uptake, e.g., nerves, retina, and the kidneys. Therefore, in these cells, an increase in plasma glucose levels results in high intracellular levels of glucose, with the subsequent production of sorbitol and fructose due to the enzymes aldose reductase and sorbitol dehydrogenase (89–91) (Figure 22.3). Intracellular sorbitol accumulation is driven by the conversion of glucose to sorbitol that is faster than the conversion of sorbitol to fructose. This increase is coupled with an inability of cells to transport sorbitol across the cell membrane (92). The accumulation of sorbitol is believed to lead to vascular complications observed in diabetic patients. Prevention of sorbitol formation has led to a search for aldose reductase inhibitors; however, no significant clinical improvements have been found with such compounds, of which Sorbinil is one (93, 94). Another consequence of sorbitol accumulation is the gradual depletion of mobile osmolytes (taurine, betaine, and myo-inositol) from the intracellular compartment of aldose reductase-containing cells, rendering their essential osmoregulation and volume regulation systems inadequate (95) (Figure 22.4). Histological evaluation of nerve tissue from diabetic animals clearly showed that aldose reductase-containing cells swell, whereas cell types without aldose reductase shrink or are lost (96).
FIGURE 22.3 Sorbital formation.
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FIGURE 22.4 Effect of hyperglycemia on intracellular osmoregulation.
It is now apparent that a disturbance of the normal intracellular osmoregulatory functions of cells plays a key role in the development of late diabetic complications. Aside from osmoregulatory functions, alterations in taurine metabolism and homeostasis have been associated with the development of cellular dysfunctions. These observations raise the possibility of dietary manipulation with taurine supplementation. While the exact function of taurine is unknown, taurine is an ubiquitous ß-amino acid with several physiologic functions: 1) bile acid formation; 2) cell-volume regulation in the heart and retina; 3) inhibition of protein phosporylation and development; 4) formation of N-chlorotaurine by reaction with hypochlorous acid in leukocytes; and possibly 5) intracellular scavenging of carbonyl groups (86). A 70kg person has about 70 g of taurine and a plasma concentration of 100 μM and intracellular concentrations in the range of 5–50mM. Seafood and meat are the principal sources of taurine, with normal daily intake less than 200 mg/day. Among its many functions, taurine has also been classified as an antioxidant, providing protection against hypoxia-induced cell damage and against apoptosis through inhibition of ROS formation (97 98). Therefore, it has been reported to reduce oxidative stress and damage (99). Hyperglycemia accentuates the formation of carbonyl groups, reactive hydroxyl groups, and lipid peroxidation. Taurine has been found to be reactive against aldehydes. Intuitively, one could surmise that normalized or elevated intracellular concentrations of taurine, with its reactivity toward carbonyl groups, could be expected to react with the dicarbonyl intermediate and scavenge the reactive carbonyl and glycation intermediates formed intracellularly. Many assays testing antioxidative effects and oxidative stress, e.g., lipid peroxidation, are based on the detection of reactive carbonyl compounds (100). When diabetic patients with poorly controlled diabetes or ketoacidosis were studied, high urinary levels of taurine were found (101–103). The few clinical trials performed with taurine supplementation demonstrated that plasma and platelet taurine levels were reduced in these patients. Oral supplementation with 500 mg taurine three times per day resulted in normalization of platelet levels, and the plasma levels increased slightly above the level of the control group (104, 105).
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Other studies utilizing 500 mg taurine two times per day showed direct metabolic changes in type 1 diabetics by reductions of the average glucose levels in plasma and urine (106, 107). Results in type 2 diabetics have been less convincing (108). AGE formation and overabundance has been associated with an overload of detoxification pathways involved in the formation of reactive carbonyl compounds (55). Based on taurine’s reactivity toward carbonyl groups, taurine may act as a glycation scavenger, thereby preventing formation of reactive carbonyl compounds and AGE (109, 110). As a result, sorbitol accumulation could presumably increase reactive carbonyl and AGE formation through depletion of intracellular taurine (Figure 22.4). Some studies have shown an influence of taurine on kidney disease in rats (111–113). Chronic dialysis and uremic patients have been shown to have lowerthan-normal taurine levels in the plasma, muscle, and erythrocytes compared to a control group (114–119). In one study, (116), cysteine sulfonic-acid accumulation in dialysis patients was thought to indicate impairment in the biosynthetic pathway for hypotaurine and taurine. A possible role of taurine supplementation is compelling, but further studies are needed to elucidate fully the potential efficacy of such therapy. Nevertheless, a mixture of several low-molecular mass compounds, i.e., not only taurine but also myo-inositol, betaine, carnitine, cysteine, and creatine, for example, could be used to bolster the osmoregulatory capacity of cells existing in a hyperglycemic milieu (86). Also, given the observed formation of sorbitol and its negative effects, some type of therapeutic intervention aimed at preventing osmolyte depletion, i.e., prevention of sorbitol formation by aldose reductase, could be attempted. However, no aldose-reductase inhibitor has been convincingly applied in the clinical setting. This observation may be linked to the fact that the biosynthetic capacity of taurine is much higher in rodents than in man. Therefore, future treatments with aldosereductase inhibitors might be combined with taurine and the aforementioned lowmolecular mass compounds (86).
B. SELENIUM, THIAMINE, VITAMIN C, GLUTATHIONE Oxidative stress of hyperglycemia remains pivotal in the cascade of events that ultimately lead to DN. Along the way, byproducts of this abnormal state accumulate, causing cellular damage through a variety of pathways. Ongoing, basic research has focused on defining these pathways and attempting to prevent their progression to end-stage renal disease. Among the compounds that have an altered metabolism are the minerals, vitamins, and the internal antioxidant system. Due to the pro-oxidant conditions induced by hyperglycemia, the primary antioxidant enzymes in mammalian systems, SOD, catalase, and glutathione peroxidase (GSH-Px), become overwhelmed. SOD exists as Cu-Zn SOD and Mn SOD. Cu-Zn SOD resides primarily in the cytosol and the nucleus, where it converts superoxide radical into hydrogen peroxide, which in turn is converted to water by both catalase and GSH-Px (120). These three enzymes prevent tissue damage by detoxifying ROS.
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Apart from these three enzymes, there are several endogenous, as well as exogenous, antioxidants, such as glutathione, and vitamins E and C. Evidence suggests that in the diabetic state, levels of these antioxidants is decreased (121–123). Selenium (Se) is an essential trace element that is an important component at the catalytic sites of the enzyme GSH-Px. Se deficiency causes a profound reduction in GSH-Px activity in several tissues, especially the liver, resulting in oxidative stress (124–126). Se also has insulin-like properties, where Se supplementation has been shown to reduce hyperglycemia and improve glucose tolerance in diabetic rats without any effect on endogenous insulin levels (127, 128). The addition of sodium selenate to rat adipocytes has been shown to stimulate glucose transport (129). Collectively, it can be surmised that Se improves glucose metabolism and that Se deficiency causes a physiologic condition similar to hyperglycemia (120). Histologically, Se deficiency causes tubulointerstitial disease and glomerular sclerosis, but what is not known is whether this dietary deficiency also induces changes in the structure of the renal arteries (120). Also, since Se deficiency causes an increased expression of TGF-ß, that, in turn, affects the extracellular matrix proteins, a link between oxidative stress and the molecular mechanism by which this growth factor reduces antioxidant gene expression may exist. Reddie et al. (120) found that Se deficiency induced an up-regulation of TGFß expression and concomitant down-regulation of antioxidant enzyme expression; this finding was also noted by Nath et al. (130). Nevertheless, the mechanisms by which Se deficiency causes proteinuria and glomerular sclerosis are not clearly understood. A link to TGF-ß may represent the mediator by which these effects are seen as a direct effect of fibrogenesis (131–133) and proteinuria (134, 135). Additional studies have noted that hyperglycemia promotes: 1) the accumulation of triosephosphates; 2) increased de novo synthesis of diacylglycerol and PKC activation; 3) oxidative stress linked to mitochondrial dysfunction; 4) concomitant activation of the hexosamine pathway; and 5) accumulation of methylglyoxal leading to increased AGE formation (136). Increasing levels of triosephosphate glycolytic intermediates, glyceraldehydes-3-phosphate (GA3P), and dihydroxyacetonephosphate (DHAP) triggers these processes (137, 138). High-dose thiamine and befotiamine therapies have been suggested as possible ways to inhibit accumulation of triosephosphate and the multiple pathogenic pathways that it promotes. Activation of the reductive pentosephosphate pathway (PPP) by high-dose thiamine stimulates an increase in transketolase (TK) activity and promotes conversion of GA3P and fructose-6-phosphate (F6P) to ribose-5-phosphate (R5P) (136). Studies have shown that normalization of triosephosphates by activation of reductive PPP in human erythrocytes in hyperglycemic culture by high-dose thiamine is possible (139). Quantitatively, these studies have been performed in rats, where plasma thiamine was decreased in the diabetic state. This was associated with increased urinary excretion of thiamine that may be due to excessive diuresis and decreased thiamine absorption (140). Structural damage to the proximal tubular cells or metabolic derangements may be the cause of decreased thiamine reabsorption (136). Clinically, DM is associated with a mild thiamine deficiency, where two studies found 18
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percent and 76 percent, respectively, of diabetic subjects had plasma thiamine concentrations lower than the normal-range minimum (141, 142). Collectively, these studies suggest that thiamine deficiency, where replacement prevented the development of microalbuminuria and proteinuria, may exacerbate the risk of developing DN (136). However, there is no evidence that high-dose thiamine or befotiamine can prevent the progression from incipient to overt nephropathy (136). Ascorbic acid (AA) is known to be an important extracellular antioxidant. As it scavenges free radicals, it is converted to dehydroascorbic acid (DHAA) in serum and in the mitochondrial fractions of various tissues(143). AA is primarily known to inhibit lipid peroxidation initiated by a peroxyl radical initiator more than other plasma antioxidants (thiols, urate, bilirubin, and α-tocopherol) (144). This antioxidant effect has been reported in vitro (145) and in vivo (146). Hirsch et al. studied 37 subjects with diabetic nephropathy, where 18 had microalbuminuria (30–300 mg/day albuminuria) and the remainder had clinical nephropathy (> 300 mg/day albuminuria) (143). They found that subjects with clinical nephropathy had lower mean plasma AA (p = 0.0009) and higher renal clearance of AA (p = 0.005) than those with microalbuminuria. There was also an inverse relationship between creatinine clearance and AA clearance, as well as a linear association between the quantity of albuminuria and AA clearance. They surmised that patients with DN have reduced AA levels due to increased AA clearance. As a result, the decrease in the antioxidant defense mechanism may contribute to increased cardiovascular morbidity and mortality in these patients. In streptozotocin-induced diabetic rats with AA deficiency, supplemental vitamin C normalized AA levels (147). However, further studies are needed to determine if such supplementation can affect human diabetics. Lastly, glutathione (GSH) supplementation has been studied as a possible way to thwart progression of DN. GSH is the most abundant nonprotein thiol. It has many functions in vivo, with a major role being maintenance of cellular redox balance. It is a substrate of glutathione peroxidase (GSH-Px), an antioxidative enzyme that scavenges various peroxides. The physiologic role of GSH has been substantiated and studied in numerous disorders, reflecting increased oxidation as a result of abnormal GSH metabolism (148–150). Ueno et al. attempted to see whether dietary GSH could suppress oxidative stress in vivo. Diabetic rats were treated with 1g/1000g GSH as a dietary supplement. They noted a significant decrease in urinary 8-hydroxy-2′-deoxyguanosine, one marker of oxidative stress (148). Moreover, it prevented the diabetes-induced increases in urinary albumin and creatinine. Peroxynitrite production, as a result of oxidative stress, increases in the proximal tubules of patients with DN, suggesting that oxidant injury of these tubules is an important part of the pathogenesis of DN (151). In the aforementioned study, supplemental GSH improved renal function, presumably through its antioxidant effects.
V. CONCLUSIONS Diabetes mellitus, both type 1 and 2, is quickly becoming the leading health problem in the Western world (1). Improving glycemic control is essential in the prevention
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of DN. Secondary prevention focuses on preventing the progression from incipient to overt nephropathy. Currently, studies focused on the use of ACE inhibitors have implied that they can slow the development of protienuria (152). Lastly, preventing the progression of established nephropathy to ESRD has also shown ACE inhibitors to be of benefit, especially in type 1 diabetes (153). The data is less clear in type 2 diabetic subjects, even though angiotensin II receptor antagonists are believed to be protective in these patients (154). While much remains to be accomplished, it must be remembered that 30 years ago the prognosis for diabetics with nephropathy was dismal, with 90 percent of patients dying within 14 years of the gross appearance of proteinuria (1). Judicious use of antihypertensive drugs has lead to a reduction in mortality by more than 50 percent. The evolution of DN in the setting of hyperglycemia is very complex. No single, unifying pathway currently exists to explain all of the observed damage in the kidney. Oxidative stress and ROS formation, however, regardless of their etiology, remain prominent in the development of DN. The overproduction of ROS, leading to formation of AGE that eventually overwhelms cellular antioxidant systems, is indisputable. AGE formation and their subsequent effects have become pivotal in understanding the evolution of DN (46, 52). While intuitive, hyperglycemia remains the starting point for observed cellular derangements. Hyperglycemia causes in high cytosolic glucose concentrations in renal endothelial cells and pericytes that result in biochemical dysfunction: 1) activation of protein kinase C; 2) activation of hexosamine and polyol pathways; 3) metabolic pseudohypoxia from mitochondrial dysfunction with oxidative stress; and 4) accumulation of AGE (136, 155). Heilig et al. found a link between high cytosolic glucose concentrations and metabolic dysfunction by an overexpression of the GLUT1 glucose transporter in cultured rat renal mesangial cells. These normal cells acquired the characteristics of the diabetic phenotype, including increased extracellular matrix protein synthesis and activation of the polyol pathway (156). Clearly, the abnormal milieu created by the hyperglycemic state within the kidney is the direct progenitor of DN. Cellular defense mechanisms are exquisitely able to handle normal byproducts of oxidation, but in the face of ongoing oxidative stress, host defense mechanisms are overwhelmed. As a result, byproducts, such as AGE and sorbitol, accumulate, leading to further damage (53, 92). Once renal tubular integrity is compromised, essential nutrients are lost, leading to further injury (87, 121, 140). Moreover, production of TGF-ß, leading to mesangial thickening and extracellular matrix proliferation, contributes to glomerular ischemia (74). Ongoing research into the pathophysiology of DN has convinced some practitioners that dietary manipulation can be beneficial in thwarting the progression of DN. While studies, both in the laboratory and in the clinic, continue to elucidate possible therapeutic interventions, some of them have already been implemented into daily practice. Current lay literature cites research that implicates oxygen stressinduced free radicals and the depletion of antioxidants. While there has already been a movement to include antioxidant therapy in the daily regimen of diabetic patients, questions remain regarding the efficacy of this type of therapy (157, 158).
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The progression of normal renal function to overt renal failure is a continuum that seemingly affects every major defense mechanism within the kidney. In essence, the barbarians, primarily ROS, once held at bay within the normal physiologic milieu, become unfettered to proliferate and overwhelm intrinsic systems. Exogenous supplementation with taurine, vitamins C and E, glutathione, and perhaps others, may provide assistance in staving off this onslaught. Supplementation, combined with aggressive glycemic and blood-pressure control, might assume a prominent role in the management of any diabetic patient. In summary, given the complexity of events associated with hyperglycemia, it is not surprising that numerous intracellular systems are affected. The cell is uniquely qualified to support the life of the organism. Intracellular mechanisms exist to survive in an oxygen-rich environment that is inherently toxic due to the formation of ROS. In the normal cellular environment, the production of ROS is minimal and easily handled by the intrinsic antioxidant enzymes. This delicate balance is altered severely in the hyperglycemic state. In the face of unrelenting oxidative stress, as a result of hyperglycemia, that intracellular antioxidant mechanisms are compromised and the intracellular milieu altered, such that the cell can no longer function properly. Clinical consequences of hyperglycemia are well-documented, with new research finally shedding light as to how these pathologic lesions are formed. The challenge now is to determine whether therapeutic interventions, such as aggressive glucose control, hypertensive management, salt restriction, and supplementation with dietary antioxidants, will work. No one will dispute the necessity of the first three, but data concerning antioxidant therapy is inconclusive (157, 158). Preliminary evidence, as well as a priori deduction, suggests that this type of therapy may be effective, but whether oral supplementation can achieve effective intracellular levels remains to be seen.
ACKNOWLEDGMENTS Special thanks to Cheryl A. Smyth, M.S., for the illustrations and editing of this chapter, and to Karen L. Yekel for the preparation of the manuscript.
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41. Rueckschloss, U, Galle, J, Holtz, J, Zerkowski, H-R, and Morawietz, H, Induction of NAD (P) H oxidase by oxidized low-density lipoprotein in human endothelial cells, Circulation, 104:1767–1772, 2001. 42. Jaimes, EA, Galceran, JM, and Raij, L, Angiotensin II induced superoxide anion production by mesangial cells, Kidney Int., 54:775–784, 1998. 43. Mollnau, H, Wendt, M, Szocs, K, Lassegue, B, Schulz, E, Oelze, M, Li, H, Bodenschatz, M, August, M, Kleschyov, AL, Tsilimingas, N, Walter, U, Forstermann, U, Meinertz, T, Griendling, K, and Munzel, T, Effect of angiotensin II infusion on the expression and function of NAD (P) H oxidase and components of nitric oxide/cGMP signaling, Circ. Res., 90:e58–e65, 2002. 44. Pautz, A, Franzen, R, Dorsch, S, Boddinghaus, B, Briner, VA, Pfeilschifter, J, and Huwiler, A, Cross-talk between nitric oxide and superoxide determines ceramide formation and apoptosis in glomerular cells, Kidney Int., 61:790–796, 2002. 45. Morena, M, Cristol, J-P, Senecal, L, Leray-Moragues, H, Krieter, D, and Canaud, B, Oxidative stress in hemodialysis patients: is NADPH oxidase complex the culprit? Kidney Int., 61:S109–S114, 2002. 46. Wautier, MP, Chappey, O, Corda, S, Stern, DM, Schmidt, AM, and Wautier, JL, Activation of NADPH oxidase by AGE links oxidant stress to altered gene expression via RAGE, Am. J. Physiol. Endocrinol. Metab., 280:E685–E694, 2001. 47. Yim, MB, Yim, HS, Lee, C, Kang, SO, and Chock, PB, Protein glycation: Creation of catalytic sites for free radical generation, Ann. N.Y., Acad. Sci., 928:48–53, 2001. 48. Chandra, A, Srivastava, S, Petrash, JM, Bhatnagar, A, and Srivastava, SK, Active site modification of aldose reductase by nitric oxide donors, Biochim. Biophys. Acta., 131: 217–222, 1997. 49. Maxwell, SR, Coronary artery disease-free radical damage, antioxidant protection and the role of homocysteine, Basic Res. Cardiol., 95(Suppl.):S65–S71, 2000. 50. Delahanty, LM, MS, RD , Implications of the diabetes control and complications trial for renal outcomes and medical nutrition therapy, J. Renal Nutr., 8(2):59–63, 1998. 51. The DCCT Research Group, Implementation of treatment protocols in the diabetes control and complications, Diabet. Care, 18(3):361–376, 1995. 52. Forbes, JM, Cooper, ME, Oldfield, MD, and Thomas, MC, Role of advanced glycation end products in diabetic nephropathy, J. Am. Soc. Nephrol., 14:S254–S258, 2003. 53. Raj, D, Choudhury, D, Welbourne, TC, and Levi, M, Advanced glycation end products: a nephrologist’s perspective, Am. J. Kidney Dis., 35(3), 2000. 54. Brownlee, M, Lilly Lecture 1993, glycation and diabetic complications, Diabetes, 43: 836–841, 1994. 55. Baynes, JW and Thorpe, SR, Role of oxidative stress in diabetic complications — a new perspective of an old paradigm, Diabetes, 48:1–9, 1999. 56. Booth, AA, Khalifah, RG, Todd, P, and Hudson, BG, In vitro kinetic studies of formation of antigenic advanced glycation end products (AGEs). Novel inhibition of post-amadori glycation pathways, J. Biol. Chem., 272: 5430–5437, 1997. 57. Dunn, JA, Ahmed, MU, Murtiashaw, MMN, Richardson, JM, Walla, MD, and Baynes, JW, Reaction of ascorbate with lysine and protein under autoxidizing conditions: formation of N-(carboxy-methyl) lysine by reaction between lysine and products of autoxidation of ascorbate, Biochemistry, 29:10964–10970, 1990. 58. Miyata, T, Wada, Y, Cai, Z, Iida, Y, Horie, K, Yasuda, Y, Maeda, K, Kurokawa, K, and van Ypersele de Strihou, C, Implication of an increased oxidative stress in the formation of advanced glycation end products in patients with end-stage renal failure, Kidney Int., 51:1170–181, 1997.
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59. Miyata, T, Ueda, Y, Yoshida, A, Sugiyama, S, Iida, Y, Jadoul, M, Maeda, K, Kurokawa, K, and van Ypersele de Strihou, C, Clearance of pentosidine, an advanced glycation end product, by different modalities of renal replacement therapy, Kidney Int., 51:880–887, 1997. 60. Lee, WK, Akyol, M, Shaw, S, Dominiczak, MH, and Briggs, JD, Kidney transplantation decreases the tissue level of advanced glycosylation end products, Nephrol. Dial. Trans., 10:103–107, 1995. 61. Bai, P, Phua, K, Hardt, T, Cernadas, M, and Brodsky, B, Glycation alters collagen fibril organization, Connect. Tissue Res., 28:1–12, 1992. 62. Silbiger, S, Crowley, S, Shan, Z, Brownlee, M, Satriano, J, and Schlondorff, D, Nonenzymatic glycation of mesangial matrix and prolonged exposure of mesangial matrix to elevated glucose reduces collagen synthesis and proteoglycan charge, Kidney Int., 43:853–864, 1993. 63. Raabe, HM, Hopner, JH, Notbohm, H, Sinnecker, GH, Kruse, K, and Muller, PK, Biochemical and biophysical alterations of the 7S and NC1 Domain of collagen IV from human diabetic kidneys, Diabetologia,41:1073–1079, 1998. 64. Mott, JD, Khalifah, RG, Nagase, H, Shield, CF, 3rd, Hudson, JK, and Hudson, BG, Nonenzymatic glycation of type IV collagen and matrix metalloproteinase susceptibility, Kidney Int., 52:1302–1312, 1997. 65. Cooper, ME, Thallas, V, Forbes, J, Scalbert, E, Sastra, S, Darby, I, and Soulis, T, The cross-link breaker, N-phenacylthiazolium bromide prevents vascular advanced glycation end-product accumulation, Diabetologia, 43:660–664, 2000. 66. Forbes, JM, Thallas, V, Thomas, MC, Jerums, G, and Cooper, ME, Renoprotection is afforded by the advanced glycation end product (AGE) cross-link breaker, ALT711, F.A.S.E.B. J., 2003, in press. 67. Tarsio, JF, Wigness, B, Rhode, TD, Rupp, WM, Buchwald, H, and Furcht, LT, Nonenzymatic glycation of fibronectin and alterations in the molecular association of cell matrix and basement membrane components in diabetes mellitus, Diabetes, 34:477–484, 1985. 68. Charonis, AS and Tsilbary, EC, Structural and functional changes of laminin and type IV collagen after nonenzymatic glycation, Diabetes, 41: 49–51, 1992. 69. Hollenberg, NK, Price, DA, Fisher, ND, Lansang, MC, Perkins, B, Gordon, MS, Williams, GH, and Laffel, LM, Glomerular hemodynamics and the renin-angiotensin system in patients with type 1 diabetes mellitus, Kidney Int., 63:172–178, 2003. 70. Huang, JS, Guh, JY, Chen, HC, Hung, WC, Lai, YH, and Chuang, LY, Role of receptor for advanced glycation end-product (RAGE) and the JAK/STAT-signaling pathway in AGE-induced collagen production in NRK-49F cells, J. Cell Biochem., 81:102–113, 2001. 71. Forbes, JM, Cooper, ME, Thallas, V, Burns, WC, Thoms, MC, Brammar, GC, Lee, F, Grant, SL, Burrell, LA, Jerums, G, and Osicka, TM, Reduction of the accumulation of advanced glycation end products by ACE inhibition in experimental diabetic nephropathy, Diabetes, 51:3274–3282, 2002. 72. Miyata, T, van Ypersele de Strihou, C, Ueda, Y, Ichimori, K, Inagi, R, Onogi, H, Ishikawa, N, Nangaku, M, and Kurokawa, K, Angiotensin II receptor antagonists and angtiotensin-converting enzyme inhibitors lower in vitro the formation of advanced glycation end products: biochemical mechanisms, J. Am. Soc. Nephrol., 13:2478–2487, 2002. 73. Brownlee, M, Biochemistry and molecular cell biology of diabetic complications, Nature, 414:813–820, 2001.
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74. Scivittaro, V, Ganz, MB, and Weiss MF, AGEs induce oxidative stress and activate protein kinase C-II in neonatal mesangial cells, Am. J. Physiol. Renal. Physiol., 278:F676–F683, 2000. 75. Yoshida, Y, Huang, F, Nakabayashi, H, and Huang, K, Tissue distribution and developmental expression of protein kinase C isozymes, J. Biol. Chem., 263:9868–9873, 1988. 76. Ishii, H, Jirousek, M, Koya, D, Takagi, C, Xia, P, Clermont, A, Bursell, S, Kern, T, Ballas, L, Heath, W, Stramm, L, Feenre, E, and King, G, Amelioration of vascular dysfunctions in diabetic rats by an oral PKC inhibitor, Science, 272:728–731, 1996. 77. Soulis, T, Thallas, V, Youssef, S, Gilbert, R, McWilliam, B, Murray-McIntosh, R, and Cooper, M, Advanced glycation end products and their receptors co-localise in rat organs susceptible to diabetic microvascular injury, Diabetologia, 40:619–628, 1997. 78. Friedman, EA, Advanced glycosylated end products and hyperglycemia in the pathogenesis of diabetic complications, Diabet. Care, 22(Suppl. 2):B65–71, 1999. 79. Lal, MA, Brismar, H, Eklof, AC, and Aperia, A, Role of oxidative stress in advanced glycation end product-induced mesangial cell activation, Kidney Int., 61:2006–2014, 2002. 80. Li, JF and Schmidt, AM, Characterization and functional analysis of the promoter of RAGE, the receptor for advanced glycation end products, J. Biol. Chem., 272:16498–16506, 1997. 81. Kelly, DJ, Gilbert RE, Cox, AJ, Soulis, T, Jerums, G, and Cooper, ME, Aminoguanidine ameliorates over-expression of prosclerotic growth factors and collagen deposition in experimental diabetic nephropathy, J. Am. Soc. Nephrol., 12:2098–2107, 2001. 82. Oldfield, MD, Bach, LA, Forbes, JM, Nikolic-Paterson, D, McRobert, A, Thallas, V, Atkins, RC, Osicka, T, Jerums, G, and Cooper, ME, Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE), J. Clin. Invest., 108:1853–1863, 2001. 83. Osicka, TM, Yu, Y, Panagiotopoulos, S, Clavant, SP, Kiriazis, Z, Pike, RN, Pratt, LM, Russo, LM, Kemp, BE, Comper, WD, and Jerums, G, Prevention of albuminuria by aminoguanidine or ramipril in streptozotocin-induced diabetic rats is associated with the normalization of glomerular protein kinase C, Diabetes, 49:87–93, 2000. 84. Shimoike, T, Inoguchi, T, Umeda, F, Nawata, H, Kawano, K, and Ochi, H, The meaning of serum levels of advanced glycosylation end products in diabetic nephropathy, Metabolism, 49(8):1030–1035, 2000. 85. Cooper, ME, Interaction of metabolic and haemodynamic factors in mediating experimental diabetic nephropathy, Diabetologia, 44:1957–1972, 2001. 86. Hansen, SH, The role of taurine in diabetes and the development of diabetic complications, Diabet. Metab. Res. Rev., 17:330–346, 2001. 87. Pasentes-Morales, H and Schousboe, A, Role of taurine in osmoregulation in brain cells: mechanisms and functional implications, Amino Acids, 12:281–292, 1997. 88. Lang, F, Busch, GL, Ritter, M, et al. Functional significance of cell volume regulatory mechanisms, Physiol. Rev., 78:247–306, 1998. 89. Greene, DA, and Stevens, MJ, The sorbitol-osmotic and sorbitol-redox hypotheses, in Diabetes Mellitus, LeRoith, D, Taylor, SI, and Olefsky, JM, Eds., Lippincott-Raven, Philadelphia, 1996, p. 801–809. 90. Kinoshita, JH and Nishimura, C, The Involvement of aldose reductase in diabetic complications, Diabet. Metab. Rev., 4:323–337, 1988. 91. Tomlinson, DR, Aldose reductase inhibitors and the complications of diabetes mellitus, Diabet. Med., 10:214–230, 1993.
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92. Sturman, JA, Minireview — taurine in development, Life Sci., 21:1–22, 1977. 93. Sorbinil Retinopathy Trial Research Group, A randomized trial of sorbinil, an aldose reductase inhibitor, in diabetic retinopathy, Arch. Ophthalmol., 108:1234–1244, 1990. 94. The Sorbinil Retinopathy Trial Research Group, The Sorbinil Retinopathy Trial: neuropathy results, Neurology, 43:1141–1149, 1993. 95. Burg, MB and Kador, PF, Sorbitol, osmoregulation and the complications of diabetes, J. Clin. Invest., 81:635–640, 1988. 96. Suzuki, KI, Hsiao, YC, Goto, Y, and Nomura, K, Improvement of peripheral nerve impairment by ARI (M79175) administration in spontaneously diabetic rats (GK rat), in Polyol Pathway and its Role in Diabetic Complications, Sakamoto, N, Kinoshita, JH, Kador, PF, Hotta, N, Eds., Elsevier, Amsterdam, 1988, 496–501. 97. Michalk, DV, Wingenfeld, P, and Licht, CH, Protection against cell damage due to hypoxia and reoxygenation: the role of taurine and the involved mechanisms, Amino Acids, 13: 337–346, 1997. 98. Wu, QD, Wang, JH, Fennessy, F, Redmond, HP, and Bouchier-Hayes, D, Taurine prevents high-glucose-induced human vascular endothelial cell apoptosis, Am. J. Physiol., 277:C1229–C1238, 1999. 99. Devamanoharan, PS, Ali, AH, and Varma, SD, Oxidative stress to rat lens in vitro: protection by taurine, Free Radic. Res., 29:189–195, 1998. 100. Halliwell, B, Oxidative stress markers in human disease: application to diabetes and to evaluation of the effects of antioxidants, in Antioxidants in Diabetes Management, Packer, L, Rosen, P, Tritschler, HJ, King, GL, and Azzi, A, Eds., Marcel Decker, New York, 2000, 33–52. 101. Bezkrovnaya, LA and Dokshina, GA, Determination of taurine in urine (in Russian), Lab. Delo., 9:539–541, 1981. 102. Martensson, J and Hermansson, G, Sulfur amino acid metabolism in juvenile-onset nonketotic and ketotic diabetic patients, Metabolism, 33:425–428, 1984. 103. Szabo, A, Kenesei, E, Korner, A, Milteyi, M, Szucs, L, and Nagy, I, Changes in plasma and urinary amino acid levels during diabetic ketoacidosis in children, Diabet. Res. Clin. Pract., 12:91–97, 1991. 104. Franconi, F, Bennardini, F, Mattana, A, et al., Plasma and platelet taurine are reduced in subjects with insulin-dependent diabetes mellitus: effects of taurine supplementation, Am. J. Clin. Nutr., 61:1115–1119, 1995. 105. Franconi, F, Miceli, M, Fazzini, A, et al., Taurine and diabetes — humans and experimental models, Adv. Exp. Med. Biol., 403:579–582, 1996. 106. Elizarova, EP, Mizina, TYU, and Nedosugova, LV, New use of taurine — as cell membrane-stabilizing preparation for treating insulin-dependent and non-insulindependent diabetes mellitus, Patent RU2054936–C1, 1994. 107. Elizarova, EP and Nedosugova, LV, First experiments in taurine administration for diabetes mellitus — the effect on erythrocyte membranes, Adv. Exp. Med. Biol., 403:583–588, 1996. 108. Nakamura, T, Ushiyama, C, Suzuki, S, et al., Effects of taurine and vitamin E on microalbuminuria, plasma metalloproteinase-9, and serum type IV collagen concentrations in patients with diabetic nephropathy, Nephron, 83:361–362, 1999. 109. Li, H, Li, JC, Jiang, SS, Du, H, and Gu, XP, Inhibiting effect of taurine on nonenzymatic glycosylation of aortic collagen in diabetic rats (in Chinese), Chin. Pharmacol. Bull., 12:445–447, 1996. 110. Devamanoharan, PS, Ali, AH, and Varma, SD, Prevention of lens protein glycation by taurine, Mol. Cell Biochem., 177:245–250, 1997.
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111. Trachtman, H, Futterweit, S, Maeseka, J, et al., Taurine ameliorates chronic streptozocin-induced diabetic nephropathy in rats, Am. J. Physiol., 1995; 269:F429–F438. 112. Trachtman H, Lu P, Sturman JA. Immunohistochemical Localization of Taurine in Rat Renal Tissue: studies in experimental disease states, J. Histochem. Cytochem., 41:1209–1216, 1993. 113. Ha, H, Yu, MR, and Kim, KH, Melatonin and taurine reduce early glomerulopathy in diabetic rats, Free Radic. Biol. Med., 26:944–950, 1999. 114. Alvestrand, A, Furst, P, and Bergstrom, J, Plasma and muscle free amino acids in uremia: influence of nutrition with amino acids, Clin. Nephrol., 18:297–305, 1982. 115. Bergstrom, J, Alvestrand, A, Furst, P, and Lindholm, B, Sulphur amino acids in plasma and muscle in patients with chronic renal failure: evidence for taurine depletion, J. Intern. Med., 226:189–194, 1989. 116. Suliman, ME, Anderstam, B, and Bergstrom, J, Evidence of taurine depletion and accumulation of cysteine sulfinic acid in chronic dialysis patients, Kidney Int., 50:1713–1717, 1996. 117. Suliman, Me, Anderstam, B, Lindholm, B, and Bergstrom, J, Total, free, and proteinbound sulphur amino acids in uraemic patients, Nephrol. Dial. Transpl., 12:2332–2338, 1997. 118. Divino, Filho, JC, Barany, P, Stehle, P, Furst, P, and Bergstrom, J, Free amino-acid levels simultaneously collected in plasma, muscle, and erythrocytes of uraemic patients, Nephrol. Dial. Transpl., 12:2339–2348, 1997. 119. Suliman, ME, Qureshi, AR, Barany, P, et al., Hyperhomocysteinemia, nutritional status, and cardiovascular disease in hemodialysis patients, Kidney Int., 57:1727–1735, 2000. 120. Reddi, AS and Bollineni, JS, Selenium-deficient diet induces renal oxidative stress and injury via TGF-1 in normal and diabetic rats, Kidney Int., 59:1342–1353, 2001. 121. Giugliano, D, Ceriello, A, and Paolisso, G, Oxidative stress and diabetic vascular complications, Diabet. Care, 19:257–267, 1996. 122. Yu, BP, Cellular defenses against damage from reactive oxygen species, Physiol. Rev., 74:139–162, 1994. 123. Thompson, KH and Godin, DV, Micronutrients and antioxidants in the progression of diabetes, Nutr. Res., 15:1377–1410, 1995. 124. Saedi, MS, Smith, CG, Frampton, J, et al., Effect of selenium status on mRNA levels for glutathione peroxidase in rat liver, Biochem. Biophys. Res. Commun., 153:855–861, 1988. 125. Toyoda, H, Himeno, SI, and Imura, N, The regulation of glutathione peroxidase gene expression relevant to species difference and the effects of dietary selenium manipulation, Biochim. Biophys. Acta., 1008:301–308, 1989. 126. Hill, KE, Lyons, PR, and Burk, RF, Differential regulation of rat liver selenoprotein mRNAs in selenium deficiency, Biochem. Biophys. Res. Commun., 185:260–263, 1992. 127. McNeil, JH, Delgatty, HLM, and Battell, ML, Insulinlike effects of sodium selenate in streptozotocin-induced diabetic rats, Diabetes, 40:1675–1678, 1991. 128. Becker, DJ, Reul, B, Ozcelikay, AT, et al., Oral selenate improves glucose homeostasis and partly reverses abnormal expression of liver glycolytic and gluconeogenic enzymes in diabetic rats, Diabetologia, 39:3–11, 1996. 129. Ezaki, O, The insulin-like effects of selenate in rat adipocytes, J. Biol. Chem., 265:1124–1128, 1990.
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130. Nath, KA, Grande, J, Croatt, A, et al., Redox regulation of renal DNA synthesis, transforming growth factor-1 and collagen gene expression, Kidney Int., 53:367–381, 1998. 131. Roberts, AB and Sporn, MB, Transforming growth factor-, Adv. Cancer Res., 51:107–145, 1988. 132. Hoffman, BB, Sharma, K, and Ziyadeh, FN, Potential role of TGF- in diabetic nephropathy, Miner. Electrolyte Metab., 24:190–196, 1998. 133. Basile, DP, The transforming growth factor beta system in kidney disease and repair: recent progress and future directions, Curr. Opin. Nephrol. Hypertens., 8:21–30, 1999. 134. Isaka, Y, Fujwara, Y, Ueda, N, et al., Glomerulosclerosis induced by in vivo transfection of transforming growth factor- or platelet-derived growth factor gene into the rat kidney, J. Clin. Invest., 92:2597–2601, 1993. 135. Kopp, JB, Factor, VM, Mozes, M, et al., Transgenic mice with increased plasma levels of TGF-1 develop progressive renal disease, Lab. Invest., 74:991–1003, 1996. 136. Babaei-Jadidi, R, Karachalias, N, Ahmed, N, Battah, S, and Thornalley, PJ, Prevention of incipient diabetic nephropathy by high-dose thiamine and benfotiamine, Diabetes, 52:2110–2120, 2003. 137. Tilton, RG, Baier, LD, Harlow, JE, Smith, SR, Ostrow, E, and Williamson, JR, Diabetes-induced glomerular dysfunction: links to a more reduced cytosolic ratio of NADH/NAD+, Kidney Int., 41:778–788, 1992. 138. Nishikawa, T, Edelstein, D, Liang, Du, X, Yamagishi, S, Matsumura, T, Kaneda, Y, Yorek, MA, Beede, D, Oates, PJ, Hammes, H-P, Giardino, I, and Brownlee, M, Normalizing mitochondrial superoxide production blocks three pathways of hyperglycaemia damage, Nature, 404: 787–790, 2000. 139. Thornalley, PJ, Jahan, I, and Ng, R, Suppression of the accumulation of triosephosphates and increased formation of methylglyoxal in human red blood cells during hyperglycaemia by thiamine in vitro, Jpn. J. Biochem., 129:543–549, 2001. 140. Gastaldi, G, Coya, E, Verri, A, Laforenza, U, Faelli, A, and Rindi, G, Transport of thiamin in rat renal brush border membrane vesicles, Kidney Int., 57:2043–2054, 2002. 141. Saito, N, Kimura, M, Kuchiba, A, and Itokawa, Y, Blood thiamine levels in outpatients with diabetes mellitus, J. Nutr. Sci. Vitaminol., 33:421–430, 1987. 142. Havivi, E, Bar On, H, Reshef, A, and Raz, I, Vitamins and trace metals status in noninsulin dependent diabetes mellitus, Int. J. Vit. Nutr. Res., 61:328–333, 1991. 143. Hirsch, IB, Atchley, DH, Tsai, E, Labbe, RF, and Chait, A, Ascorbic acid clearance in diabetic nephropathy, J. Diabet. Comp., 12:259–263, 1998. 144. Frei, B, England, L, and Ames, BN, Proc. Natl. Acad. Sci. U.S.A., 86:6377–6381, 1989. 145. Jialal, I and Grundy, SM, Preservation of the endogenous antioxidants in low density lipoprotein by ascorbate but not probucol during oxidative modification, J. Clin. Invest., 87:597–601, 1991. 146. Wartanowicz, M, Panczendo-Kresowska, B, Ziemlanski, S, et al., The effect of alphatocopheral and ascorbic acid on the serum lipid peroxide level in elderly people, Ann. Nutr. Metab., 28:186–191, 1984. 147. McLennan, S, Yue, DK, Fisher, E, et al., Deficiency of ascorbic acid in experimental diabetes, Diabetes, 37:359–361, 1988. 148. Ueno, Y, Kizaki, M, Nakagiri, R, Kamiya, T, Sumi, H, and Osawa, T, Dietary glutathione protects rats from diabetic nephropathy and neuropathy, J. Nutr., 132:897–900, 2002. 149. Meister, A and Anderson, M, Glutathione, Ann. Rev. Biochem., 52:711–760, 1983.
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Pathophysiology and Management of Diabetic Gastropathy Tan Attila, M.D. and Timothy R. Koch, M.D.
CONTENTS I. II. III. IV. V. VI.
Introduction................................................................................................428 Physiological Basis for Gastric Smooth-Muscle Activity ........................428 Pathophysiology of Diabetic Gastropathy.................................................429 Symptoms of Diabetic Gastropathy ..........................................................431 Perspectives on Evaluation of Gastric Emptying......................................431 Contemporary Methods for Evaluation of Gastric Emptying ..................432 A. Upper-Gastrointestinal X-Ray Series................................................433 B. Scintigraphic Assessment of Gastric Emptying ...............................433 C. Tracer Methods..................................................................................433 D. Ultrasonography ................................................................................434 E. Magnetic Resonance Imaging (MRI) ...............................................434 F. Electrogastrography (EGG)...............................................................434 VII. Evaluation of Patients with Suspected Diabetic Gastropathy ..................435 VIII. Treatment Strategies in Diabetic Gastropathy ..........................................436 A. Introduction .......................................................................................436 B. Dietary and Supportive Therapy .......................................................436 C. Optimizing Glycemic Control...........................................................436 D. Metoclopramide.................................................................................437 E. Erythromycin.....................................................................................437 F. Cisapride............................................................................................437 G. Domperidone .....................................................................................438 H. Tegaserod...........................................................................................438 I. Refractory Gastropathy .....................................................................438 IX. Future Studies ............................................................................................439 References..............................................................................................................439
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I. INTRODUCTION Diabetes mellitus, with an estimated prevalence of 3 percent to 10 percent of the population, is the fourth leading cause of death in the U.S. This disease complex can affect almost every organ system, including the gastrointestinal tract. Pathophysiologic changes involving the gut can be related to either acute hyperglycemia or chronic changes resulting from neuropathic or myopathic processes. This chapter will focus on the pathophysiology, diagnosis, and management of diabetic gastropathy. The clinical presentation of diabetic gastropathy is not specific and may overlap with both structural disorders and functional dyspepsia. Nausea, vomiting, bloating, early satiety, postprandial fullness, and upper-abdominal discomfort are the most common presenting symptoms.1 Abdominal pain, which is likely due to gastric distension or retension, may be an important component of the overall symptomatology.2 Interestingly, symptoms do not correlate well with gastric-emptying rate; therefore, an improvement in the gastric-emptying rate does not always result in symptomatic improvement, or vice versa.
II. PHYSIOLOGICAL BASIS FOR GASTRIC SMOOTH-MUSCLE ACTIVITY Gastrointestinal-contractile activity is regulated by smooth-muscle electromechanical properties.3 Gastric smooth muscle, similar to other smooth muscle, is characterized by a voltage-tension curve. In this relationship, depolarization of smoothmuscle cell membrane results in increased smooth-muscle tonic contraction. Slow waves, the basic gastric smooth-muscle electrical event, are periodic, regular depolarizations from the cell’s resting membrane potential.4 A slow wave follows a set sequence during changes in resting membrane potential: initially, a rapid upstroke depolarization, a partial repolarization, a sustained plateau potential, and then complete repolarization to the resting membrane potential. This chain of events is largely the result of activation and deactivation of calcium channels and calcium-dependent potassium channels. Only slow waves exceeding a threshold depolarization will result in an action potential leading to smooth-muscle contraction. The basic rhythmic activity of gastric smooth-muscle cells is thought to originate from the interstitial cells of Cajal, which are located in the greater curvature at the junction of proximal and distal stomach.5–8 Interstitial cells of Cajal are found throughout the gastrointestinal tract. Both extrinsic nerves innervating the stomach and the intrinsic gastric nervous system are in constant interaction with the interstitial cells of Cajal, and thus may modulate relaxation and contraction of gastric smooth muscle. The regional variation of the relationship between electrical activity and tension development is the result of a proximal-to-distal gradient in cell restingmembrane potentials from –48 mV in the fundus to –75 mV in the pylorus.6,9 This difference is likely related to differences in the density of calcium-dependent potassium channels, since a chemical voltage clamp involving different concentrations of potassium chloride can change both the resting-membrane potential and the tonic contraction of smooth muscle obtained from different regions of the stomach.10 This
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relationship has been suggested to be the electrical basis for contraction and relaxation in canine gastric smooth muscle.10 This relationship may aid in understanding the varying mechanical functions of different gastric compartments, as well as the propagation of slow waves in an organized fashion from the proximal body to the pylorus. In human stomach, gastric pacemakers generate rhythmic depolarizations at a frequency of three cycles per minute, resulting in circular muscle contractions.6,11 Abnormal rhythms of gastric myoelectrical activity, termed gastric dysrhythmias, originate from abnormal or ectopic gastric pacemakers. A suggested classification system includes a definition for tachygastria (> 6 cycles/min), bradygastria (< 3 cycles/min), bradytachyarrythmia, or absent activity.12, 13
III. PATHOPHYSIOLOGY OF DIABETIC GASTROPATHY In this chapter, we will address the pathophysiology, symptoms, and treatment options in patients with diabetic gastropathy. Potential pathophysiological abnormalities include: gastric dysrrhythmias,14–16 antral hypomotility,17 pylorospasm,18 and gastroparesis.14,19 There are several potential mechanisms to explain altered gastric physiology in patients with diabetes mellitus (Table 23.1). Almost 50 percent of diabetic patients have some form of neuropathy, such as peripheral, autonomic, proximal, or focal neuropathy, but gastrointestinal symptoms are not seen in all of these patients.20 Although the pathophysiology of diabetic neuropathy has not been clearly determined, the highest rates of diabetic neuropathy have been seen among patients with long-standing disease, especially in those patients with poor glycemic control.20,21 Although autonomic dysfunction, particularly vagal neuropathy,17,22–23 has been traditionally regarded as the likely origin for diabetic gastropathy, morphologic abnormalities of the vagus nerve or gastric myenteric plexus in patients with diabetes mellitus have not been routinely identified using conventional histology.24 Neuropathies, such as axonopathy in sympathetic nerves25 and ultrastructural and morphometric changes in parasympathetic nerves,26 have been described in animal models of diabetes mellitus.27,28 A decrease in the interstitial cells of Cajal, decreased inhibitory neurotransmitter systems containing neuronal nitric-oxide synthase, vasoactive intestinal peptide, or tyrosine hydroxylase immunopositive nerve fibers, and
TABLE 23.1 Potential Pathophysiologic Mechanisms for Diabetic Gastropathy 1. 2. 3. 4.
Neuropathy Myopathy Glycemic Control Impaired Antioxidant Capacity
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TABLE 23.2 Effects of Hyperglycemia on Upper Gastrointestinal Function 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
Delayed Gastric Emptying Accelerated Gastric Emptying Gastric Myoelectrical Disturbances Inhibition of Migrating Motor Complexes Inhibition of Antral Motility Pyloric Contractions Inhibition of Gallbladder Contractions Slowing of Small Intestinal Transit Disturbances of Esophageal Motility Decreased Lower Esophageal Sphincter Tonic Contraction
increased levels of excitatory neurochemical and substance P have been observed in the gut of long-standing diabetic patients.29 Further research examining the neuropathic aspects of diabetic gastropathy is needed to better define this potential pathophysiological feature. There is a complex relationship between glycemic control and upper-gastrointestinal function. Postprandial glucose levels both determine and are determined by the delivery rate of nutrients from the stomach to the small intestine. Studies in both healthy individuals and diabetic individuals have revealed that hyperglycemia can affect gastrointestinal function (Table 23.2). It has been previously shown that hyperglycemia can induce: 1) delayed gastric emptying;30–34 2) rapid gastric emptying;35 3) gastric myoelectrical disturbances;36 4) inhibition of migrating motor complexes; 5) inhibition of antral motility;37 6) pyloric contractions;38 7) inhibition of gallbladder contractions and small-intestinal transit;39,40 8) altered esophageal motility; and 9) decreased lower esophageal sphincter pressure.41 Normalization of blood-glucose levels in diabetic patients has been shown to improve gastric-emptying times.33 Previous studies have shown that secretion of the pancreatic hormone, human Pancreatic Polypeptide (hPP), is regulated by vagalnerve input. Hyperglycemia can reduce hPP secretion, as well as gastric secretory and plasma hPP responses to modified sham feeding in humans; these findings support the notion of impaired vagal-cholinergic activity during hyperglycemia.42,43 Very low plasma levels of hPP have been reported in diabetic patients with cardiac autonomic neuropathy and delayed gastric emptying.44 In support of this concept, patients with poorly controlled diabetes mellitus have an increased perception of upper-gastrointestinal symptoms, such as nausea, fullness, early satiety, and upperabdominal pain.45–47 The exact mechanisms by which hyperglycemia leads to disturbances in gastric motility has not been fully delineated. Unfortunately, much of the available information on the effects of blood-glucose concentration on upper-gastrointestinal motor and sensory function has been observational. Available data on potential mechanisms that may mediate these effects are sparse. Major neurochemicals involved in the regulation of gastrointestinal motor
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function include nitric oxide (NO),48–50 vagally mediated cholinergic input, and vasovagal reflexes.51,52 In animal studies utilizing diabetic rats, there is evidence supporting the presence of impaired NO-synthase expression in the gastric myenteric plexus.53 Delayed gastric emptying can be reversed by restoration of neuronal NOsynthase expression through addition of insulin or addition of the phosphodiesterase inhibitor sildenafil, which increases NO signaling.54 As an additional possible mechanism, impaired antioxidant status, which is associated with accelerated liquid gastric emptying,55 has been noted in individuals with impaired glucose tolerance and diabetes.56 However, a potential association with delayed gastric emptying has not yet been delineated. Defective cholinergic neuromuscular transmission in the myenteric plexus,57 impaired release of vasoactive intestinal polypepetide and calcitonin gene-related peptide during stimulation of enteric nerves,58 and impaired NO-mediated relaxation of the duodenum59 have been observed in diabetic rats. Indomethacin, a prostaglandin-synthesis inhibitor, reverses gastric dysrhythmia induced by hyperglycemia.60 Additional studies are needed to examine the effects of neurohumoral and cellular mechanisms, and to elucidate the effects of abnormal glucose homeostasis on gastrointestinal motor and sensory function. Although animal studies provide insight as to the mechanisms of diabetic gastropathy, we should be very careful in extrapolating this information into human disease. These observations suggest that the effect of glucose homeostasis on the gastrointestinal system is multifactorial, and more work is required to explore the pathophysiology of this common problem. In addition to the pathophysiological effects of glucose homeostasis on gastrointestinal motility, factors that modulate the rate of gastric emptying must be taken into consideration, such as volume, acidity, osmolarity, nutrient density, fat content, ileal fat, colonic/rectal distention, and use of medications.
IV. SYMPTOMS OF DIABETIC GASTROPATHY Although gastrointestinal symptoms are common among diabetic patients seen in diabetic clinics,62 the prevalence of most gastrointestinal-tract symptoms is similar in persons in the community without diabetes mellitus.63 In subspecialty clinics, 76 percent of diabetic patients who participated in a survey had one or more gastrointestinal symptoms (Table 23.3), including constipation, diarrhea, fecal incontinence, and upper-abdominal symptoms, including nausea and vomiting.62 These patients are not immune to the presence of functional gastrointestinal symptoms, perhaps leading to an overestimation of symptom prevalence.
V. PERSPECTIVES ON EVALUATION OF GASTRIC EMPTYING Beaumont made the earliest comments on the rates of gastric emptying in the early 19th century during his observations utilizing a patient with a traumatic gastric fistula.63 Von Luebe performed the first definitive gastric-emptying study by a single
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TABLE 23.3 Clinical Presentation for Patients with Diabetic Gastropathy 1. 2. 3. 4. 5. 6.
Abdominal Pain Nausea Emesis Abdominal Bloating Diarrhea Constipation
gastric aspiration seven hours after liquid-meal ingestion.64 Rehfuss introduced repeated sampling of gastric contents at regular intervals.65 Hunt and Spurrell used an aspiration technique to measure the volume of a residual test solution and the concentration of a marker that was believed to estimate the amount emptied.66 To overcome the need for repeated gastric intubation, George described a method using double-sampling of the stomach contents.67 A marker was administered following the initial sampling of a test meal. The marker concentration in the subsequent sampling allowed calculation of the remaining gastric volume, and the chloride concentration of the sample enabled determination of the rate of gastric secretion. Recovery of a gastric marker from the duodenum, with the help of duodenal and gastric intubation through a triple lumen assembly, allowed measurement of gastric emptying. In addition, distal-duodenal sampling allowed measurement of pancreatic and biliary secretions.68 The first gastric x-ray studies concentrated on gastric motility rather than evaluation of gastric-emptying time.69,70 Subsequent x-ray contrast studies examined the emptying of liquid barium sulfate or a radiopaque meal. With these techniques, only complete gastric-emptying time of radiopaque material could be calculated, because the volume and density of gastric residual barium could not be determined radiographically. Dissociation of barium into liquid phase allowed assessment of only liquid emptying in tests using solid meals impregnated with barium granules.71 Comparison of a barium test meal with scintigraphic gastric emptying did not reveal a correlation between the magnitude of retained barium at six hours and the halftime, as well as percentage of gastric isotope remaining at six hours after ingestion of a test meal.72 Therefore, results from these two tests are not comparable.
VI. CONTEMPORARY METHODS FOR EVALUATION OF GASTRIC EMPTYING The presence of multiple methods to evaluate gastric emptying is an indication of the absence of a precise and widely available technique (namely, a gold standard). Different techniques have limitations that need to be overcome. The following section critically analyzes and summarizes contemporary methods used for the assessment of gastric emptying of solids.
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A. UPPER-GASTROINTESTINAL X-RAY SERIES Since radiocontrast material is not a physiological meal and residual gastric barium can not be quantitatively measured, unless there is significant prolongation of gastric emptying, an upper-gastrointestinal X-ray series is not sufficiently sensitive to comment on gastric emptying. The primary role of these X-ray studies is to exclude a significant mucosal abnormality or a gastric-outlet obstruction.
B. SCINTIGRAPHIC ASSESSMENT
OF
GASTRIC EMPTYING
This test is sensitive, quantitative, noninvasive, easy to perform, and a physiologic method. Therefore, this test is currently considered to be the gold standard for the assessment of gastric emptying in research and clinical practice. The technique is based on the measurement of the disappearance of a radioisotope from the gastric region during scintigraphic scanning. Evaluation of gastric emptying of solids is a more sensitive technique, since gastric emptying of liquids is usually preserved even in the presence of abnormal solid gastric emptying. Gastric emptying of liquids can be clinically useful if the presence of rapid gastric emptying, termed dumping syndrome, is suspected. There are important, basic points that alter the sensitivity and specificity of scintigraphic gastric-emptying studies.73 First, radioisotope marker should effectively bind to substrate, be nonabsorbable, be resistant to a wide range of pH, and be stable during the procedure. All studies should contain the same meal volume, composition, and caloric content. A standard patient position should be preserved to prevent variations due to the effect of posture. Appropriate corrections for radioisotope decay, three-dimensional motion of intragastric material, penetration, attenuation, and scattering must also be considered. The use of a variety of radioisotopes, meals, and separate protocols by individual hospital centers impede the comparison of gastric-emptying studies from different institutions. Most major centers use either technetium99-labeled scrambled egg or chicken liver. Simplified standardized scintigraphic gastric-emptying protocols have been studied in order to establish normal gastric-emptying values, as well as to screen patients with suspected gastric dysmotility.74,75 In these studies, one-half emptying time of a gastric radioisotope (t1/2) is a commonly assessed parameter. Unfortunately, scintigraphic gastric-emptying studies do not provide information with regards to the etiology and pathophysiology of gastric dysmotility. There is frequently no direct correlation between gastric-emptying time, patient symptoms, and their response to therapy.76
C. TRACER METHODS These methods are based on the assumption that measurement of the appearance of a marker substance either in the blood or in expired air can serve as an indirect estimation of gastric emptying. Gastric emptying should be the rate-limiting step in the appearance of a marker substance either in the blood or in expired air. Specifically, the amount of gastric content that enters the duodenum should directly correlate with the amount that is absorbed and appeared in the blood or expired air. It is
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assumed that the absorption, transport, and metabolism of a marker are constant both interindividually and intraindividually. Mucosal diseases that alter absorption, pancreatic diseases, hepatic diseases, and pulmonary diseases, as well as hemodynamic variations, can alter the accuracy of these studies. Paracetamol,77 C13-octanoic acid,78–82 and C13-acetate have been used as markers in these tracer studies.83 In contrast to scintigraphic studies, the absence of ionizing radiation in C13 breath tests enables the safe evaluation of children and pregnant women. Tracer methods can be used in centers without gamma camera, in physician’s offices, or at a patient’s hospital bedside. These tests are considered as test choice in certain centers in Europe, but are not widely used at this time in the U.S.
D. ULTRASONOGRAPHY Real-time ultrasonographic evaluation of gastric emptying is based upon the measurement of changes in the cross-sectional area of the antrum in response to a test meal.84–86 The return of antral area and volume to the fasting baseline are considered to mark the final emptying time. Gastric-contraction frequency can also be measured by ultrasonography.87 Ultrasonography has been suggested to be equivalent to and a valid alternative to the use of scintigraphy.88,89 The main advantages of this method are that it is noninvasive, widely available, and there is absence of ionizing radiation. This makes ultrasonography suitable for repeated examinations. However, it is timeconsuming, operator dependent, and difficult to perform in obese patients. It is also difficult to perform this test in the presence of excessive abdominal gas, it generally measures liquid gastric emptying, and it is not suitable for patients following partial gastrectomy.
E. MAGNETIC RESONANCE IMAGING (MRI) This noninvasive, radiation-free technique is very promising for providing information on gastric emptying, anatomical morphology, and gastric secretion.90,91 Improvements in MRI technology could allow the study of gastric motility.92,93 The cost and availability of MRI presently limit its clinical utility.
F. ELECTROGASTROGRAPHY (EGG) EGG is a noninvasive method for the recording of gastric myoelectrical activity by placing electrodes on the anterior abdominal wall.95 The correlation between the cutaneous EGG recordings and myoelectrical activity recorded from gastric serosal electrodes has been previously validated.96–98 Important parameters that can be obtained with the use of EGG include different frequency components and relative power change.99 Normal gastric slow-wave frequency is considered to range between two and four cycles per minute. Conditions below this range are termed bradygastria, and above this range are termed tachygastria, or, as a general term, gastric arrhythmia. The relative power change corresponds to the gastric-contractile strength. Since gastric myoelectric activity is only one of many factors that alter gastric emptying, the correlation between EGG and gastric emptying is variable.100–103 According to a recent expert consensus opinion, the positive predictive value of an abnormal EGG
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History and Physical Examination
Laboratory Tests (CBC, TSH, Electrolytes), Abdominal X-Ray
Upper Endoscopy +/– Upper GI-Small Intestinal X-Ray
Mechanical Obstruction
No Obstruction
Treatment
Scintigraphy, Electrogastrography
Abnormal
Prokinetics, Antiemetics, Dietary Modification
Normal
Consider Etiologies, Symptomatic Treatment
FIGURE 23.1 Suggested evaluation of suspected diabetic gastropathya. Modified from suggestions of Hasler, WL and Chey, WD, Gastroenterology, 125, 1860, 2003.
to predict delayed gastric emptying averages 65 percent, while the accuracy of a normal EGG to predict normal gastric emptying averages 75 percent.104 Gastric dysrhythmias rather than gastric retension may be a better prognosticator of uppergastrointestinal symptoms.105 Therefore, EGG may be a complementary study rather than a replacement for standard gastric-emptying studies. Further studies are needed to clarify the potential role for and indications for performance of EGG.
VII. EVALUATION OF PATIENTS WITH SUSPECTED DIABETIC GASTROPATHY Suggestions for the potential evaluation of patients with suspected diabetic gastropathy are outlined in Figure 23.1. Major historical features can include a history of long-standing, insulin-dependent diabetes mellitus or a prior history of peptic-ulcer disease. The patient may have known diabetic nephropathy or diabetic retinopathy, which could support a diagnosis of gut autonomic neuropathy. A history of migraine headaches could support the presence of cyclical-vomiting syndrome. Suggestive gastrointestinal symptoms of diabetic gastropathy may include nausea, emesis, weight loss, history of dehydration, or early satiety. It is quite important to try to elicit the potential use of medications that can alter gastric emptying, including use of over-the-counter, nonsteroidal, antiinflammatory drugs or antihistamines, or prescription narcotics or anticholinergic compounds, such as antispasmotics. Nonsteroidal, antiinflammatory drug use may be detected by a serum platelet aggregation assay. Use of narcotics may be detected by urine screening. In young individuals, bulimia must be considered.
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On physical examination, potential evidence for a peripheral neuropathy (stocking, glove) should be sought. Examination of the extremities includes looking for evidence of sclerodactyly. Upon examination of the abdomen, percussion in the upper abdomen or shaking the upper abdomen may confirm the presence of a succussion splash. It can be helpful to perform auscultation of the abdomen during percussion of the upper abdomen, which is designed to elicit a splashing sound due to the presence of air and fluid in the stomach. Normally, less than 200 ml of fluid is present in the stomach following an overnight fast. Laboratory testing should include examination for potential thyroid dysfunction, hypokalemia, chronic renal failure, or hypercalcemia. Upper endoscopy is preferred in order to exclude ulcer disease or an obstruction at the pylorus or proximal duodenum. In the absence of obstruction, solid-meal gastric-emptying studies by scintigraphy are more readily available to look for evidence of delayed gastric emptying.
VIII. TREATMENT STRATEGIES IN DIABETIC GASTROPATHY A. INTRODUCTION The medical management of diabetic gastric disorders is challenging and may become frustrating for both clinicians and their patients. Present management principles include dietary and supportive care, optimizing care of an underlying etiology, and symptomatic relief. Medicines that alter gastrointestinal motility, such as anticholinergic medications and opiate agonists, should be avoided. Patients who do not respond to dietary and lifestyle modifications, improved glycemic control, and pharmacologic agents may be candidates for endoscopic or surgical intervention for symptomatic and supportive management.
B. DIETARY
AND
SUPPORTIVE THERAPY
Dietary modifications, such as use of low-residue, low-lipid, high-liquid-content meals in small but frequent portions may decrease bezoar formation, improve symptoms and prevent malnutrition, dehydration, and electrolyte imbalances. Some patients may benefit from a gastroparesis diet.106 Enteral feeding can permit adequate nutritional support and hydration in those patients who do not tolerate oral intake. Parenteral nutrition is reserved for patients in whom enteral feeding is not possible.
C. OPTIMIZING GLYCEMIC CONTROL Hyperglycemia may cause antral hypomotility and pyloric contractions,107 affect gastric motility,108 and impair the efficacy of prokinetic agents.109,110 Gastric-emptying disorders may result in erratic glycemic control due to variability of glucose availability or absorption. Optimizing glycemic control may improve gastric dysmotility and patient symptoms. It is not presently clear whether improved nutrition alters patient symptoms via a mechanism that could include increased tissue levels of antioxidants.
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D. METOCLOPRAMIDE Metoclopromide, the only Food and Drug Administration-approved agent for the treatment of gastroparesis, has both prokinetic and antiemetic effects through its antidopaminergic, 5-HT3 antagonist, and 5-HT4 agonist properties.106 Its prokinetic effects are limited to the upper-gastrointestinal tract. The usual oral dose ranges from 5 mg to 20 mg before meals and at bedtime, and is best provided in syrup form if gastroparesis is suspected. It can also be given to patients intravenously or subcutaneously if there is intolerance to oral intake. Although metoclopramide provides symptomatic relief and accelerates gastric emptying,111–113 its prokinetic effects are not sustained over a long period of time.114 It appears that its symptomatic relief may be due to its central antiemetic properties rather than being related to its prokinetic effects. Contrary to early studies, a more recent publication did not show any symptomatic, prokinetic benefit over use of a placebo.115 Numerous adverse events affect up to 20 percent of patients, including development of acute dystonic reactions, extrapyramidal effects, drowsiness, fatigue, lassitude, restlessness, akathisia, irritability, elevation of serum prolactin level, Parkinson-like symptom profile, and tardive dyskinesia (which may be irreversible after the discontinuation of the drug).113,116–118 The poor side-effect profile and inconsistent efficacy on gastric emptying may limit the long-term use of metoclopramide in patients with diabetic gastropathy and gastric retention.
E. ERYTHROMYCIN Erythromycin is a macrolide antibiotic that has prokinetic properties through its presumed activation of motilin receptors.119 This agent may increase the amplitude and frequency of antral contractions, as well as initiation of gastric phase three contractions of the migrating motor complex.120–121 There is a motilin-receptor gradient in mammalian gastrointestinal tract, with the highest concentrations identified in the upper-gastrointestinal tract.122 Administration of erythromycin has been reported to improve solid and liquid gastric emptying in diabetic, postvagotomy, and idiopathic gastroparesis.123–127 Intravenous doses in acute treatment range between 1 to 3 mg/kg every eight hours. The commonly used oral doses are between 50 to 250 mg/kg every six to eight hours. Although the optimal dosing and route of administration has not yet been resolved, oral regimen does not appear to be as effective as intravenous administration.128 Unfortunately, the long-term efficacy of erythromycin has been unsatisfactory and may include the risks of long-term antibiotic use.129 Adverse events induced by erythromycin include abdominal pain, cramping, nausea, and vomiting.
F. CISAPRIDE Cisapride, a prokinetic agent with a mixed 5-HT3 antagonist and 5-HT4 agonist activity, has been extensively evaluated in those patients with gastrointestinal dysmotility and gastroesophageal-reflux disease. Its effects on gastric emptying are likely due to stimulation and coordination of antral-pyloro-duodenal motility and possibly due to changes in gastric-outlet resistance.130–135 Although cisparide has
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been shown to accelerate gastric emptying in multiple studies, the correlation between improved gastric emptying and control of patient symptoms has remained less convincing.136–139 Reports of arrythmias and sudden death related to prolongation of the QT interval resulted in significant restrictions on the routine use of cisapride in the United States.140–142 Most of these adverse events occurred in the context of concomitant systemic diseases or drugs that could prolong cisapride metabolism.
G. DOMPERIDONE Domperidone, similar to metoclopromide, is an agent with both prokinetic and antiemetic properties related to its peripheral dopamine 2 receptor antagonist activity; this agent blocks dopamine’s inhibitory effects on smooth muscle.143 Domperidone is not available routinely in the United States, but it is available in Canada. Its antiemetic property is due to its antidopaminergic action on the central chemoreceptor trigger zone. Unlike metoclopromide, this agent does not cross the blood–brain barrier; therefore, adverse central nervous system side effects are less likely.144,145 Domperidone has been shown to improve liquid and solid gastric emptying and symptoms during the acute treatment of patients with diabetic gastroparesis.144,146 The long-term treatment effects on gastric emptying and symptoms have been variable.146–148 Side effects of domperidone are related to elevated serum prolactin levels, headache, diarrhea, somnolence, and abdominal pain.143
H. TEGASEROD Tegaserod is a serotonergic (5-HT4) receptor partial agonist and has been approved by the FDA for treatment of women with constipation-predominant irritable-bowel syndrome.149 Although it increases orocecal transit time with preliminary promising results on gastric emptying, further studies are needed to determine its role in the management of gastroparesis.150–152 Use of tegaserod has been associated in routine medical care with the development of diarrhea, and possibly ischemic colitis.
I.
REFRACTORY GASTROPATHY
Some patients with refractory diabetic gastropathy undergo repeated hospitalizations for dehydration, develop protein-calorie malnutrition, or require frequent outpatient encounters. Frequent hospitalizations and outpatient encounters for refractory nausea, vomiting, and dehydration can be major burdens to health-care costs, as well as to the patient’s quality of life. Acceptable management of these difficult problems in refractory patients has been developed in medical centers that utilize a team approach. Management decisions can include input from an endocrinologist, a gastroenterologist, a nutritionist, a therapeutic radiologist, and a gastrointestinal surgeon. Therapeutic options that utilize pharmacologic agents are limited for the treatment of refractory gastroparesis. Surgically or endoscopically placed gastro-jejunal or jejunal feeding tubes provide nutrition and rehydration by using a defined formula diet or elemental diet, and permit delivery of medications in a patient with a poorly emptying stomach. A gastrostomy or jejunostomy port allows simultaneous decompression of a dilated stomach or small intestine.153,154 Unfortunately, it is extremely
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difficult and time-consuming to maintain gastrojejunostomy tubes that have been placed by therapeutic endoscopy. These devices are best managed in specialized centers that have extensive experience in their utilization and limitations. The use of total parenteral nutrition can be considered, especially in those patients with a generalized gastrointestinal motility disorder. Total parenteral nutrition should be reserved for those individuals who have not responded clinically during the use of an elemental diet. Data on the long-term effects of parenteral and enteral nutrition and micronutrients on diabetic gastroparesis is lacking. Early data appears promising in specialty centers that have studied an externalstimulation device with temporary electrodes to pace the stomach.155–157 These studies have shown improvement in symptoms and gastric emptying. Although these devices are available in the United States, further controlled trials are needed to define their role in the management of refractory diabetic gastroparesis. Select patients with refractory diabetic gastroparesis have been referred to surgery for total gastrectomy and formation of an esophago-jejunostomy. This extensive procedure should be reserved for those medical centers in which there is experience in the complex preoperative and postoperative evaluation and management of these patients.
IX. FUTURE STUDIES Diabetes mellitus is a common medical problem that can result in gastrointestinal dysmotility secondary to acute hyperglycemic changes or chronic changes resulting in neuropathic or myopathic disorders. The most common presenting symptoms of patients with diabetic gastroparesis are nausea, vomiting, bloating, early satiety, postprandial fullness, and upper-abdominal discomfort and pain. Available clinical treatments are often unsatisfactory for refractory patients. Future research goals could include studies of micronutrient supplementation or studies of improved glycemic control by pancreas or islet-cell transplantation. It will be important to assess their effects on clinical symptoms, gastric emptying, and myopathic and neuropathic changes in the gut.
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5. Thuneberg, L, Interstitial cells of Cajal, in Handbook of Physiology: The Gastrointestinal System, Vol. 1, Shultz, SG, Wood, JD, and Rauner, BB, Eds., Oxford University Press, New York, 1989, chap. 10. 6. Szurszewski, JH, Electrophysiological basis of gastrointestinal motility, in Physiology of the Gastrointestinal Tract, Vol. 1, Johnson, LR, Christensen, J, Jackson, MJ, Jacobson, ED, and Walsh, JH, Eds., Raven Press, New York, 1987, chap. 12. 7. Hanani, M and Freund, HR, Interstitial cells of Cajal — their role in pacing and signal transmission in the digestive system, Acta. Physiol. Scand., 170, 177, 2000. 8. Horowitz, B, Ward, SM and Sanders, KM, Cellular and molecular basis for electrical rhythmicity in gastrointestinal muscles, Ann. Rev. Physiol., 61, 19, 1999. 9. El-Sharkawy, TY, Morgan, KG, and Szurszewski, JH, Intracellular electrical activity of canine and human gastric smooth muscle, J. Physiol., 279, 291, 1978. 10. Morgan, KG, Muir, TC, and Szurszewski, JH, The electrical basis for contraction and relaxation in canine fundal smooth muscle, J. Physiol., 311, 475, 1981. 11. Hinder, RA and Kelly, KA, Human gastric pacesetter potential: Site of origin, spread, and response to gastric transection and of proximal vagotomy, Am. J. Surg., 133, 29, 1997. 12. Koch, KL and Stern, RM, Electrogastrography, in Illustrated Guide to Gastrointestinal Motility, Kumar, D and Wingate, D, Eds., Churchhill Livingstone, London, 1993, 290. 13. Chen, JDZ and McCallum, RW, Clinical applications of electrogastrography, Am. J. Gastroenterol., 88, 1324, 1993. 14. Koch, KL, Stern, RM, Stewart, WR, and Vasey, MW, Gastric emptying and gastric myoelectrical activity in patients with diabetic gastroparesis: Effect of long-term domperidone treatment, Am. J. Gastroenterol., 84, 1069, 1989. 15. Rothstein, RD, Alavi, A, and Reynolds, JC, Electrogastrography in patients with gastroparesis and effect of long-term cisapride, Dig. Dis. Sci., 38, 1518, 1993. 16. Koch, KL, Electrogastrography: Physiological basis and clinical application in diabetic gastropathy, Diabet. Tech. Ther., 3, 51, 2001. 17. Malagelada, JR, Rees, WD, Mazzotta, LJ, and Go, VLW, Gastric motor abnormalities in diabetic and postvagotomy gastroparesis: Effect of metoclopramide and bethanechol, Gastroenterology, 78, 286, 1980. 18. Mearin, FO, Camilleri, M, and Malagelada, JR, Pyloric dysfunction in diabetics with recurrent nausea and vomiting, Gastroenterology, 90, 1919, 1986. 19. Quigley, EMM, Gastric motor and sensory function, and motor disorders of the stomach, in Sleissenger and Fordtran’s Gastrointestinal and Liver Disease, Feldman, M, Friedman, LS, and Sleisenger, MH, Eds., WB Saunders, Philadelphia, 2002, 691. 20. http://diabetes.niddk.nih.gov/dm/pubs/neuropathies. 21. Fedele, D and Giugliano, D, Peripheral diabetic neuropathy. Current recommendations and future prospects for its prevention and management, Drugs, 54, 414, 1997. 22. Camilleri, M and Malagelada, JR, Abnormal intestinal motility in diabetics with the gastroparesis syndrome, Eur. J. Clin. Invest., 14, 420, 1984. 23. Dooley, CP, el Newihi, HM, Zeidler, A, and Valenzuela, JE, Abnormalities of the migrating motor complex in diabetics with autonomic neuropathy and diarrhea, Scand. J. Gastroenterol., 23, 217, 1988. 24. Yoshida, MM, Schuffler, MD, and Sumi, SM, There are no morphologic abnormalities of the gastric wall or abdominal vagus in patients with diabetic gastroparesis, Gastroenterology, 94, 907, 1988. 25. Yagihashi, S and Sima, AA, Diabetic autonomic neuropathy in the BB rat. Ultrastructural and morphometric changes in sympathetic nerves, Diabetes, 34, 558, 1985.
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Index 5-hydroxytryptamine. See Serotonin 8-isoprostaglandin F2 alpha, 321 higher concentrations in poorly controlled diabetes, 324 negative correlation with sudomotor function, 326, 328 suppression by vitamin E, 336 synthesis as measure of oxidative stress, 328, 330 vs. insulin requirement, 334
A Abdominal bloating, in diabetic gastropathy, 432 Abdominal obesity, 181–182 beneficial effects of exercise on, 185–186 reduced with metformin and flutamide, 192 as risk factor in childhood diabetes, 179 Abdominal pain, in diabetic gastropathy, 428, 432 Acanthosis nigricans, 180 Acarbose, 222 in diabetes prevention in children, 191 low tolerance by adolescents, 196 therapeutic efficacy in diabetes, 35 Accelerated gastric emptying, 430 Acipimox, 166–167 Activities of daily living (ADL), 6 Adenosine triphosphate (ATP), 80, 348 Adherence. See Diet adherence Adhesion molecules, links to AGE production, 408 Adipocyte-derived signals, 11 Adipocytokines, 11 as therapeutic candidates, 195–196 Adiponectin deficiency with insulin resistance, 11 reduced expression in obese subjects, 182 secretion by fat cells, 11 therapeutic possibilities of, 195 Adipose tissue expression of TNFα in, 85 high capacity for heat production, 80 increased sensitivity with reduced abdominal fat mass, 185–186 role in glucose homeostasis, 162 Adjustable gastric banding (AGB), 114. See also Gastric banding
Adrenal glands, associations with insulin levels and weight loss, 207 Adrenocorticotropic hormone (ACTH), 9 Adult Treatment Program III (ATP III) criteria for metabolic syndrome, 58 definition of metabolic syndrome, 57–58 Advanced glycation end products (AGE), 363, 389, 400 formation of, 406, 415 free-radical production by, 364 link to oxidative stress, 402 link to PKC activation, 408 physiological effects of, 405 reduction after kidney transplantation, 406 role in diabetic nephropathy, 404–409 role in etiology of PNS neuropathy, 382 Aerobic exercise, 51 effect not dependent on exercise intensity, 66 increase in muscle-oxidative activity and insulin sensitivity with, 186 increased ADP concentrations with, 308 African Americans beneficial exercise effects on systolic blood pressure, 66 disproportionate suffering from diabetes complications, 228 poor control of diabetes, 154 prevalence of diabetes among, 142, 181 prevalence of obesity among, 231 qualifying criteria for metabolic syndrome, 60 reduced HbA1c testing frequency among, 232 relative degree of insulin resistance among, 228 relative risk of diabetic nephropathy, 152 risk of diabetes at lower BMIs, 146 risk of diabetic nephropathy, 399 risk of posttransplantation diabetes, 145–146 visceral fat stores among, 60 African countries. See Developing countries Age non-dependence of glucose tolerance on, 68 and risk of vascular complications, 368 AGE inhibitors, renoprotective effects of, 408 AGE receptor (RAGE), 364 consequences of activation, 407 Aging as end effect of AGEs, 405 insulin resistance and, 88
449
450
Nutrition and Diabetes: Pathophysiology and Management
Agouti-related protein (AgRP), promotion of hyperphagia and obesity by, 8 Akesis formula, 354 Albumin-excretion rate (AER), 404 Alcohol consumption as risk factor for diabetes type 2, 147–148 dietary recommendations for weight loss, 49 Aldose reductase inhibitors (ARIs), 387 Alpha-glucosidase inhibitors, 222, 228 Alpha-lipoic acid protective effects in type 2 diabetes, 352 targeting of PNS oxidative injury with, 386 American Diabetes Association, 44 guidelines for diagnosis of diabetes, 143–145 American Society for Bariatric Surgery, 125 American Society for Clinical Nutrition, 44 Amino acids benefits of supplementation with high-fat feeding, 208 catabolism of, 163 and high-protein diets, 218–220 Amputation higher rates among minorities, 229 prevalence in African countries, 254 prevention among minority diabetics, 424 risk in diabetes, 150–151 Amylin, 197 Amyloid, deposition in pancreatic islets, 180–181 Analysis of variance (ANOVA), 322 Angiotensin converting enzyme (ACE) inhibitors, 242 attenuation of AGE formation with, 408 in prevention of renal microvascular and peripheral nerve disease, 388–389, 415 Animal studies, impact of dietary factors in glycemia, 206–208 Anorexigenic neuropeptides, 9 cocaine- and amphetamine-regulated transcript (CART), 9–10 melanocortins, 9 serotonin, 10 Anticonvulsants, topiramate, 104–105 Antidepressants continuation after surgery, 128 thiazolidinediones, 238 Antidiabetic agents, 236–237. See also Drug development approaches based on limiting fatty acids availability, 166–167 beta-3 agonists, 169 combination therapy, 239 design based on nutrient interactions, 165–166 dichoroacetate (DCA), 168
discontinuation after surgery, 128 dose reduction with weight loss, 45 exendin-IV, 36 GLP-1 analogues, 17–18, 30–31 inhibition of fatty-acid oxidation by, 167 inhibition of gluconeogenesis by, 168–169 insulin secretagogues, 237 metformin, 168, 237–238 mixed-type glucokinase activators, 313 non-necessity after gastric bypass, 118 nutritionally based therapeutic approach, 170–172 Pioglitazone, 170 PPARs, 169–170 reduced response among overweight/obese persons with diabetes, 44 role in obesity management, 104–105 rosiglitazone, 170 simultaneous use of multiple, 236 (See also Combination therapy) troglitazone, 169–170 Antiepileptics, zonisamide, 105 Antiobesity drug development strategies ghrelin antagonism, 16 NPY antagonism, 8 Antioxidant formulas, 354, 371 Antioxidant supplementation alpha-lipoic acid, 352, 386 beta-carotene, 351 coenzyme Q10, 352 glutathione, 351–352 for glycemic control in type 2 diabetes, 349 innovative antioxidant formulations, 354–355 trace metals, 353 vitamin C, 350–351 vitamin E, 350, 370–371 Antioxidant therapies aldose reductase inhibitors (ARIs), 387 alpha-lipoic acid, 386 growth factors, 387–388 targeting of PNS oxidative injury with, 386 Antioxidants, 362 amelioration of thromboembolic risk by, 367 defenses in chronic diabetes, 336–337 enhancement of nitric-oxide bioavailability by, 337 high levels associated with decreased diabetes risk, 347 increase as therapeutic strategy for pancreatic β-cell preservation, 312–313 micronutrients and enzymes as separate systems of, 354 neutralization of reactive-oxygen species by, 345
Index
451
protective effects in pancreatic β-cells, 308 in repair of pancreatic β-cells, 311–312 trace elements as, 353 trials in diabetes, 337 Antral hypomotility, 429 erythromycin therapy for, 437 Anxiety, association with binge eating, 102 Apoptosis, 307 caution in prevention in pancreatic β-cells, 313 in glomerular cells via oxidative stress, 402 high sensitivity of pancreatic β-cells to, 304 intrinsic and extrinsic pathways in pancreatic β-cells, 309 manifestations in pancreatic β-cells, 308–311 mechanisms in PNS injury, 383 model in neurons, 384 promotion by nitric oxide, 335 Appetite, 6 CNS control of, 18 reduction through metformin therapy, 168 Appetite control, role of physical activity in, 72 Arcuate nucleus (ARC), 7 Asian Americans, response to antidiabetic agents, 228 Asians beneficial exercise effects on hypertension, 66 prevalence of diabetes among, 181 Asthma, in children with diabetes, 187 Atherogenesis in childhood obesity and diabetes, 187–188 as end effect of AGEs, 405 Atkins Diet program, 215 ATP/ADP regulation, 304–306 Attila, Tan, 427 Autonomic function, and uric acid in type 1 diabetes, 331–332 Axokine, 104
B β-cell function adverse effect of chronic hyperglycemia on, 333 oxidative stress and, 333–335 progressive decline due to glucose toxicity and lipotoxicity, 349 β-cell rest concept, 314 Back pain, disappearance after surgery, 132 Bales, Connie W., 43 Bariatric surgery, 53, 111 biliopancreatic diversion, 119–120 current surgical therapies for morbid obesity, 114–120
defined, 112 gastric bypass, 117–118 history, 112–114 Lap-Band, 126 laparoscopic adjustable gastric banding, 115–117 laparoscopic options, 120 patient selection, 114 postoperative management, 125–132 predictors of complications, 126–132 preoperative evaluation for, 114 risk factors, 112 Roux-en-Y gastric bypass, 125–126 Bartholin gland abscess, as presenting symptom in childhood diabetes, 187 Basal energy expenditure, 6 Basal insulin, 240 BDNF, 388 Behavioral issues, as barrier to diet modification, 102 Beta-3 agonists, 169 Beta-cell mass, 183. See also Progressive betacell failure and benefits of pharmacologic treatment of young persons, 197 mechanisms of lipotoxicity in, 184 reduction in, 180 Biguanides, 168–169, 220–221 Biliopancreatic diversion, 113, 114, 119–120 Binge-eating disorder, 9, 102, 130 reduction with topiramate, 105 Blindness higher rates among minorities, 229 in pregnancy, 270 Blood, water volume of, 284–285 Blood-glucose regulation, nutrient interactions in, 162–163 Blood-glucose simulations, 281–282 comparison of three control algorithms, 294–295 detailed glucose model, 283–285 detailed insulin model, 285–286 exercise model, 288 GLUCOSIM software, 289–291 healthy-person model, 287 illustrative case studies, 291–295 insulin injection to subcutaneous and intraperitoneal areas, 292–294 models for, 282–283 overall model for glucose and insulin, 286–287 simulation software, 289 simulation with continuous insulation regulation by pump, 292 Blood pressure
452
Nutrition and Diabetes: Pathophysiology and Management
criteria for metabolic syndrome, 58, 59 decrease postsurgically, 128 exercise training effects on, 64–66 importance of monitoring during pregnancy, 277 improvements with TZDs, 238 lowering with physical activity, 49 negative correlation with nitric oxide, 330 poor control in African countries, 254 reductions after gastric bypass, 118 reductions with TZD therapies, 194 Blunted muscle insulin-signal transduction, obesity and, 81–83 Boan, Jarol, 99, 125 Body composition diet-specific gender effects with high-protein diets, 219 effects of leptin on, 15 Body-mass index (BMI), 44, 112 and capacity for voluntary exercise, 190 defined, 99 in definition of obesity, 99–100 ideal body-weight goal, 46 independence of cardiorespiratory fitness from, 63 prepregnancy, 145 recommendations for OW/OB with diabetes, 52 reduction with topiramate, 105 Bogalusa Heart Study, 187 Bone-mineral density, preserved with aerobic exercise, 51 Brachial-artery endothelial dysfunction, 187 Brain stem, role in feeding control, 7 Branched-chain amino acids, as metabolic fuel, 163 Breast-feeding encouraging in diabetic women, 278 lower risk of childhood diabetes with, 181, 189 Brown adipose tissue, leptin in, 12
C C-reactive protein in differential diagnosis of diabetes in children, 180 inclusion in criteria for metabolic syndrome, 59 Caffeine, reducing intake in children and adolescents, 198 Calcium inverse correlation with diabetes risk, 185
low intake as risk factor in childhood diabetes, 179 Calcium channel blockers, possible role in reducing oxidative stress, 371 Calcium-channel oxidative stress, 307, 309 Caloric restriction, 46–48, 53 recommendations for OW/OB with diabetes, 52 recommendations for weight reduction by body mass index, 47 Cancer, risks with excess body mass, 44 CAPRIE study, 149–150 Carbohydrate intake acarbose limitation of GI absorption, 191 complex carbohydrates, 211 GLP-1 secretion and, 30 glycemic index considerations, 210 human studies in dietary effects of, 209–210 reduced FPG and insulin levels with lowcarbohydrate diets, 213 Carbohydrate metabolism beneficial effects of exercise training on, 186 and metabolic inflexibility in obesity, 89–91 Cardiac defects, due to poor glycemic control in diabetic gravidas, 270–271 Cardiorespiratory fitness and clustering of factors in metabolic syndrome, 62 importance to diagnosis and etiology of metabolic syndrome, 60–63 independence from body-mass index, 63 interindividual differences in, 103 inverse association with metabolic syndrome, 58 rationale for including in metabolic syndrome, 59, 71–72 as reflection of long-term habitual activity, 63 Cardiovascular disease risk, 240 association with microalbuminuria, 400 in childhood diabetes and obesity, 187–188 with excess body mass, 44 guidelines for monitoring and surveillance of, 230 increased with GIP-receptor antagonists, 37 metabolic syndrome and, 57 reduced with physical activity, 49 reduced with TZD therapy, 195 Carnitine palmitoyltransferase 1 (CPT-1) and fat oxidation in skeletal muscle, 86–87 metabolics of, 165 as rate-limiting enzyme in fatty-acid metabolism, 167 Carotid intima-media thickness (CIMT), in young adults, 187 Catalase (CAT), 401
Index Caucasians beneficial exercise effects on hypertension, 66 qualifying criteria for metabolic syndrome, 60 risk of type 1 diabetes and progression to nephropathy, 400 Central nervous system (CNS), localization of food control in, 7 Cerebrovascular disease, 369 as complication of diabetes, 151–152 Childhood diabetes, 177–178 acute complications, 186–187 atherogenesis and, 187–188 cardiovascular disease and, 187–188 complications, 186–188 contribution of soft drinks to, 185 diagnosis, 178–180 hypertension and, 187–188 islet autoimmunity in, 179–180 lifestyle interventions in prevention of, 189–190 lower risk with breast-feeding, 181 pathogenesis of, 180–184 pharmacologic treatment of, 197–198 presenting manifestations, 186–187 prevention in high-risk subjects, 189–196 risk factors, 180–184 role of diet in, 184–185 role of exercise in, 185–186 Cholecystitis, as presenting symptom in childhood diabetes, 187 Cholecystokinin, 18 Cholesterol dietary recommendations for weight loss, 49 lowering with metformin therapy, 192 Chromium supplementation, effect on glycemic control, 353 Chronic obstructive pulmonary disease (COPD), cautions with metformin use, 220–221 Chylomicro triacyl-glycerol (TAG), clearance by GIP, 31 Cigarette smoking discouraging in children and adolescents, 198 as risk factor for diabetes type 2, 147–148, 209 and risk of vascular complications, 368 Cinar, Al, 281 Circuit training, 52 Cirrhosis association with impaired glucose metabolism, 146 as presenting symptom in childhood diabetes, 187 Cisapride, in therapy of diabetic gastropathy, 437–438 Clopidogrel, 149–150
453 CNS neuropeptides, modulation of food intake by, 10 Cocaine- and amphetamine-regulated transcript (CART), anorexigenic effects of, 9–10 Coenzyme Q10, protective effects in type 2 diabetes, 352 Cofactors, role in glycemic control, 353 Combination therapy, 239 Combination training, health benefits of, 52 Comorbidities, association with obesity, 111 Complex-carbohydrate intake, 211, 235 Complications. See also Side effects cerebrovascular, 369 in childhood diabetes, 186–187 coronary disease, 369 diabetic foot, 230 at diagnosis in developing countries, 253–254 early presentation in African countries, 263 following laparoscopic adjustable gastric banding, 116 following laparoscopic biliopancreatic procedures, 120 following open gastric bypass, 118 guidelines for monitoring and surveillance of, 230 health-care costs associated with, 140 immediate postoperative period, 127–128 and levels of oxidative stress, 346 likelihood with late diagnosis, 230 macrovascular, 369–370 microvascular, 368–369 multifaceted approach to prevention of, 197–198 nephropathy, 368–369 peripheral vascular, 369–370 predictors of, 126–127 prevention as primary goal of diabetic management, 229 prevention in ethnic minorities, 240–242 retinopathy, 368 risk among African Americans, 228 role of AGEs in pathogenesis of, 364, 409 signaling pathways underlying development of, 349 six weeks to two months postsurgery, 129–130 two to twelve months postsurgery, 130–132 vascular, 361–362 Congenital abnormalities, due to maternal diabetes, 270 Congestive heart failure in African presentations, 254 as contraindication for troglitazone, 222 as contraindication for TZDs, 238
454
Nutrition and Diabetes: Pathophysiology and Management
Constipation in diabetic gastropathy, 431, 432 tegaserod treatment for, 438 Continuous snacking. See also Grazing lifestyle as postsurgical complication, 131 Contraception. See also Planned pregnancy importance for diabetic women, 278 Coping mechanisms, in postsurgical follow-up, 131 Corn syrup, association with diabetes prevalence, 210 Coronary heart disease, 369 association with obesity, 99, 112 as complication of diabetes, 149–150 impact of pregnancy in pre-existing diabetes, 270 and low-fat diet recommendations, 210 Corticotropin releasing hormone (CRH), 7 CPI 975, 167 CPT-1 inhibitors, 167 Creatinine, microalbuminaria as ratio of excretion of, 241 Cross-sectional studies, importance of physical fitness/exercise to etiology of metabolic syndrome, 60–63 Cultural/social factors, as barrier to diet modification, 101–102
D Dagogo-Jack, Samuel, 5, 227 Delayed gastric emptying, 430 improvements through restoration of NOsynthase expression, 431 Dental disease, as complication of diabetes, 153 Depression association with binge eating, 102 as barrier to diet modification, 102 Detailed glucose model, 283–285 Detailed insulin model, 285–286 Developing countries clinical presentation at diagnosis, 253 coexistence of malnutrition with obesity, 257 complications of diabetes in, 253–254 cultural aspects of diabetes care, 255 diabetes management in, 249–250 dietary management in, 256–257 epidemiology of diabetes in, 250–251 insulin therapy issues in, 259–260 ketosis-prone atypical diabetes mellitus in, 252–253, 260–261 lifestyle management of diabetes, 256–259 pathophysiology of diabetes in, 251–253
pharmacological diabetes management, 259–261 physical activity in lifestyle management, 257–259 prevalence estimates of diabetes, 262 state of diabetes education, 255–256 tropical diabetes in, 251–252 type 1b diabetes in, 252–253 use of oral hypoglycemic agents in, 259 Diabesity, 44 Diabetes antioxidant defenses in chronic, 336–337 antioxidant trials, 337 approaches to management of obesityassociated, 205, 210–212, 220, 223 association of oxidative stress with, 345 association with increased FAT/CD36, 88–89 beneficial glycemic effects of high-protein diets, 218–219 in childhood, 177–198 (See also Childhood diabetes) clinical presentation in developing countries, 253–254 decreased leptin response in, 13 defined, 142–143 in developing countries, 250–251 diagnostic criteria, 143–145 diet and exercise interventions, 43, 147 diminished GLP-1 secretion in, 35 diminished response to insulinotropic action of GIP in, 34 dose-response effect of exercise on, 68 effect on uric-acid excretion, 332 effects on nitric oxide, 328–330 enteroinsular axis in, 33–34 epidemic proportions of, v epidemiology, 139 estimated prevalence in Africa, 250, 262 GIP receptor/postreceptor defects in, 34 health-care expenditures associated with, 140 high-protein diets in management of, 218–220 hypertension, atherogenesis, and cardiovascular disease in, 187–188 impact on pregnancy, 270–272 improved glycemic control with subcutaneous GLP-1 injection, 17 increased SOD and GPX activity in, 347 level of health care in, 153–154 link to excess body weight, 44 long-term improvements postpartum, 269 low-carbohydrate diets in nutritional management of, 213–217 low-fat diets in nutritional management of, 210–212 mental health and, 148
Index metabolic syndrome and, 57 microalbuminuria as risk factor for, 147 MUFA diets in nutritional management of, 212–213 nutritional management, 210–220 oxidative injury in peripheral neuropathy, 381–390 oxidative stress and vascular complications in, 361–371 pathophysiology in developing countries, 251–253 pharmacologic treatment of, 197 pharmacotherapy in prevention of, 190–196 physical limitations and, 148 in pregnancy, vi, 267–268 (See also Gestational diabetes) premature mortality in, 153 prevalence, 140–142, ix prevalence of undiagnosed among minorities, 230–231 prevention in high-risk children, 189–196 reduced incretin effect in, 33 reduced onset after biliopancreatic diversion, 120 relationship to obesity, 99, 100–101 risk factors, 145–148, 181 therapeutic aspects of GLP-1 and GIP in, 34–37 treatment approaches to oxidative stress and vascular complications in, 370–371 treatment design based on nutrient interactions, 165–166 Diabetes care cost in developing African countries, 261–263 cultural aspects in African countries, 255 organization in developing countries, 254–255 Diabetes Control and Complications Trial (DCCT), 381, 403 Diabetes education, 234–235 in African countries, 255–256 in pregnant women with diabetes, 278 Diabetes management, 205 animal studies of at-risk subject, 206–208 biguanide therapy, 220–221 carbohydrate intake in human studies, 209–210 cultural barriers in minorities, 231–232 in developing countries, 249–263 diabetes education strategy, 234–235 dietary effects on subjects at risk, 206–210 dietary fat intake in human studies, 208–209 in gestational diabetes, 272–275 goal setting in, 233 goals of, 229–230 high-protein diets, 218–220
455 insulin therapy, 222–223 internal triage strategy, 233 ketosis-prone diabetes, 260–261 low-carbohydrate diets, 213–217 low-fat diets, 210–212 MEDEM strategy for, 228 MUFA diets, 212–213 nonpharmacological measures, 234–236 nutritional management options, 210–220 obesity and physical inactivity as barriers to, 231 oral hypoglycemic agents, 220–222 pharmacologic management options, 220–223 promoting pseudohypoglycemia awareness, 233–234 psychological barriers in minorities, 231–232 role of nutrition in, v socioeconomic barriers in minorities, 231–232 strategies and tactics for minorities, 233–240 sulfonylureas therapy, 221 TZD therapies, 222 in U.S. minorities, 227–243 (See also Ethnicity) Diabetes Prevention Program, 69, 103, 192 Diabetes software, 282 Diabetes type 1, 140 biochemical measures of oxidative stress, 322 decreased uric acid in, 331–332 early changes in peripheral-nerve function, 322–323 early expressions of oxidative stress, 324–326 effect of exercise on glucose-insulin interaction in, 288 hemodynamic consequences of nitrosative stress in, 330–331 increased protein-bound nitrotyrosine in, 326 oxidative stress and peripheral-nerve function in early, 326–328 oxidative stress in, 319–320, 320–321 patient characteristics, 321–322 peripheral-nerve testing, 322 in pregnancy, 268, 275–278 prothrombotic environment and platelet activation in, 367 research design for oxidative stress, 321–322 risk of diabetic nephropathy in, 399 role of NADPH oxidase in, 401 statistical analysis in research design, 322 uric acid and autonomic function in, 331–332 web-based simulations of blood-glucose dynamics for, 281 Diabetes type 2 association with oxidative stress, 346–348 differentiation from type 1 in children, 180
456
Nutrition and Diabetes: Pathophysiology and Management
hyperlipidemia as first step in pathogenesis of, 349–350 low levels of trace minerals in, 347 low levels of vitamin C in, 347 low levels of vitamin E in, 347 oxidative stress and glycemic control in, 345–346 oxidative stress in, 335–336 oxidative stress in pathogenesis of, 348–349 in pregnancy, 275–278 trace elements and glycemic control in, 353 TRAP activity decreased in, 336 vitamin E supplementation in management of, 350 Diabetes type 1b, 252–253 Diabetic angiography cerebrovascular complications, 369 clinical manifestations, 368 coronary disease, 369 macrovascular complications, 368–369 microvascular complications, 368–369 nephropathy, 368–369 peripheral vascular disease, 369–370 retinopathy, 368 risk factors for progression of, 368 Diabetic coma, at presentation in African countries, 253 Diabetic complications, 149. See also Complications cerebrovascular disease, 151–152 coronary-vascular disease, 149–150 dental disease, 153 diabetic nephropathy, 152 erectile dysfunction, 152 peripheral neuropathy, 150–151 peripheral vascular disease, 150–151 retinopathy, 152–153 Diabetic foot, 230 Diabetic gastropathy, 427–428 cisapride in therapy of, 437–438 dietary and supportive therapy for, 436 domperidone therapy for, 438 electrogastrography in evaluation of, 434–435 erythromycin therapy for, 437 and evaluation of gastric emptying, 431–432 evaluation of patients with suspected, 435–436 and methods for evaluation of gastric emptying, 432–435 metoclopramide therapy for, 437 MRI evaluation of, 434 optimizing glycemic control in, 436 pathophysiology of, 429–431
physiological basis for gastric smooth-muscle activity, 428–429 potential mechanisms of, 429 scintigraphic assessment of gastric emptying in, 433 symptoms of, 431, 432 tegaserod therapy for, 438 tracer methods in evaluation of, 433–434 treatment of refractory, 438–439 treatment strategies, 436–439 ultrasonography in evaluation of, 434 upper-GI x-rays in evaluation of, 433 Diabetic ketoacidosis (DKA) among minorities, 232 in pregnancy, 269, 277 Diabetic mothers, 181 Diabetic nephropathy, 147, 152, 399–400 association with thiamine deficiency, 413–414 as cause of end-stage renal disease, 399 impact of pregnancy on, 269 medical nutrition therapy in, 409–414 NADPH oxidase in development of, 401–403 prevalence among minorities, 229 renin-angiotensin system (RAS) overactivity in, 407 role of advanced glycation end products in, 404–409 role of oxidative stress and hyperglycemia in, 401–404 severity correlated with AGE accumulation, 405 slowing of progression by medical nutrition therapy, 409 Diagnostic criteria childhood diabetes, 178–180 diabetes mellitus, 143–145 Diarrhea in diabetic gastropathy, 431, 432 as side effect of acarbose therapy, 191 as side effect of orlistat therapy, 191 Dichoroacetate (CDA), 168 Diet effects on glycemia in animal studies, 206–208 as risk factor in development of diabetes, 209 role in childhood diabetes, 184–185 virtues of traditional diets in African countries, 257 Diet adherence adverse effect of depression on, 102 higher with MUFA diets, 212–213 poor with low-fat diets, 212 practical strategies for improving, 105 Dietary interventions, 44 abandonment in favor of surgery, 106
Index
457
in African countries, 256–257 barriers to, 101–102 in diabetic gastropathy, 436 health benefits of, 44–45 in management of existing disease, 45 for minority diabetics, 235–236 predictors of poor outcome, 106 in prevention of childhood diabetes, 189 preventive effects of, 45 Dietary reference intakes, 50 Dieting, high failure rate of, 101 Dohm, G. Lynis, 79 Domperidone, in therapy of diabetic gastropathy, 438 DPP-IV enzyme, poor specificity of, 35 DPP-IV inhibitors, improvement in glycemic control with, 35 DRG neurons, glucose-induced oxidative stress in, 385 Drug development approaches, 161, 165–166, 172–173 inhibition of fatty-acid oxidation, 167 inhibition of gluconeogenesis, 168–169 limiting availability of fatty acids, 166–167 uncoupling of energy during fatty-acid oxidation, 169–170 Drugs. See also Antidiabetic agents; Pharmacological agents role in obesity management, 104–105 Dumping syndrome, 129 Dyslipidemia, 230, 362 contributions to oxidative stress, 366 in pathophysiology of vascular injury and oxidative stress, 365–366 pharmacologic strategies and reduction of macrovascular complications, 370
E Early satiety, in diabetic gastropathy, 428, 430 Eating disorders, 102, 130 Eating habits, changes postsurgically, 131 Edema, as side effect of TZDs, 238 Educational levels in developing African countries, 256 and diabetes prevalence, 142 Electrogastrography (EGG), in evaluation of gastric emptying, 434–435 Electrolyte deficiencies, with bariatric surgery, 113 Electron transport chain (ETC), 304 disruption by hyperglycemia, 382 disruption by nitric oxide, 335
as source of reactive oxygen species production, 306 Emesis. See Vomiting Emotional lability, following bariatric surgery, 130 End-stage renal disease (ESRD), 399. See also Diabetic nephropathy End-to-end anastomosis (EEA) stapler, 113 Endothelium, consequences of AGE receptor activation on, 407 Energy expenditure, increased during leptin treatment, 14 Energy generation, from nutrients, 162 Energy homeostasis, 6, 18 Enforced wakefulness, and hypocretin levels, 8 Entabi, Fateh, 361 Enteroinsular axis, 27–28 in diabetes, 33–34 glucagon-like peptide-1 (GLP-1) and, 30–31 glucose-dependent insulinotropic polypeptide (GIP), 28–29 insulin secretion and, 28–31 Environmental factors, as barrier to diet modification, 101 Enzyme-Linked Immunosorbent Assay (ELISA), 322 Enzymes, antioxidant roles of, 354, 362, 401 Erectile dysfunction beneficial effects of NO on, 328 as complication of diabetes, 152 Erythromycin, in therapy of diabetic gastropathy, 437 Esophago-jejunostomy, 439 Ethnicity and exercise effects on blood pressure, 66 in posttransplantation diabetes, 145–146 and prevalence of diabetes, 140–141 and qualifying criteria for metabolic syndrome, 60 and relative roles of visceral vs. subcutaneous fat, 184 studies of relationships between fitness and metabolic syndrome, 62 Etomoxir, 167 Excess body weight link to diabetes, 44 management of existing disease, 45 preventive effects of, 45 Excess weight loss (EWL), after gastric banding surgery, 117 Exendin-IV, 36 Exercise. See also Volitional exercise aerobic, 51
458
Nutrition and Diabetes: Pathophysiology and Management
beneficial effects on fat storage and distribution, 185–186 challenges to adoption of regular pattern, 103 combination training, 52 combined with energy restriction, 103 consistent effects across race and gender subgroups, 64 duration as user input in GLUCOSIM, 290 health benefits of, 44–45 importance to diagnosis/etiology of metabolic syndrome, 60–63 increase in hypocretin levels with, 8 interactions with environment and genetics, 73 interventions for minority diabetics, 235–236 interventions for weight reduction, 49–51 metabolic response to, 288 metabolic syndrome and, 63–64 moderate in model simulations, 288 in post-surgical follow-up, 132 in prevention of childhood diabetes, 189 recommendations for OW/OB with diabetes, 52 resistance training, 51–52 role in childhood diabetes, 185–186 role in management of obesity, 103–104 scalability of, 235 specificity of, 235 stimulation of glucose transport by, 81 Exercise capacity, as predictor of death in asymptomatic women, 71 Exercise-induced hypoglycemia, 288 Exercise model simulation, 288 Exercise prescription goals, 235 Exercise training effects on blood pressure, 64–66 effects on fasting plasma glucose, 67–69 effects on HDL cholesterol, 66–67 effects on insulin sensitivity, 69–70 effects on triglycerides, 66 effects on waist circumference, 70–71 and individual components of metabolic syndrome, 64 intensity, frequency, and duration of, 65–66 interindividual differences in trainability, 103–104 Extracellular matrix (ECM) proteins, in glomerular mesangium, 406
F Falling, risk in diabetes, 148 Fasting leptin decreases in, 12 metabolics of, 162
and uncoupling protein expression, 80 Fasting glucose changes during pregnancy, 269 criteria for metabolic syndrome, 58 exercise training effects on, 57, 68 increases with high-fat, simple carbohydrate diets, 206 Fat distribution beneficial effects of exercise on, 185–186 and diabetes in children, 181–182 upper-body, 148 Fat-free diets, 211 Fat intake GIP secretion and, 28, 32 GLP-1 secretion and, 30 human studies in dietary patterns, 208–209 ratio of polyunsaturated-to-saturated, 209 restriction of, 235 Fat oxidation greater with low-intensity exercise, 70 inability of previously obese women to increase, 90, 91 increased with weight loss plus exercise, 186 and metabolic inflexibility in obesity, 89–91 Fat subtypes, 213 Fatty-acid-binding protein-plasma membrane (FABPpm), 88 Fatty-acid oxidation inhibition as drug development approach, 167 inhibition by L-glutamine, 170 reactive oxygen substances as products of, 349 reduced in obesity, 86, 87 role of leptin in, 183 in skeletal muscle, 86–88 uncoupling of energy during, 169–170 Fatty-acid translocase (FAT/CD36), 88 Fatty-acid transport, into skeletal muscle, 8–89 Fatty-acid transporter protein 1 (FATP1), 88 Fatty-acid uptake, increased in obese muscle in response to insulin, 90 Fatty acids limiting availability to control blood glucose, 166–167 metabolism of, 161 Fatty acyl-CoAs, 87 Fatty liver, in obese diabetic children, 187 Feeding control, CNS localization, 7 Feinglos, Mark N., 205 Fetal glycosuria, 272 Fetal growth restriction, 272 association with diabetic nephropathy, 269 in gestational diabetes, 268
Index Fetal macrosomia, 271 importance of monitoring during pregnancy, 274 with maternal diabetes, 268 metabolic complications with, 272 risk with gestational diabetes, 270 Fetal monitoring, 268 Fetal respiratory-distress syndrome, 272 Fiber, vi, 235 dietary recommendations for weight loss, 49 inverse correlation with risk of diabetes, 185 low intake as risk factor in childhood diabetes, 179 in traditional diets of African countries, 257 Fibrocalculous pancreatic diabetes, 251, 252 Flatulence as side effect of acarbose therapy, 191 as side effect of orlistat therapy, 191 Fluid retention as side effect of TZDs, 238 with troglitazone, 222 Flutamide, 192 Follow-up, and successful weight loss, 102 Food, use in relieving stress, 102 Food and Nutrition Board, Institute of Medicine, 47 Food intake appetite and satiety in, 6 CNS localization of, 7 gastrointestinal peptides in, 16–18 hypothalamic neuropeptides stimulating, 7–9 increased with ghrelin administration, 16 inhibition by anorexigenic neuropeptides, 9–19 neuroendocrine regulation of, 5–6 neuropeptide Y (NPY) as stimulator of, 7–8 pancreatic signals, 14–16 peptide YY stimulation by, 17 peripheral signals regulating, 10–14 restriction as main strategy of weight control, 6 stimulation by hypocretins, 8–9 stimulation by orexins, 8–9 Food intolerances, association with bariatric surgery, 130 Food obsessions, 128–130 Food tolerances, postsurgical, 131 Foot inspection, 242 Foot ulcerations, in African presentations, 253 Footwear selection, 242 Framingham Risk Score, 71 Framingham Study, 149, 151 Free fatty acids (FFAs), 163
459 chronic exposure and lipotoxicity in pancreatic β-cells, 310 impairment of endothelial function by, 365–366 in persons with abdominal obesity, 182 reduced rate of release with thiazolidinediones, 194, 238 reductions associated with reduced insulin resistance, 167 reductions with PPARs, 169 Freemark, Michael, 177 Fridlyand, Leonid E., 303 Fructose, lipogenic action of, 185 Funding limitations, in African health-care delivery systems, 255
G Gallstone formation, postsurgical, 130 Gastric banding, 115–117 Gastric bypass, 113, 117–118 Gastric dysrhythmias, 429, 431 Gastric emptying accelerated with cisapride, 438 delay with GLP-1, 31, 33 delayed or accelerated in diabetic gastropathy, 430 evaluation of, 431–432 improvement with glycemic control, 430 methods for evaluation of, 432–435 scintigraphic assessment of, 433 Gastric pacemakers, 429 Gastric smooth-muscle activity, 428–429 Gastric vagal afferent signals, inhibition by ghrelin, 16 Gastroesophageal-reflux disease, 437–438 Gastrointestinal motility, beneficial effects of NO on, 328 Gastrointestinal peptides, 27–28 cholecystokinin, 18 ghrelin, 16 glucagon-like peptide-1, 17–18 peptide YY, 17 role in food intake, 16 Gastrojejunostomy tubes, 439 Gastropathy. See Diabetic gastropathy Gender and diet-specific effects on body composition, 219 effect on nitric oxide and 8-iso-PGF2α, 325 male preponderance of ketosis-prone atypical diabetes, 252 Genetic diversity, in exercise trainability, 104
460
Nutrition and Diabetes: Pathophysiology and Management
Genetics in diabetes of sub-Saharan African countries, 250 GIP deficiency and, 34 and predisposition to obesity, 91 and risk of childhood diabetes, 179 Gestational diabetes, 267–268 advisability of induced delivery, 274 cesarean delivery options, 274 dietary management of, 273 as early revelation of propensity to diabetes type 2, 268 fetal-growth monitoring in, 274 impact on pregnancy, 270–272 management of, 272–275 prevalence, 267 rising incidence of, 272 as risk factor for diabetes type 2, 145 standard screening for, 273 Ghrelin, vi, 16 diurnal rhythm of, 16 Gingivitis, 153 GIP-receptor antagonists, 37 Glargine, 240 Glomerular filtration rate decline in diabetic nephropathy, 368 diminishment in progression of nephropathy, 408 in incipient and progressive nephropathy, 400 Glomerulosclerosis, as end effect of AGEs, 405 GLP-1 analogues, DPP-IV resistant, 36 Glucagon emergency kit, 223 Glucagon-like peptide-1 (GLP-1), 17–18, 30–31, 313 alternative modes of delivery, 34–35 antiobesity therapy with, 37 delay in gastric emptying with, 31 DPP-IV inhibition and therapeutic efficacy, 35 enhanced release with metformin, 168 extending biologically active half-life of, 35 extrapancreatic effects, 33 and insulin response to oral glucose, 31 limitations as therapeutic agent in diabetes, 30, 34 multiple antidiabetic actions of, 33 plasma levels and nutrient content, 29 rapid degeneration in vivo, 30 therapeutic aspects in diabetes, 34–37 Glucocorticoid-leptin interactions, 13 Gluconeogenesis inhibition as target of drug development, 168–169 physiology of, 162 Glucoregulation, effects of leptin on, 15
Glucose and amino-acid metabolism, 218 chronic exposure leading to damage to pancreatic β-cells, 310 as major fuel in nutrient metabolism, 162–163 metabolism of, 161 Glucose absorption, GIP secretion proportional to, 28 Glucose-clamp technique, as gold standard for insulin resistance testing, 143 Glucose-dependent insulinotropic polypeptide (GIP), 28–29 extrapancreatic effects, 31–33 limitations as therapeutic agent, 34 plasma levels and nutrient content, 29 as potential obesity hormone, 31–33 role in etiology of obesity, 32 therapeutic aspects in diabetes, 34–37 therapeutic aspects in obesity, 37 Glucose disposal enhanced by vitamin C, 350 improved by glutathione supplementation, 352 Glucose-fatty-acid cycle, 163 Glucose homeostasis during exercise, 288 nutrient interactions and, 161 nutrient metabolism and, 163–165 Glucose-insulin model interactions, 286–287 Glucose metabolism, impairment by oxidative stress, 348 Glucose-stimulated insulin secretion (GSIS) connection of ROS production in pancreatic β-cells with, 306–308 enhancement of, 312–314 mechanisms of, 304 role of calcium-channel elevation in, 309 Glucose tolerance beneficial effects of exercise on, 68 deterioration with fat-free, high-carbohydrate diet, 211 improved through TZD therapy, 195 improving through DPP-IV-resistant GLP-1 analogues, 35 Glucose toxicity, 310, 333 in DRG neurons, 385 oxidative stress as cause of, 335 and progressive decline in β-cell function, 349 Glucose transport blunted in muscle of obese individuals, 81 intact in insulin-resistant muscle, 82 Glucose uptake and ATP/ADP regulation, 304–306
Index enhanced with GLP-1, 33 enhanced with GSH, 3352 increased with metformin, 191 GLUCOSIM software, 282, 289–291 input page, 291, 292 Glutathione peroxidase, 308, 347, 401, 413 decreased in blood of diabetic patients, 336–337 protective effects against oxidative stress, 351–352 protective effects in diabetic nephropathy, 412–414 role in slowing of diabetic nephropathy, 414 selenium as cofactor for, 353 Glyburide recommended use during labor, 275 use in gestational diabetes, 274 Glyburide/metformin, 239 Glycemic control correlation with rate of congenital abnormalities in diabetic gravidas, 270 in diabetic gastropathy, 436 with diet and exercise, 44 effect of chromium supplementation on, 353 effect on sympathetic nerve function, 323 effects on oxidative stress and serum uric acid, 324 failure to moderate macrovascular complications, 370 hemoglobin A1c maintenance, 228 importance in preventing microvascular complications, 241 improved with coenzyme Q10, 352 improved with high-protein, high-fat, lowcarbohydrate diets, 48 improved with physical activity, 49 and improvement of gastric-emptying times, 430 and oxidative stress in type 2 diabetes, 345–346 positive effect on renal function, 404 in prevention of childhood diabetes, 189 as primary goal of diabetes management, 229 and risk of vascular complications, 368 slowing of peripheral neuropathy via, 381 studies of antioxidant supplementation effects on, 349–353 through weight loss, 45 Glycemic index, vi–vii, 147, 210, 217 Glycemic load, 210, 217 Glycogen synthesis, stimulation by L-glutamine, 171
461 Glycosylated hemoglobin (HbA1c) beneficial effect of exercise on, 67 importance of monitoring during pregnancy, 276 negative correlation with uric acid, 331 Goal setting, in diabetes management for minorities, 233 Grazing lifestyle, 131 as postsurgical complication, 130 Growth factors links to AGE production, 408 in treatment of peripheral neuropathy, 387–388 Growth hormone, resistance caused by food restriction, 190 GSIS-ROS hypotheses, 309 and pancreatic β-cell repair mechanisms, 311–312 Guanidine derivatives, 191 Gut, ability to affect endocrine responses, 27
H Harms, Roger, 267 HbA1c beneficial effect of exercise on, 67 effect of chromium supplementation on, 353 as gold standard for glycemic control, 234 negative association with uric acid, 324 reduced testing frequency among African Americans, 232 reduced with CoQ10 supplementation, 352 standards for glycemic control, 229 HDL cholesterol levels criteria for metabolic syndrome, 58, 59 decreased with high carbohydrate intakes, 48 decreased with increased FFAs, 365 dose-response relationship between exercise and, 67 exercise training effects on, 66–67 reduced in insulin resistance, 183 reductions with low-carbohydrate diets, 215 Health care access, problems in African countries, 253 Health-care expenditures associated with diabetes, 140, 141–142 in developing African countries, 261–263 for obesity-related diseases, 111 Health care providers, as barriers to effective management among minorities, 232 Health insurance, lack among minorities, 231 Healthy diets, perceived expense and time consumption of, 101 Healthy-person model, 287
462
Nutrition and Diabetes: Pathophysiology and Management
Hemoglobin A1c as gold standard for glycemic control, 228 as indicator of poor blood glucose control, 140 Hepatic steatosis, 189, 192 Heritage Family Study, 63–64 Hexosamine pathway, 306 High body mass, cultural tolerances of, 232 High-carbohydrate diets deterioration of glucose tolerance with, 211 FPG increases with, 213 high-carbohydrate, low-fat diets, 211–212 triglyceride increases with, 48 vs. high-protein diets, 218 High-fat diets effects on development of obesity and hyperglycemia in mice, 206 FPG decreases with MUFA diets, 213 high-fact, low-sucrose, 208 human vs. animal studies, 208 High-glycemic foods. See Glycemic control High-liquid-content meals, in therapy of diabetic gastropathy, 436 High-monounsaturated fat diets, 48 High Pressure Liquid Chromatography (HPLC), 322 High-protein diets increased thermogenesis with, 220 in management of diabetes, 218–220 recent success in weight reduction, 48 Hispanic populations prevalence of diabetes among, 142, 181 prevalence of obesity and physical inactivity among, 231 relative risk of amputations, 151 response to antidiabetic agents, 228 risk of diabetic nephropathy among, 399 risk of retinopathy, 152 Hoeldtke, Robert D., 319 Hormonal disorders, as risk factor in childhood diabetes, 179 Hormone-replacement therapy, associations with heart disease and diabetes, 150 Hunger, CNS control of, 18 Hygienic considerations, in African countries, 260 Hyperglycemia, 230, 349, 362 development in presence of stress, 206 effect on β-cell function, 333 effect on intracellular osmoregulation, 411 effects on upper gastrointestinal function, 430 exercise-induced, 288 induction of superoxide production by, 363 and oxidative stress, 320, 382 in pathophysiology of vascular injury and oxidative stress, 363–365 in pregnancy, 268
role in diabetic nephropathy, 401–404 vulnerability of sympathetic nervous system to, 323 Hyperhomocystinuria, 403 Hyperinsulinemia, 349 Hyperlipidemia, 349 activation of NADPH oxidase by, 402 as first step in pathogenesis of type 2 diabetes, 350 Hyperphagia with AgRP treatment, 8 with genetic serotonin deficiency, 10 Hypertension, 230 in African Americans, 152 association with obesity, 99 in childhood obesity and diabetes, 187–188 exercise-training effects on, 64–66 metabolic syndrome and, 57 pharmacologic strategies and reduction of macrovascular complications, 370 questionable inclusion in metabolic syndrome criteria, 60 reduction after biliopancreatic diversion, 120 and risk of vascular complications, 368 risk with excess body mass, 44 treatment during pregnancy, 277 Hypertriglyceridemia association with endothelial dysfunction, 365 association with insulin resistance, 62 and disordered postprandial GIP secretion, 31 with high carbohydrate intakes, 48 induction with GIP-receptor antagonists, 37 reducing risk with high-monounsaturated fat diets, 48–49 Hypocretins, stimulation of food intake by, 8–9 Hypoglycemia exercise-induced, 288 patient education on management of, 223 protection with high-protein diets, 218 sulfonylureas association with, 221 and women with pregestational diabetes, 269 Hypothalamic neuropeptides agouti-related protein (AgRP), 8 hypocretins, 8–9 neuropeptide Y (NPY), 7–8 orexins, 8–9 stimulation of food intake by, 7 Hypothalamic-pituitary-adrenal axis, 7 Hypothalamus, role in feeding control, 7
I Ideal bodyweight (IBW) tables, 112
Index IGF-1, potential for worsening of ocular findings by, 388 Illinois Institute of Technology, 282 Impaired fasting glucose (IFG), 231 in children, 180 Impaired glucose tolerance (IGT), 144, 181, 231 association with progression of atheromatous lesions, 187 in children, 180 defined, 142–143 Diabetes Prevention Program study results, 192 Incretins, 27, 33 Inflammatory pathways, and insulin action in obesity, 85 Infusion-pump therapy simulation, 290, 292, 295 InResponse antioxidant formula, 354, 355 Insoluble fiber, limiting of fat absorption by, 185 Insulin after failure of oral hypoglycemic agents, 221 increased with high-carbohydrate, low-fat diets, 212 as pancreatic signal regulating food intake, 14–15 pharmacokinetic model of, 284, 285 rate of concentration change in circulating blood, 286 reduced with low-carbohydrate diets, 215 role in glucose homeostasis during exercise, 288 role in satiety and meal termination, 15 as signal for leptin secretion, 15 starting dose and daily dose, 222–223 stimulation of vasodilatation by, 188 weight gain promotion by, 46 Insulin independence, with leptin therapy, 14 Insulin injection simulation, 292–294 Insulin production, decline in total, 180 Insulin resistance, 44, 303, 362 and abdominal fat stores, 182 and activation of PKC, 83 among African Americans, 228 and blunted muscle insulin-signal transduction in obesity, 81–83 defect in insulin signaling as cause of, 82 defined, 142–143, 143 effects of smoking on, 147–148 hepatic role in, 168 and inflammatory pathways in obesity, 85 links to physical inactivity, 231 low prevalence among overweight persons, 100 mechanisms in obesity, 85 metabolic syndrome and, 59 necessitating higher insulin dosages, 46
463 pathogenesis in children, 180–184, 188 in pathophysiology of vascular injury and oxidative stress, 366–367 in physiologically normal pregnancy, 268 in pregnancy, 273 proposed mechanism in skeletal muscle, 86 relationship to intramyocellular lipid accumulation, 83–84 role of oxidative stress in, 366–367 trials of metformin in, 192 variables associated with, 62 Insulin Resistance and Atherosclerosis (IRAS) study, 208 Insulin secretagogues, 228, 237 combining with sensitizers, 239 Insulin secretion direct injury to pancreatic β-cells by, 310 enhanced with glutathione supplementation, 352 enteroinsular axis and, 28–31 glucagon-like peptide-1 (GLP-1) and, 30–31 glucose-dependent insulinotropic polypeptide (GIP) and, 28–29 impairment through increased UCP2 production, 385 improving through DPP-IV-resistant GLP-1 analogues, 36 inhibition by L-glutamine, 170 inhibition by nitric oxide, 335 masking of damage to pancreatic β-cells by, 310 partially reversible defects in African type 1B, 253 proposed mechanism of pancreatic β-cell damage and reduced, 307 response to specific sugars, 185 Insulin sensitivity dramatic improvement after delivery, 269 effect of exercise on, 103 exercise training effects on, 69–70 improved with low-carbohydrate diets, 215 improved with resistance training, 51 increased with GLP-1, 37 increased with leptin, 13 increased with metformin therapy, 192 increased with sulfonylureas, 221 increased with TZD therapy, 195 increased with vitamin C, 350 increased with weight loss, 45 restored after weight loss, 84 Insulin sensitizers, 228 combining with secretagogues, 239 Insulin signaling, defect as cause of insulin resistance, 82
464
Nutrition and Diabetes: Pathophysiology and Management
Insulin suppressor agents, 191 metformin, 191–194 thiazolidinediones, 194–195 Insulin therapy, 222–223 benefits in pregnancy, 267–268 cessation as cause of diabetic ketoacidosis among minorities, 232, 261–262 cost and availability issues in developing countries, 259–260 depletion of circulating vitamin E levels by, 347 in developing African countries, 259–260 in diabetic children and adolescents, 197 guidelines for gestational diabetes, 273–274 importance of stopping after delivery, 277 indications for, 239–240 in ketosis-prone diabetes, 261 Insurance reimbursement, for plastic surgery following bariatric surgery, 132 Intensity of exercise, irrelevance to insulin sensitivity changes due to exercise, 69 Interleukin-6 (IL-6), 182 Intermittent exercise, 103 Internal hernia, 126 Internal model controllers (IMC), 290 Internal triage, 233 International Expert Committee, 144 Interstitial cells of Cajal decrease in diabetic gastropathy, 429 in physiology of smooth muscle, 428 Intestinal mucosa, GLP-1 secretion in, 30 Intracellular nonenzymatic glycosylation reaction, 306 effect of hyperglycemia on, 411 Intracellular osmoregulation beneficial effects of taurine supplementation on, 412 destructive effect of sorbitol accumulation on, 410 Intracerebral hemorrhage, 151 low relative prevalence in diabetics, 369 Intramyocellular lipid accumulation, and skeletalmuscle insulin resistance, 83–84 Intrauterine fetal death, 274, 276 Iron deficiency, 129–130 Islet autoimmunity, in childhood diabetes, 179–180 Islet insulin secretion model, 287 Isoprostanes, as products of lipid peroxidation, 347
J Jejunoileal bypass, 113 Juvenile diabetes, 178. See also Childhood diabetes
K Kaminsky, Alexander J., 381 Kendall, William F., 139 Ketoacidosis (DKA) in African presentations, 253 in childhood diabetes, 179 exercise-induced, 288 as presenting symptom in childhood diabetes, 187 Ketone bodies, as metabolic fuel in starvation, 162 Ketosis, in pregnancy, 269 Ketosis-prone atypical diabetes, 250, 252–253 management of, 260–261 patient education for, 260 remission periods, 261 Kidney transplantation, reduction of AGE levels after, 406 Kidneys. See also Microvascular complications; Renal failure beneficial effects of taurine on, 412 expression of NAPDH oxidase and ROS in, 402 renoprotective effects of AGE inhibitors, 408 role in glucose homeostasis, 162 Koch, Timothy R., 427 Kraus, William E., 57
L L-alanine, effect of supplementation on body weight, 208 L-glutamine effect of supplemental on body weight, 172, 208 inhibition of insulin secretion and fatty-acid oxidation by, 170–171 Lactic acidosis, with metformin use, 220, 238 Lap-Band, 114, 115, 126 Laparoscopic adjustable gastric banding, 115–117 Laparoscopic bariatric surgery, 114, 120 Late diagnosis in African countries, 253, 254, 261 and likelihood of complications, 230–231 LDL cholesterol decrease in NO levels by oxidized, 366
Index decreases with high-carbohydrate, low-fat diets, 211–212 gender differences in, 60 and low-fat diet recommendations, 210 as potent NADPH oxidase activator, 402 reduction after gastric bypass, 118 Left ventricle, wall thickness increased in diabetes, 149 Leptin, 11–12 action with insulin, 12–14 behavioral and metabolic effects, 15 as exogenous therapy for human obesity, 14 increased in obese subjects, 12 mechanism of action, 12 NPY as antagonist to, 7 role in fatty-acid oxidation, 183 Leptin resistance, 12, 14, 183, 184 axokine bypass of, 104 Lien, Lillian F., 205 Lifestyle, as risk factor in childhood diabetes, 179 Lifestyle change challenges in obesity management, 101–103 and prevention of diabetes, 100 and reduction in risk of diabetes, 209 resistance to, in lifestyle interventions, 190 stages of, 102 Lifestyle interventions challenges in obesity management, 101–103 in developing countries, 256–259 duration as predictor of success, 102–103 effects with metformin, 193 exercise interventions, 49–52 greater effectiveness than pharmacologic therapy, 193 indications and goals, 45 limited long-term success of, 190 for minority diabetics, 235–236 necessity of frequent follow-ups for success, 101 in preventing diabetes in high-risk children, 189–190 and prevention of diabetes, 100 as principal recommended therapy for OW/OB, 44 recommendations for children and adolescents, 198 reducing risk of progression to diabetes, 69 vs. pharmacotherapy in children and adolescents, 196 weight-reduction (WR) diets, 46–49 Lipid metabolism beneficial effects of exercise training on, 186 fatty-acid oxidation in skeletal muscle, 86–88
465 fatty-acid transport into skeletal muscle, 88–89 and metabolic inflexibility in obesity, 89–91 in obesity, 85–88 Lipid peroxides association with oxidative stress, 346 expression as malondialdehyde (MDA), 347 isoprostanes, 347 measurement of degradation products, 347 Lipid profiles, worsened with high carbohydrate intakes, 48 Lipolysis inhibition of, 166 reduced rates with thiazolidinediones, 194 Lipoprotein subclass distributions, by group and gender/race statistical comparisons, 61 Lipotoxicity, and progressive decline in β-cell function, 349 Liver role in glucose homeostasis, 162 role in insulin resistance, 183 Locus of control, 232 Low-carbohydrate diets, 48–49, 101, 214 dropout rates and study limitations, 216 effects diminishing over time, 185 FPG reductions with, 215 improved triglyceride concentrations with, 185 long-term inefficacy of, 216 in nutritional management of diabetes, 213–217 Low-fat diets, 48, 214 inefficacy in sustained weight loss, 101 low-fat, low sucrose, 170–171, 208 in nutritional management of diabetes, 210–212 poorer triglyceride concentration results with, 185 in therapy of diabetic gastropathy, 436 Low-intensity exercise, beneficial effects on insulin sensitivity, 70 Low literacy rates, as barriers to effective diabetes management, 231 Lower-extremity function, limitations in diabetes, 148
M Macronutrient distribution, 46, 213 high-monounsaturated fat diets, 48–49 low-carbohydrate diets, 48–49 low-fat diets, 48
466
Nutrition and Diabetes: Pathophysiology and Management
in mice diets, 206–208 optimal for weight reduction, 48 Macrovascular complications, 369–370 Magnesium inverse correlation with diabetes risk, 185 lack of effect on fasting plasma glucose and HbA1c, 351 low intake as risk factor in childhood diabetes, 179 Magnetic resonance imaging, in evaluation of gastric emptying, 434 Malabsorption, after bariatric surgery, 113 Maladaptive eating disorders, 102 Malnutrition coexistence with obesity in African countries, 257 implications for dietary management in African countries, 256–257 link to diabetes in African countries, 251 Malnutrition-related diabetes mellitus, 251 Malondialdehyde (MDA), 335 elevated in patients with microalbuminuria, 347 Mass balance equations, 283 Maturity onset diabetes of the young (MODY), 178, 180. See also Childhood diabetes Mbanya, Jean Claude, 249 Meal initiation ghrelin as signal for, 16 NPY as trigger of, 7 Meal size, correlation with number of people present, 102 Medic-Alert bracelet, 223 Medical nutrition therapy (MNT), 403, 409 selenium, thiamine, vitamin C, and glutathione in, 412–414 sorbitol and taurine in, 410–412 Medications expense and fatal outcomes in African countries, 255 as risk factor in childhood diabetes, 179 Meglitinides, 222 Melanocortins, anorexigenic effects of, 9 Mental health, diabetes and, 148 Mesangial cells consequences of AGE receptor activation on, 407 expansion leading to capillary narrowing, 408 Metabolic fuel, competition between nutrients as sources of, 163–165 Metabolic inflexibility obesity and, 89–91 in previously obese women, 90
Metabolic syndrome, 57–58, 81 ATP III criteria for, 58 controversies over definition, 58–60 differential criteria weighting among height, gender, ethnicity, 60 ethnicity and qualifying criteria, 60 exercise and, 63–64 exercise training and individual components of, 64–71 importance of physical fitness/exercise to diagnosis and etiology of, 60–63 and maximal treadmill time, 62 as prediabetic state, 59 predictive capacity of individual diagnostic conditions, 59 rationale for including cardiorespiratory fitness in, 71–72 sedentary lifestyle and, 71 suggested research directions, 73 Metabotropic glutamate receptors (mGluRs), moderation of cellular injury by, 389 Metformin, 100, 220–221, 237–238, 312 availability in African countries, 259 failure of long-term therapy, 238 with flutamide, 192 gastrointestinal side effects, 238 improvement of endothelium-dependent vasodilation by, 367 inhibition of gluconeogenesis by, 168 metabolic effects of, 191 persistence of effects after discontinuation, 194 use in prevention of childhood diabetes, 191–194 Metformin/glipizide, 239 Methylglyoxal, 336 Metoclopramide, in therapy of diabetic gastropathy, 437 Microalbumin-creatinine concentrations, 241 Microalbuminuria in children with diabetes, 187 in diabetic nephropathy, 400 importance of monitoring in pregnancy, 269 and oxidative stress, 346 prevalence in minorities, 241 reduced risk with tight glycemic control, 404 as risk factor for diabetes type 2, 147 Microvascular complications, 140, 368–369 in diabetic children, 187 prevalence among minorities, 229 prevention in minorities, 240–241 reactive oxygen species links to, 319 Miglitol, 222 Migraine headaches, and clinical-vomiting syndrome, 435
Index Mild diabetes, relationship between exercise and glucose tolerance in, 69 Minipumps, delivery of subcutaneous GLP-1 via, 34 Minorities. See also Ethnicity barriers to effective diabetes management, 230–232 combination therapy for, 239 consequences of external locus of control, 232 diabetes education for, 234–235 diabetes management in underrepresented, 227–229 diet and exercise interventions for, 235–236 goals of diabetic management, 229–230 indications for insulin therapy, 239–240 medications for treatment of diabetes, 236–237 monitoring measures, 234 neighborhood fitness-center initiatives, 235 obesity and physical inactivity as barriers to effective management, 231 poor access to medical care, 228 poor outcomes in diabetes, 228 prevalence of microvascular complications among, 229 prevention of amputation, 242 prevention of diabetic complications, 240–242 provider problems as barrier to effective diabetes management, 232 socioeconomic, cultural, psychological barriers to management of diabetes, 231–232 undiagnosed diabetes among, 230–231 Mitochondrial activity accelerated synthesis in pancreatic β-cells, 312 dual role of pancreatic β-cell mitochondrial uncoupling, 311 impaired in obesity, 81 Mitochondrial oxidative phosphorylation rate, 306–307 Mitoptosis. See also Apoptosis in oxidative stress, 308 Mixed-type glucokinase activators, 313 Model predictive controllers (MPC), 290 Modified fat/high-monounsaturated fatty acid (MUFA) diets, 212–213 Monitoring, education, dietary modification, exercise, medications (MEDEM) strategy, 228, 234 Monoamine oxidase inhibitors, reduction of blood glucose levels by, 167 Monotherapy. See also Antidiabetic agents; Combination therapy long-term failure of, 239
467 Monounsaturated fatty acid (MUFA) diets, 212–213 reductions in plasma glucose levels with, 217 Morbid obesity, 125 defined, 112 surgical treatment of, 112–120 Morgan, Linda M., 27 Mortality rates BMI and, 112 in diabetes, 153 diabetes in pregnancy, 267–268 due to Roux-en-Y procedure, 126 Lap-Band procedure, 126 in sub-Saharan African countries, 253 Motivation, as barrier to diet modification, 102 Muscle consequences of AGE receptor activation on, 407 diminished uptake of FFAs by, 365 glycolytic degradation of glucose producing ATP, 163 impaired repair mechanisms with oxidative stress, 348 increase in glucose utilization with metformin, 237 metabolic alterations associated with obesity, 79–80 as percentage of body mass, 80 role in altered metabolism of obesity, 79 role in glucose homeostasis, 162 Muscle contraction, stimulation of glucose transport by, 81 Muscle mitochondria, and uncoupling protein in obesity, 80–81 Myocardial infarction benefits of intensive glucose control in, 241 BMI and risk of, 112 lower postsurvival rates among minorities, 229 as major cause of death in adults with diabetes, 197 postinfarction mortality in diabetic patients, 362, 369 reduction with insulin therapy, 240 reduction with vitamin E, 371 risk among diabetics, 362 Myocardial oxygen consumption, in pregnancy, 270
N NAPDH oxidase and development of diabetic nephropathy, 403 role in formation of ROS, 401
468
Nutrition and Diabetes: Pathophysiology and Management
in type 1 diabetes, 401 Narcolepsy, and hypocretins/orexins, 8 Nasal sprays, of DPP-IV-resistant GLP-1 analogues, 36 Nateglinide, 222, 237 National Diabetes Data Group guidelines, 142–143, 143–144 National Health and Nutrition Examination Survey (NHANES III), 81 National Institutes of Health (NIH) Consensus Development Conference Statement on Gastrointestinal Surgery for Morbid Obesity, 114 guidelines for treatment of OW/OB adults, 112 Native Americans prevalence of diabetes among, 141–142, 181 response to antidiabetic agents, 228 Nausea in diabetic gastropathy, 428, 430, 431, 432 refractory, 438 Neighborhood fitness center initiatives, 235 Nephropathy, 230, 234, 368–369. See also Diabetic nephropathy indicators of incipient, 242 Netherlands Zutphen Study, 209 Neural-tube defects, 270–271 Neuronal injury mechanisms in diabetes, 382–384 modulation by mGluRs, 389 Neuropathy, 230, 234. See also Peripheral neuropathy in African countries, 253 in childhood diabetes, 187 impact of pregnancy on, 269 increased TBARS in, 335 oxidative injury in, 381–390 as premature aging of nervous system, 389 prevalence among minorities, 229 Neuropeptide Y (NPY), 7–8 as leptin antagonist, 12 Neutral Protamine Hadedorn, 222–223 Nicotinic acid, 166 Night-eating syndrome, 102 Nitric oxide, 322 adverse effects on β-cell function, 335 beneficial effects on vascular tone and gastrointestinal motility, 328 bioavailability in diabetes, 328 dual protective/neurotoxic roles, 384 effects of diabetes on, 328–330 higher concentrations in diabetic patients, 324 increased bioavailability with vitamin E, 337 inhibition by oxidative stress, 365 interactions with oxidative stress, 320
negative correlation with blood pressure, 330 negative correlation with sudomotor function, 326, 328, 330 and nitrosative injury in PNS, 384–385 platelet aggregation with reduction in, 188 and restored vasodilation with vitamin C infusion, 365 role in GI motor function, 430–431 vasodilative properties of, 330–331, 364 Nitrogen products, accumulation and toxicity, 162 Nitrosative stress hemodynamic consequences of, 330–331 role in peripheral neuropathy, 384–385 vs. oxidative stress, 332–333 Ni trotyrosine, in early type 1 diabetes, 326 Nonadherence. See also Diet adherence importance of physician empathy with, 105 to low-fat diets, 212 Nonesterified fatty acids, 11 North American Association for the Study of Obesity, 44 Nurses Health Study, 181, 209 Nutrient absorption, drugs limiting, 190–191 Nutrient interactions in blood-glucose regulation, 162–163 characteristics of energy generation, 162 and glucose homeostasis, 161 metabolism and effect on glucose homeostasis, 163–165 and nutritionally based therapeutic approaches, 170–172 treatment design based on, 165–166 Nutrition, in diabetes management, v Nutritional deficiencies, as postsurgical complication, 129–130
O Obese people, discrimination by health professionals, 102 Obesity association with diabetes, 146 association with increased FAT/CD36, 88–89 atherogenesis and, 187–188 bariatric surgery for, 111–121 as barrier to effective management in minorities, 231 cardiovascular disease and, 187–188 challenges of lifestyle change, 101–103 counteracting with leptin therapy, 12 defined, 99–100 effects of adrenalectomy on, 207 and energy homeostasis, 6 genetic factors in, 91
Index hyperinsulinemia and, 32 hypertension and, 187–188 impaired mitochondrial activity in, 81 inflammatory pathways and insulin action in, 85 insulin resistance in, 81–85 and leptin, 12 lipid metabolism in, 85–88 mechanisms of insulin resistance in, 85 and melanocortin pathway, 9 metabolic alterations in muscle and, 79–80 metabolic inflexibility in, 89–91 muscle mitochondria and uncoupling protein in, 80–81 nonsurgical management, 99–106 prevalence among U.S. minorities, 231 protective effects of uncoupling proteins against, 80 rapid increase in prevalence, 99 recommendations for individuals with diabetes, 52 relation to AgRP, 8 relation to diabetes, 100–101 role of drugs in management, 104–105 role of exercise in management of, 103–104 as second-leading preventable cause of death, 99 therapeutic aspects of GIP and GLP-1 in, 37 treatment with GIP-receptor antagonists, 37 trends in U.S. population, 45 One-repetition maximum (1 RM), 51 Opara, Emmanuel C., 161, 345 Oral glucose tolerance test (OGTT), 142 recommended use postpartum, 275 reliability of, 143 for suspected gestational diabetes, 273 Oral hypoglycemic agents, 220, 236 alpha-glucosidase inhibitors, 222 biguanides, 220–221 independence achieved through leptin therapy, 14 insulin monotherapy after failure of, 221 meglitinides, 222 simultaneous use with insulin therapy, 240 sulfonylureas, 221 thiazolidinediones, 222 use in developing African countries, 259 use in gestational diabetes, 274 Orexins, stimulation of food intake by, 8–9 Orlistat, 104 in diabetes prevention in children, 190–191 low tolerance by adolescents, 196 Outcome data, laparoscopic adjustable gastric banding, 115
469 Ovarian hyperandrogenism diabetes among teenage girls with, 181 effects of metformin on, 192 Overnutrition, links to obesity, insulin resistance, diabetes, 32 Overweight increase in prevalence, 99 recommendations for individuals with diabetes, 52 trends in U.S. population, 45 Oxidative stress, 362 association with type 2 diabetes, 346–348 and β-cell function, 333–335 biochemical measures of, 322 calcium-channel induced, 307 as cause of glucose toxicity, 335 in chronic diabetes, 335–336 contributions of dyslipidemia to, 366 defined, 345 in diabetic gastropathy, 429 in DRG neurons, 385 in early diabetes, 324–326 and glycemic control in type 2 diabetes, 345–346 hyperglycemia-induced, 363 impairment of glucose metabolism by, 348 impairment of muscle repair by, 348 inhibition of NO synthesis by, 364 lack of direct therapeutic strategies against, 370 link to AGE production, 402 manifestations of, 308–311 mechanisms in neuronal injury, 382–384 in pancreatic β-cells, 303–304 in pathogenesis of type 2 diabetes, 346, 348–349 pathophysiology in vascular injury, 362–367 patient characteristics, 321–322 peripheral-nerve testing, 322 prevention by use of GSIS inhibitors, 314 protective effects of vitamin E in, 387 reducing via ACE inhibitors, 388–389 research design and methods, 321–333 role in diabetic nephropathy, 400, 401–404 role in diabetic neuropathy, 381–390 role of UCP2 in decreasing, 311 statistical analysis of study results, 322 targeting with antioxidant therapies, 386–390 treatment approaches, 370–371 in type 1 diabetes, 319–320, 320–321 uncoupling proteins and, 385–386 and vascular complications, 351–371 vs. nitrosative stress, 332–333
470
Nutrition and Diabetes: Pathophysiology and Management
P Pacific Islanders, response to antidiabetic agents, 228 Pancreatic β-cells action of mixed-type glucokinase activators on preserving, 313 and β-cell rest concept, 314 cellular repair mechanisms, 311–312 connection of ROS production with GSIS mechanism in, 306–308 development of lipotoxicity in, 310 dual role of mitochondria uncoupling, 311 glucose toxicity hypothesis, 310 glucose uptake and ATP/ADP regulation in, 304–306 high sensitivity to apoptosis, 304 impairment of insulin production as mechanism of diabetes, 303 increase of UCP2 expression to decrease oxidative stress in, 311 intrinsic and extrinsic apoptotic pathways in, 309 low levels of free-radical detoxifying enzymes in, 308 mechanisms of failure, 307 oxidative stress mechanisms in, 303–304 preservation of cell function and islet mass, 312–314 preservation through decreased apoptosis, 312 role of thiazolidinediones in proliferation of, 313 and ROS overproduction, 308 therapeutic potential actions for, 312–313 Pancreatic insulin release model, 287 Pancreatic polypeptide, 15–16 Pancreatic signals, 14 insulin, 14–15 pancreatic polypeptide, 15–16 Pancreatitis, as presenting symptom in childhood diabetes, 187 Paraventricular nucleus (PVN), 7 PARP, 195 in neuronal injury pathway, 384 role in pathogenesis of vascular dysfunction, 365 Patient contacts, necessity of frequent, 233 Patient education, role in diet counseling, 101 Patient selection, for bariatric surgery, 114 Peptide YY, 17 Periodontitis, 153 Peripheral hormones adipocyte-derived signals, 11 adipocytokines, 11 leptin, 11–14
modulation of food intake by, 11 in regulation of food intake, 10–11 Peripheral nerve blood flow, improvement with alpha-lipoic acid, 386 Peripheral-nerve function early changes in type 1 diabetes, 322–323 improvements with vitamin E administration, 337 longitudinal study of, 321 and oxidative stress in early diabetes, 320, 326–328 reactive-oxygen species links to, 319 Peripheral-nerve testing, 322 Peripheral neuropathy, 150–151, 369–370. See also Neuropathy in examination for diabetic gastropathy, 436 frequency at presentation in African countries, 254 mechanisms of diabetic injury in, 382–384 miscellaneous approaches to reduction of oxidative injury in, 388–390 nitric oxide and nitrosative injury in, 384–385 slowing via glycemic control, 381 Peripheral vascular disease, 150–151 Peroxisome proliferators-activated receptors (PPARs), 90–91, 166, 169–170, 238 thiazolidinediones binding to, 194, 222 Peroxynitrite, 321 increased in proximal tubules of diabetic nephropathy patients, 414 as intermediate between protein nitration and oxidative stress, 336 NO conversion to, 328 pressor effect in humans, 331 role in PNS oxidative injury, 382 Peterson's space, 117 Pharmacokinetic models, glucose and insulin, 284 Pharmacologic management options schematic, 221 Pharmacological agents. See also Antidiabetic agents; individual agents alpha-glucosidase inhibitors, 228 biguanides, 220–221 combination therapy, 239 decreasing glucose and lipid concentrations by, 312 design based on nutrient interactions, 165–166 drugs limiting nutrient absorption, 190–191 insulin secretagogues, 228 insulin sensitizers, 228 insulin suppressors and sensitizers, 191–195 insulin therapy, 222–223 metformin, 191–194 miscellaneous pharmacologic approaches, 195–196
Index oral hypoglycemics, 220–222 preventing childhood diabetes with, 190–196 recommendations in diabetes prevention, 196 role in obesity management, 104–105 sulfonylureas, 197, 221 thiazolidinediones, 194–195, 222 in treatment of childhood diabetes, 197 use in African countries, 259–261 Phenformin hydrochloride, 168 Philipson, Louis H., 303 Phosphorylation, of insulin receptor by protein kinase C, 83 Physical activity. See also Exercise; Volitional exercise appetite control and, 72 cultural acceptability considerations, 259 importance to weight reduction, 49 increased with leptin treatment, 14 increasing intensity and duration of, 104 in lifestyle management of developing countries, 257–259 need for population-based promotion in African countries, 258 predictive TEE equations, 47 as reflection of recent activity levels only, 63 Physical fitness. See also Cardiorespiratory fitness and clustering of metabolic abnormalities, 62 importance in diagnosis/etiology of metabolic syndrome, 60–63 Physical inactivity as barrier to effective management in minorities, 231 as major culprit in obesity epidemic, 71–72 and risk of diabetes, 209 Physical limitations, diabetes and, 148 Pioglitazone, 170 prevention of loss of β-cell mass by, 313 Planned pregnancy, 275 importance for diabetic women, 271 Plastic surgery, following bariatric surgery, 132 Platelet activation normalization with oral taurine supplementation, 411 and prothrombotic environment in type 1 diabetes, 367 Polycystic ovarian syndrome (PCOS) diabetes among adolescent girls with, 181 effects of TZD therapy on, 194 improvements with TZD therapy, 195 Polydipsia, 144, 178, 186 in ketosis-prone diabetes, 260 Polyphagia, 144 Polyuria, 144, 178, 186 in ketosis-prone diabetes, 260
471 Port-related complications, after gastric banding, 116, 126 Portion sizes, reduced postsurgically, 128 Post Valsalva R-R interval ratios, 323, 328 Postabsorptive state, 162 Postnatal weight gain/obesity, as risk factor in childhood diabetes, 179 Postoperative anastomotic leak, 127 Postoperative management in bariatric surgery, 125 Lap-Band, 126 predictors of complications, 126–132 Roux-en-Y gastric bypass, 125–126 short-term complications, 127–128 six weeks to two months, 129–130 two to twelve months postsurgery, 130–132 Postprandial fullness, 430 in diabetic gastropathy, 428 Posttransplantation diabetes, as risk factor for diabetes type 2, 145–146 Prader-Willi syndrome, 181 Prediabetes. See Impaired fasting glucose (IFG); Impaired glucose tolerance (IGT) Preeclampsia, 277 association with diabetic nephropathy, 269 higher risk among diabetic gravidas, 272 Pregnancy congenital abnormalities due to maternal diabetes, 270 diabetes during, 267–268 dramatic insulin sensitivity improvements postpartum, 269 fetal respiratory-distress syndrome, 272 hypertensive complications of, 276 impact of diabetes on, 270–272 impact on pre-existing diabetes, 268–270 importance of planning in diabetes, 271 infusion-pump therapy in, 275 physiological antagonism to insulin, 268 preterm labor in diabetic women, 277 timing of delivery for diabetic mothers, 277 Prenatal/perinatal growth and weight gain, as risk factor in childhood diabetes, 179 Preoperative evaluation, for bariatric surgery, 114 Prepregnancy body-mass index (BMI), 145 Preterm labor, in diabetic women, 277 Programmed cell death (PCD). See Apoptosis Progressive beta-cell failure as indication for insulin therapy, 239 as mechanism in diabetic patients of African ancestry, 251 and reduced response to metformin, 238 Proportional-integral-derivative (PID) controllers, 290
472
Nutrition and Diabetes: Pathophysiology and Management
Protein-bound nitrotyrosine, increased in early type 1 diabetes, 326 Protein-deficient pancreatic diabetes, 251 Protein kinase B, 364 Protein kinase C (PKC), 400 and AGEs in neuronal injury, 389 insulin resistance and, 83 links to AGE, 408 role in oxidative PNS injury, 382 Protein malnutrition, 120 after bariatric surgery, 113 Protein nitration, and oxidative stress, 336 Prothrombosis, in diabetic vascular injury, 367 Pseudohypoglycemia, promoting awareness in minorities, 233–234 Psychiatric illness, as predictor of postsurgical complications, 126–127 Psychological issues, as barrier to diet modification, 102 Purser, Jama L., 43 Pylorospasm, 429
R Race management of diabetes in underrepresented U.S.minorities, 227–243 as risk factor in gestational diabetes, 145 and risk of diabetic nephropathy, 152 Randle hypothesis, 163–164 Reactive oxygen species (ROS), 303, 345, 362 decreased with GSIS inhibitors, 314 links with peripheral-nerve dysfunction and microvascular disease, 319 mechanisms of stress on β-cell function, 334 overproduction leading to apoptosis in pancreatic β-cells, 308 prevention by uncoupling proteins, 383 production in pancreatic β-cells, 306–308 as products of fatty-acid oxidation, 349 and reduction of endothelial injury by aldose reductase inhibitors, 387 role in diabetic nephropathy, 400 sources of production, 306 Recurrent gestational diabetes, 145 Regression analysis, of biochemical parameters and peripheral-nerve function, 322 Renal failure continuum leading to, 416 higher rates among minorities, 229 prevention among minority diabetics, 241–242 Renal hypertrophy, 368 Renal transplantation, and risk of diabetes, 145
Renin-angiotensin system (RAS) overactivity, in pathogenesis of diabetic nephropathy, 407–408 Renin/prorenin ratios, 323 with suppressed uric acid in diabetes, 328 Repaglinide, 222, 237 Resistance training, 51–52 effects on insulin sensitivity and metabolic syndrome, 73 in prevention of childhood diabetes, 189 Resource constraints, as barrier to diet modification, 101 Resting energy expenditure (REE), 6 decline with age, 6 Retinopathy, 230, 234, 368 caution regarding IGF-I therapy in humans, 388 in children with diabetes, 187 as complication of diabetes, 152–153 ethnic risks of, 152 impact of pregnancy on, 270 present at diagnosis in African countries, 253, 254 prevalence among minorities, 229 Reverse glucose-fatty-acid cycle, 165 Risk factors in bariatric surgery, 112 childhood diabetes, 180–184 for diabetes type 2, 145–148, 179 Rosiglitazone, 170 Rosiglitazone/metformin, 239 Roux-en-Y gastric bypass, 113, 114, 117, 118, 125–126 as gold standard weight-loss operation, 118 Russell, James W., 381
S San Luis Valley Diabetes Study, 208–209 Satiety, 6 GLP-1 as gut-derived signal for, 17, 33, 37 and postprandial pancreatic polypeptide levels, 16 role of insulin in, 15 Saturated fat dietary recommendations for weight loss, 49 in pathogenesis of childhood diabetes, 184–185 Scintigraphic assessment, of gastric emptying, 433 SDZ, 167 Secretins, 27 Sedentary lifestyle
Index discouraging in prevention of childhood diabetes, 189 metabolic syndrome and, 71 as risk factor for childhood diabetes, 185 Selective serotonin reuptake inhibitors, inconsistent effects on body weight, 10 Selenium as cofactor for glutathione peroxidase, 353 insulin-like properties of, 413 protective effect in diabetic nephropathy, 412–414 Self-monitoring, 102 in gestational diabetes, 273, 276 optimal frequency for, 234 promoting among minority diabetics, 234 underuse among persons with diabetes, 154 Serotonin, anorexigenic effects of, 10 Severe childhood obesity, 9 Shoulder dystocia, 274 increased risk with vacuum-assisted and forceps deliveries, 275 risks with diabetic gravidas, 271 Sibutramine, 104 Sibutramine Trial in Obesity Reduction and Maintenance (STORM), 104 Side effects acarbose, 191 amylin, 197 cisapride, 438 erythromycin, 437 gastrointestinal with metformin use, 238 metoclopramide, 437 orlistat, 190–191 sulfonylureas, 237 troglitazone, 195 TZDs, 197, 238 Simulation software, 282 for dynamic blood-glucose variations, 289–291 physiologic organ compartments, 283 tissue categorization in, 285 user inputs in GLUCOSIM, 289–290 Skeletal muscle fatty-acid oxidation in, 86–88 lipid content and insulin resistance, 84 Sleep apnea in children with diabetes, 187 reductions after biliopancreatic diversion, 120 risks with obesity, 112 Sleep regulation, role of hypocretins in, 8 Sleeve gastrectomy, 113, 119 Slentz, Cris A., 57 Small bowel obstruction, 131 Small for gestational age (SGA), 181
473 Small intestine, GIP secretion from K cells in, 28 Small-vessel disease, 151 Smoking cessation, 242 Sobngwi, Eugene, 249 Social difficulties, postsurgical, 132 Socioeconomic status, and diabetes prevalence, 142 Sodium, dietary recommendations for weight loss, 49 Soft drinks, contribution to childhood diabetes and obesity, 185 Sorbitol, in diabetic nephropathy, 410–412 Spontaneous weight loss, rarity in absence of disease, 6 Spot urine specimens, 241, 242 Statin drugs antioxidant properties of, 371 reduction of blood lipid concentrations by, 312 Statistical analysis, in studies of oxidative stress in type 1 diabetes, 322 Stomach, secretion of ghrelin in, 16 Stomal stenosis/stricture, 126, 129 STOP-NIDDM trial, 191 Stress and development of hyperglycemia in mice, 206 use of food to relieve, 102 Stroke increased rate of recurrence and dementia, 362 as major cause of death in adults with diabetes, 197, 240 patterns associated with diabetes, 151–152 prevalence in African presentations, 253 Strong Heart Study, 141 Subcortical infarction, 151 Subtotal gastrectomy, 113, 119 Succussion splash, 436 Sucrose, precipitation of hunger by, 185 Sudomotor function, negative association with nitric oxide, 326, 328, 330 Sugar disease, perceptions in African countries, 255 Sulfonylureas, 221, 236, 237 availability in African countries, 259 limitations in use with children and adolescents, 197 and prolongation of remission in ketosisprone diabetes, 261 Superoxide dismutase, 308, 347, 382, 401, 412–413 reduced activity in insulin resistance, 366–367 zinc as cofactor for, 353 Supplementation, after bariatric surgery, 113 Surgeon experience, as predictor of complications, 126
474
Nutrition and Diabetes: Pathophysiology and Management
Surgical treatment. See also Bariatric surgery of morbid obesity, 112–120 patient abandonment of diet interventions in favor of, 106 Sweating associations with nitric oxide and 8-isoPGF2α, 327 decreased in early diabetes type 1, 326 ratio above/below waist, 326, 328 Sw eet eating, food aversion after surgery, 129 Sympathetic nerve function and increased ratio of sweating above/below waist, 326 measures of, 323 Sympathetic nervous system, vulnerability to adverse effects of chronic hyperglycemia, 323 Systolic blood pressure, association with insulin resistance, 62
T Taurine as glycation scavenger, 412 protective effect in diabetic nephropathy, 410–412 Tegaserod, in therapy of constipationpredominant irritable-bowel syndrome, 438 Tetradecylglycidic acid (TDGA), 167 Thermic effect of food (TEF), 6 Thermogenesis, increased with high-protein diets, 220 Thiamine, protective effect in diabetic nephropathy, 412–414 Thiazolidinediones (TZDs), 169–170, 222, 238, 312 for adolescents who fail metformin therapy, 196 improvement of endothelium-dependent vasodilation by, 367 metabolic effects of, 191 potential complications of, 195 in prevention of childhood diabetes, 194–195 role in activation of β-cell proliferation, 313 side effects, 197 Thiobarbituric acid reactive substances (TBARS), 347, 366 increased in patients with neuropathy, 335 Thioredoxin, 308 Three-pool insulin input model, 285 Thyfault, John P., 79 Thyroid releasing hormone (TRH), 7
TNF-alpha, as mediator of insulin resistance, 11 Tooth loss, 153 Topiramate, 104–105 Total energy expenditure (TEE), 6, 46 Total gastrectomy, 439 Total radical trapping antioxidant parameter (TRAP) assay, 336 assessment of antioxidant status by, 347 Trace elements and glycemic control in type 2 diabetes, 353 low levels in diabetes type 2 patients, 347 Tracer methods, in evaluation of gastric emptying, 433–434 Trans-fat intake, and risk of diabetes, 209 Transdermal patches, DPP-IV-resistant GLP-1 analogues, 36 Transition metals, 353. See Trace elements Treadmill time, association with metabolic syndrome, 62–63 Triglycerides. See also Hypertriglyceridemia criteria for metabolic syndrome, 58, 59 decline with TZD therapy, 194 exercise training effects on, 66 gender differences in, 60 increased storage in skeletal muscle in obesity, 85 increased uptake by PPARs, 169 increased with high-carbohydrate, low-fat diets, 212 reductions after gastric bypass, 118 reductions with metformin therapy, 192 Troglitazone, 169–170, 222 hepatotoxicity of, 170 trials in Diabetes Prevention Program study, 192–193 Tropical diabetes, 250, 251–252 Tumor necrosis factor alpha (TNF-α), as link between adiposity and insulin resistance, 85 Tyrosine-kinase activity, depressed in muscle of obese persons, 82
U Ultrasonography, in evaluation of gastric emptying, 434 Uncoupling proteins in obesity, 80–81 and oxidative injury in peripheral neuropathy, 383, 385–386 relation to impaired glucose-induced insulin secretion, 384 role in pancreatic β-cell oxidation, 311
Index
475
Undiagnosed diabetes, among minorities, 230–231 United Kingdom Prospective Diabetes Study (UKPDS), 67 Upper-abdominal discomfort, in diabetic gastropathy, 428, 431 Upper gastrointestinal function. See also Diabetic gastropathy effects of hyperglycemia on, 430 Upper-gastrointestinal x-rays, in evaluation of gastric emptying, 433 Urban lifestyle in etiology of diabetes in African countries, 250–251, 257 and lack of physical activity in developing countries, 258–259 Uremia, as end effect of AGEs, 404, 405 Uric acid, 321 and autonomic function in type 1 diabetes, 329, 331–332 degradation by reactive-oxygen species, 331 negative association with HbA1c, 324, 331 oxidative stress as primary cause of suppression, 331 suppression in diabetic patients, 324 Urinary albumin, criteria for metabolic syndrome, 59 Urinary tract infections, as presenting symptom in childhood diabetes, 187
V Vagal neuropathy, 429 Vaginal candidiasis, as presenting symptom in childhood diabetes, 187 Vanillymandelic acid, 323 Vascular complications cerebrovascular disease, 369 coronary disease, 369 macrovascular, 369–370 microvascular, 368–369 nephropathy, 368–369 and oxidative stress in diabetes, 361–371 peripheral vascular disease, 369–370 retinopathy, 368 Vascular injury pathophysiology of, 362–367 prothrombotic environment of, 367 Vascular tone, beneficial effects of NO on, 328 Vasodilation improvements through metformin and TZDs, 367 by nitric oxide, 330–331
Visceral fat stores, 181–182 decreased with leptin, 13 ethnicity and, 60 gender differences in, 60 as risk factor in childhood diabetes, 179 Vitamins and minerals, vii antioxidant roles of, 362 beta-carotene supplementation and glycemic control, 351 depletion of vitamin E levels by insulin infusion, 347 dietary recommendations for weight loss, 49 low levels of vitamin E in type 2 diabetes, 347 low Vitamin C levels in diabetes type 2, 347 low Vitamin D intake as risk factor in childhood diabetes, 179 protective effect of vitamin C in diabetic nephropathy, 412–414 scavenging activity of vitamin E, 401 selected dietary reference intakes for adults, 50 selenium effects in diabetic nephropathy, 412–413 in slowing of progression of diabetic nephropathy, 409 targeting of PNS oxidative injury with, 387 thiamine protective effects in diabetic nephropathy, 413 trace elements and glycemic control, 353 vitamin C and enhanced insulin sensitivity, 350 vitamin C in maintenance of blood glucose levels, 147 vitamin C in mitigation of diabetic nephropathy, 414 vitamin C infusion and restoration of NO vasodilation, 365, 387 vitamin C supplementation and glycemic control, 350–351 vitamin deficiencies with orlistat therapy, 190 vitamin E and normalization of retinal blood flow, 371 vitamin E and reduction in cardiovascular complications, 370–371 vitamin E and suppression of 8-iso-PGF2α, 336 vitamin E protection of pancreas, 337 vitamin E supplementation and glycemic control, 350 VLDL cholesterol increases with high-carbohydrate, low-fat diets, 212 increases with high levels of circulating FFAs, 365
476
Nutrition and Diabetes: Pathophysiology and Management
Volitional exercise, as main strategy in weight control, 6 Vomiting in diabetic gastropathy, 428, 431, 432 domperidone therapy for, 438 prolonged after surgery, 128–129 refractory, 438
W Waist circumference controversies over definitions in metabolic syndrome, 60 criteria for metabolic syndrome, 58 exercise training effects on, 70–71 as risk factor for diabetes, 146 Waist-to-hip ratio, 146 criteria for metabolic syndrome, 59 Watkins, Michael T., 361 Web-based simulations, 281–282 Weight classification, 100 Weight gain, as symbol of good living in African countries, 255 Weight loss with Atkins Diet-like programs, 215–216 barriers in urban America, 235 complications from rapid, 130 development of noninvasive methods of, 121 in diagnosis of diabetes, 144 effects of high-protein diets on, 219–220 factors associated with success, 102 with high-protein vs. high-carbohydrate diets, 218 leptin decreases following, 12 long-term after biliopancreatic diversion, 120 with low-carbohydrate diets, 214, 215 with metformin therapy, 220 rarity of spontaneous in absence of disease, 6 recommendations for OW/OB with diabetes, 52
restoration of insulin sensitivity after, 84 surgery as most effective long-term treatment for, 121 as symbol of poor living in African countries, 255 Weight-loss-promoting medications, 53 Weight obsessions, 128–130 Weight-reduction (WR) diets, 46 calorie-reduction diets, 46–48 estimated Kcal reductions based on bodymass ranges, 47 indications and body-weight goals for optimal health, 46 low-carbohydrate diets, 48–49 low-fat diets, 48 overall diet composition, 49 Wisconsin Epidemiologic Study of Diabetic Retinopathy, 152 World Health Organization (WHO) 1985 criteria for diagnosis of diabetes, 144 criteria for metabolic syndrome, 59 definition of metabolic syndrome, 57
X Xanthine oxidase, 364
Y Young, Carlton Joseph, 399
Z Zinc, as cofactor for SOD, 353 Zonisamide, 105
