The Year in Diabetes 2001

THE YEAR IN DIABETES 2001

THE YEAR IN DIABETES 2001 Edited by

Ramón Gomis and Simon Page

CLINICAL PUBLISHING SERVICES OXFORD

Clinical Publishing Services Ltd Oxford Centre for Innovation Mill Street, Oxford OX2 OJX, UK Tel: +44 1865 811116 Fax: +44 1865 251550 Web: www.clinicalpublishing.co.uk Distributed by: Plymbridge Distributors Ltd Estover Road Plymouth PL6 7PY, UK Tel: +44 1752 202300 Fax: +44 1752 202333 E mail: [email protected] © Clinical Publishing Services Ltd 2001 First published 2001 This edition published in the Taylor & Francis e-Library, 2005. “To purchase your own copy of this or any of Taylor & Francis or Routledge’s collection of thousands of eBooks please go to www.eBookstore.tandf.co.uk.” All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, without the prior permission in writing of Clinical Publishing Services Ltd A catalogue record for this book is available from the British Library ISBN 0-203-01180-5 Master e-book ISBN

ISBN0953733963 (Print Edition) The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this work. Commissioning Editor: Jonathan Gregory Project Manager: Rosemary Osmond

Preface

Research is the key to medical progress. Even if no-one doubts that this is true, doctors embroiled in the business of daily clinical practice do not devote the time needed to keep abreast of advances in fundamental and experimental medicine, as though these findings were nothing to do with them. Very often, public access to biomedical information makes the patient run straight to their doctor and ask why they are suffering from the illness concerned and about the latest treatments that may relieve their suffering. Putting it another way, the doctor is obliged not only to have the latest information about the illness, but also be capable of informing their client about the relevance of information transmitted by the general media and have an opinion about the future viability or non-viability of the options broadcast. Hence, the importance of commenting on clinical trials, advances and fundamental research in progress. Armed with this analysis and commentary, the reader will have the advantage over those with only partial or biased information. Another important point worth mentioning is that the complications of an illness have immense social impact, whether through their incidence, severity or the expense that they incur. No-one should wonder why diabetes, in terms of its incidence, the severity of its complnes for dealing with it. These guides are an invaluable aid for general practitioners and for specialists alike. Remember that cardiovascular complications, against a background of diabetes mellitus, dyslipidaemia, obesity and high blood pressure, call for a global approach and need to be studied from all angles. Consequently, it is important to establish clear guidelines that cannot be misinterpreted and that can be used for working efficiently on the diagnosis of diabetes mellitus and its treatment. Nor should we overlook the importance of diabetes and pregnancy. It is a field in which adequate treatment prevents much suffering. This treatment is within the reach of the clinic that is aware of the importance of diagnosing diabetes mellitus during the early stages of pregnancy and is prepared to use intensive treatment with the sole aim of maintaining glucose homeostasis and keeping fats within normal limits. In The Year in Diabetes, we have aimed to provide a gateway to the research published over the previous year, to assist you, the physician, in managing this condition in the most up-to-date and appropiate way. Ramon Gomis Simon Page

Contents

Part I

Contributors

vii

Preface R Gomis

iv

Acknowledgements

ix

Diabetes management guidelines 1.

Diabetes management guidelines according to the American Diabetes Association

2.

Criteria for diagnosing diabetes

3 43

Part II Clinical trials 3.

Clinical trials in the process of development

55

4.

Recent results of clinical trials

63

Part III Advances in type 1 diabetes mellitus 5.

Current status of type 1 diabetes mellitus

107

6.

Chronic complications of diabetes and endothelial dysfunction

120

7.

Management of diabetes mellitus

136

Part IV Insulin resistance: type 2 diabetes mellitus and obesity 8.

Type 2 diabetes mellitus and cardiovascular risk

156

9.

Diabetes and obesity

172

Part V Diabetes and pregnancy 10.

Diabetes and pregnancy

195

Part VI Diabetes research 11.

Diabetes research

217

List of abbreviations

239

vi

Index of papers reviewed

244

General index

252

Contributors

General Editors RAMÓN GOMIS, MD, Head of the Endocrinology and Diabetes Department, Clinic Hospital, Barcelona, Spain SIMON PAGE, MD FRCP, University Hospital, Queen’s Medical Centre, Nottingham NG7 2UH, United Kingdom Editorial Coordinator ÀNGELS COSTA, MD, August Pi I Sunyer Institute of Biomedical Investigation, University Hospital Clinic, Barcelona, Spain Endocrinology and Diabetes Department, University Hospital Clinic, Barcelona, Spain EVA AGUILERA MARGARITA JANSÀ MONICA RECASENS GEMMA SESMILO OLGA SIMÓ MERCÈ VIDAL August Pi I Sunyer Institute of Biomedical Investigation (IDIBAPS), Barcelona, Spain SILVIA BARCELÓ CARMEN BENITO AIDA CABALLERO MARC CLARET HELENA COROMINOLA IMMA CORONADO ÀNGELS COSTA MARIA JOSÉ COVES MARTA E FABREGAT

viii

ELENA FERNÁNDEZ LILLIAM FLORES MÓNICA GUDAYOL CONXI MORA ROSA MORINIGO BELÉN NADAL ISABEL ROJAS

Acknowledgements

The editors would particularly like to acknowledge the work of Dr Àngels Costa in coordinating the compilation of The Year in Diabetes 2001, which owes much to her energy and efficiency. In producing this book, Dr Àngels Costa has shown exemplary dedication and efficiency. She has cleverly involved everyone in it and has elicited the best information from each contributor. Even in her youth and during the early stages of her brilliant professional career, her maturity, her achievements and the critical bases of her decisions gave her distinction. Without the dynamism of Dr Àngels Costa, the quality of the comments and speed of completion would probably not have been accomplished. In addition, by involving suitable people in the project, she has been able to select good references and the most promising tests and subjects for debate. In praising her work, we must not forget the collaborative efforts of her team of physicians, based at the Endocrinology and Diabetes Department of the Barcelona Clinic Hospital, who provided summaries and commentaries on the key papers. I doubt that few projects were planned as collectively as this one. We think that the reader will appreciate it and from a different perspective will appreciate the joint vision and the emphasis on balance, and will not set aside critical opinion. We shall welcome it. It only remains for us to congratulate and thank the publisher for their confidence in the Endocrinology and Diabetes Department of the Barcelona Clinic Hospital. The Editors

Part I Diabetes management guidelines

Diabetes management guidelines

Introduction The American Diabetes Association (ADA) is the USA’s leading non-profit health organization and it provides diabetes research, information and advocacy. The aim of the organization is to prevent and cure diabetes and to improve the lives of all people affected by diabetes. The ADA funds research, publishes scientific findings and provides information and other services to people with diabetes, their families, health care professionals and the public. The ADA is also actively involved in advocating for scientific research and for the rights of people with diabetes. The ADA regularly publishes its clinical practice recommendations in the January supplement of the journal Diabetes Care. Important themes this year include the ADA’s decision to follow the trend of evidence-based medicine and to appraise the scientific evidence supporting each of its recommendations. Amongst the 2001 recommendations are a series of innovative aspects that are worth pointing out. 1. An action plan for dealing with acute hyperglycaemic complications has been introduced. 2. The target blood pressure has been reduced to<130/80 mmHg. 3. Information has been added about screening for type 2 diabetes mellitus amongst the child and adolescent population. 4. The therapeutic option that involved the sulphonylureas (glibenclamide) in gestational diabetes and for post-partum monitoring of those women with pre-gestational diabetes who displayed ongoing intermediate oral glucose tolerance has been reviewed. 5. More emphasis is now being placed on the benefits of treating diabetes with aspirin. 6. For the first time it is clear that the pre-pubertal stage of diabetes and its metabolic control may be very important in the later development of microvascular complications. 7. Information about the value of continuous out-patient blood glucose monitoring systems has been added. As with any recommendations those that apply to clinical practice in diabetes are not intended to ‘fetter’ the professional, nor do they claim to de-individualize any working guidelines. On the contrary, they aim to guide all actions that very often elude empirical evaluation. As in many other aspects of life, unfamiliarity with these recommendations should not be used as a pretext for non-use wherever possible.

1 Diabetes management guidelines according to the American Diabetes Association

Screening for type 2 diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl): 20–3.

Comment Type 2 diabetes is the commonest form of diabetes, accounting for approximately 90% of all cases. As it has a long pre-symptomatic phase, it can often go undetected for years. People with undiagnosed type 2 diabetes are at high risk of developing both microvascular and macrovascular complications. The detection and early treatment of this condition can reduce these serious complications. Screening for diabetes is very important, particularly in high-risk patients (see Table 1.1). Experts recommend conducting screening checks every 3 years, as there is little likelihood of someone developing diabetes or its complications within this period in asymptomatic patients following a previously negative test. Diabetes screening tests Fasting plasma glucose (FPG) and the oral glucose tolerance test (OGTT) are two adequate tests for detecting diabetes. An FPG≥126 mg/dl (7 mmol/l) or a blood glucose test 2 h after an OGTT of≥200 mg/dl (11.1 mmol/l) indicates that the test should be repeated in order to confirm diabetes. Table 1.1 Major risk factors for type 2 diabetes • • • • • • • •

Family history of diabetes (i.e. parents or siblings with diabetes) Obesity (i.e.≥20% over desired body weight or BMI≥27 kg/m2 Race/ethnicity (e.g. African-Americans, Hispanic Americans, Native Americans, Asian-Americans, Pacific Islanders) Age≥45 years Previously identified IFG or IGT Hypertension≥140/90 mmHg in adults) HDL cholesterol level≤35 mg/dl (0.90 mmol/l) and/or a triglyceride level ≥250 mg/dl (2.82 mmol/1) History of GDM or delivery of babies over 9 lb

Source: American Diabetes Association (2000).

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© Clinical Publishing Services Ltd

People with an FPG of ≥110 mg/dl (6 mmol/1) and<126 mg/dl (7 mmol/1) are now regarded as having impaired fasting glucose (IFG), whereas those with a blood glucose 2 h after a 75 g OGTT of≥140 mg/dl (7. 8 mmol/1) and<200 mg/dl (11.1 mmol/l) are considered as having impaired glucose tolerance (IGT). Both IFG and IGT are risk factors for future diabetes. The screening is also considered to have yielded positive results if the plasma glucose is≥160 mg/dl irrespective of the length of time that has elapsed since the last meal. Diabetes screening programmes The aim of these programmes is to identify people in the pre-symptomatic phase. High-risk populations should be targeted in order to maximize the sensitivity and specificity of screening. Various questionnaires, such as that of the American Diabetes Association (ADA), inquire about the risk factors for developing diabetes. However, these population screenings must have mechanisms for offering medical assessment to people who have positive screening tests. On occasions, although it is not very advisable and has no diagnostic value, a capillary blood glucose reading is taken using a glucometer. A capillary blood glucose value of≥110 mg/dl or a non-basal capillary reading of≥140 mg/dl would merit further formal laboratory investigation. Standards of medical care for patients with diabetes mellitus American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S32.

Comment Diabetes is a chronic illness that requires continuing medical care and education. People with diabetes should receive care from a physician-coordinated team, including physicians, nurses, dietitians and mental health professionals. An important aim of treatment is to achieve near normal or normal glucose levels in order to prevent acute and chronic complications of the disease. This requires comprehensive education in self-management and intensive treatment programmes. Specific glycaemic targets are shown in Table 1.2. Medical nutrition therapy (MNT) should be provided to all patients. Frequent self-monitoring of blood glucose (SMBG) at least three to four times a day is advised in type 1 diabetes and possible hospitalization for initiation of therapy should be considered. Individual characteristics should be particularly considered in patients with type 2 diabetes. Daily SMBG is important in those treated with insulin or sulphonylureas. An extensive initial visit should provide a basis for continuing care for all patients with diabetes. The components of the initial visit are listed in Table 1.3. Table 1.2 Glycaemic control for people with diabetes Normal

Goal

Additional action suggested

<100

80–120

<80/>140

Whole blood values Average preprandial glucose (mg/dl)*

DMG ACCORDING TO THE AMERICAN DIABETES ASSOCIATION

Normal

Goal

Additional action suggested

Average bedtime glucose (mg/dl)*

<110

100–140

<100/>160

Average preprandial glucose (mg/dl)† Average bedtime glucose (mg/dl)†

<110

90–130

<90/>150

<120

110–150

<110/>180

<6

<7

>8

Plasma values

HbAlc (%)

The values shown in this table are by necessity generalized to the entire population of individuals with diabetes. Patients with comorbid diseases, the very young and older adults and others with unusual conditions or circumstances may warrant different treatment goals. These values are for non-pregnant adults. ‘Additional action suggested’ depends on individual patient circumstances. Such actions may include enhanced diabetes self-management education, comanagement with a diabetes team, referral to an endocrinologist, a change in pharmacological therapy, initiation of or an increase in SMBG or more frequent contact with the patient. Glycosylated haemoglobin (HbAlc) is referenced to a non-diabetic range of 4.0–6.0% (mean 5.0% and SD 0. 5%). *Measurement of capillary blood glucose. †Values calibrated to plasma glucose. Source: American Diabetes Association (2000). Table 1.3 Components of the initial visit I. Medical history A. B. C.

D. E. F. G. H. I. J. K. L. M.

Symptoms, laboratory results related to diagnosis Nutritional assessment, weight history Previous and present treatment plans 1. Medications 2. MNT 3. Self-management training 4. SMBG and use of results Current treatment program Exercise history Acute complications History of infections Chronic diabetic complications Medication history Family history CHD risk factors Psychosocial/economic factors Tobacco and alcohol use

II. Physical examination A.

Height and weight

5

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II. Physical examination B. C. D. E. F. G.

Blood pressure Ophthalmoscopic examination Thyroid palpation Cardiac examination Evaluation of pulses Foot examination

H. Skin examination I. Neurological examination J. Oral examination K. Sexual maturation (if peripubertal) III. Laboratory evaluation A. Fasting plasma glucose (optional) B. GHb C. Fasting lipid profile D. Serum creatinine E. Urinalysis F. Urine culture (if indicated) G. TSH (type 1 patients) H. Electrocardiogram (adults) IV. Management plan A. Short- and long-term goals B. Medications C. Medical nutrition therapy D. Lifestyle changes E. Self-management education F. Monitoring instructions G. Annual referral to eye specialist H. Specialty consultations (as indicated) I. Agreement on continuing support/follow-up J. Pneumococcal and influenza vaccines Source: American Diabetes Association (2000). Table 1.4 Potential components of continuing care visits I. Contact frequency A. Daily for initiation of insulin or change in regimen B. Weekly for initiation of oral glucose-lowering agent(s) or charge in regimen C. Routine diabetes visits 1. Quarterly for patients who are not meeting goals 2. Semiannually for other patients

DMG ACCORDING TO THE AMERICAN DIABETES ASSOCIATION

II. Medical history A. Assess treatment regimen 1. Frequency/severity of hypo-/hyperglycaemia 2. SMBG results 3. Patient regimen adjustments 4. Adherence problems 5. Lifestyle changes 6. Symptoms of complications 7. Other medical illnesses 8. Medications 9. Psychosocial issues 10. Tobacco and alcohol use III. Physical examination A. Physical examination annually B. C.

Dilated eye examination annually Every regular diabetes visit 1. Weight 2. Blood pressure 3. Previous abnormalities on the physical exam D. Foot examination annually: more often in patients with high-risk foot conditions IV. Laboratory evaluation A. GHb 1. Quarterly treatment changes or patients is not meeting goals 2. Twice per year if stable B. Fasting plasma glucose (optional) C. Fasting lipid profile annually, unless low risk D. Microalbumin measurement annually (if indicated) V. Evaluation of management plan A. Short- and long-term goals B. Medications C. Glycaemia D. Frequency/severity of hypoglycaemia E. SMBG results F. Complications G. Control of dyslipidaemia H. Blood pressure I. Weight J. MNT K. Exercise regimen L. Adherence to self-management training

7

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M. Follow-up of referrals N. Psychosocial adjustment 0. Knowledge of diabetes P. Self-management skills Q. Smoking cessation, if indicated R. Annual influenza vaccine Source: American Diabetes Association (2000).

Continuing care is essential in evaluating the patient’s progress in achieving treatment goals or the plan for helping the patient meet those goals. Examinations for detecting chronic complications early should also be performed. A detailed list of the potential components of continuing care visits is listed in Table 1.4. Special considerations should be given to children and adolescents as well as to pregnant women. Intercurrent illnesses usually affect glycaemic control and patients require more frequent monitoring and interaction with the diabetes care team. Patients treated with oral agents or nutrition therapy only may require insulin during an illness. Acute complications, including diabetic ketoacidosis and hyperosmolar non-ketotic syndrome, require prompt consultation with a diabetologist and, depending on the severity, treatment should be carried out in hospital. Severe or frequent hypoglycaemia requires careful evaluation. Annual retinal examinations are required and early treatment of retinopathy should be provided when necessary. Early detection and treatment of hypertension is required for diabetic patients. The primary goal of therapy for adults should be to decrease blood pressure (BP) to<130/85 mmHg. In children, BP should be decreased to the age-adjusted ninetieth percentile values. Life style modifications, such as weight loss, exercise, a reduction in dietary sodium and limits on alcohol consumption, should be reinforced. If life style modifications do not achieve specified goals, medications should be added in a stepwise fashion. Angiotensin-converting enzyme (ACE) inhibitors have been proven particularly beneficial in patients with diabetes and microalbuminuria. Repeat timed or overnight urine collections or measurements of albumin to creatinine ratios should be obtained periodically in order to detect early nephropathy (microalbuminuria) or overt nephropathy (clinical albuminuria). ACE inhibitors are recommended when nephropathy is present and protein restriction to 0.8 g/kg body weight/day (10% of daily calories) should be instituted with the onset of overt nephropathy. Control of dyslipidaemia and other cardiovascular risk factors should be reinforced. When cardiac disease is present, testing for risk stratification is warranted. It is important to diagnose neuropathy when present and to consult with an appropriate medical specialist when necessary. Patient education for regular foot care and consulting with a specialist when required must be also reinforced. Extended guidelines for complications of diabetes are provided in other parts of the book. Nutrition recommendations and principles for people with diabetes mellitus American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S43.

Comment MNT is integral to total diabetes care and an essential component of successful diabetes management. Achieving nutrition-related goals requires a coordinated team effort. It is recommended that a registered dietitian, skilled in implementing diabetes MNT, be the team member providing nutrition care and education.

DMG ACCORDING TO THE AMERICAN DIABETES ASSOCIATION

9

Effective nutrition self-management training requires an individualized approach. Monitoring of glucose and glycated haemoglobin, lipids, BP and renal status is essential in evaluating nutrition-related outcomes. If goals are not met, changes must be made in the overall diabetes care and management plan. A nutrition assessment is used for determining the nutrition prescription. Sensitivity to cultural, ethnic and financial considerations is of prime importance. This paper reflects current scientific nutrition and diabetes knowledge. However, there are limited published data for some recommendations and, under these circumstances, recommendations are based on clinical experiences and consensus. This position statement |1| is based on a technical review |2|, which discusses published research and issues that remain unresolved. Goals of MNT Although the overall goal of MNT is to assist individuals with diabetes in making changes in nutrition and exercise habits leading to improved metabolic control, there are additional specific goals. 1. Maintenance of as near-normal blood glucose levels as possible by balancing food intake with insulin or oral glucose-lowering medications and physical activity. 2. Achievement of optimal serum lipid levels. 3. Pro vision of adequate calories for maintaining or attaining reasonable weights for adults, normal growth and development rates in children and adolescents, increased metabolic needs during pregnancy and lactation or recovery from catabolic illnesses. Reasonable weight is defined as the weight an individual and health care provider acknowledge as achievable and maintainable in both the short and long term. 4. Prevention and treatment of the acute and long-term complications of diabetes. 5. Improvement of overall health through optimal nutrition. Nutrition and Your Health: Dietary Guidelines for Americans |3| and The Food Guide Pyramid |4| summarize nutrient needs and nutritional guidelines for all healthy Americans. The First Step in Diabetes Meal Planning |5| is more specific for individuals with diabetes. However, all three provide guidelines that can be used by people with diabetes and their family members in making healthy food choices. Nutrition therapy and type 1 diabetes A meal plan based on an individual’s usual food intake should be determined and used as the basis for integrating insulin therapy into the individual’s usual eating and exercise patterns. It is recommended that individuals eat at consistent times that are synchronized with the action time of the insulin preparation used. Further, individuals need to monitor their blood glucose levels and adjust their insulin doses for the amount of food usually eaten. Intensified therapy, including multiple daily injections, continuous subcutaneous insulin infusion (CSII) using an insulin pump and rapid-acting insulin, allows for more flexibility in the timing of meals and snacks, as well as in the amount of food eaten. Individuals on intensified insulin regimens can make adjustments for rapid- or short-acting insulin in order to cover the carbohydrate content of their meals and, possibly, snacks and for deviations from usual eating and exercise habits.

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Nutrition therapy and type 2 diabetes The primary MNT goals for individuals with type 2 diabetes are to achieve and maintain glucose, lipid and BP goals. Hypocaloric diets and weight loss usually improve short-term glycaemic levels and have the potential for improving long-term metabolic control. However, traditional dietary strategies and even very low-calorie diets, have usually not been effective in achieving long-term weight loss. Emphasis for individuals with type 2 diabetes needs to expand beyond weight loss to achieving and maintaining nearnormal blood glucose levels. Several additional strategies can be implemented. However, there is no one proven strategy or method that can be uniformly recommended. A moderate caloric restriction (250–500 calories less than the average daily intake) and a nutritionally adequate meal plan with a reduction of fat, in particular saturated fat, accompanied by an increase in physical activity should be recommended. A hypocaloric diet (independent of weight loss) is associated with increased sensitivity to insulin and improvement in blood glucose levels. Moderate weight loss 205– 208, kg) (10–20 lb), irrespective of starting weight, has been shown to reduce hyperglycaemia, dyslipidaemia and hypertension. The spacing of meals (spreading nutrient intake, in particularly carbohydrates) is another strategy that can be adopted. Regular exercise can help facilitate long-term life style changes. However, if individuals with diabetes have made all the life style changes they are able to make and metabolic control has not improved, an oral glucose-lowering agent and/or insulin may need to be added to their MNT. Many individuals with refractory obesity may have limited success with the above strategies. As new pharmacological agents (for people with a body mass index (BMI)>27 kg/m2 with other health risks or problems, e.g. diabetes or>30 kg/ m2 without other health risks or problems) become available, they may prove to be effective. Gastric reduction surgery is available for people with a BMI>35 kg/m2. Studies on the long-term efficacy and safety of these methods are however needed. Protein There are limited scientific data upon which to establish firm nutritional recommendations for protein intake for individuals with diabetes. At the present time, there is insufficient evidence to support protein intakes either higher or lower than the average protein intake for the general population. For people with diabetes, this translates into approximately 10–20% of daily caloric intake from protein, which can be derived from both animal and vegetable sources. With the onset of overt nephropathy, lower intakes of protein should be considered. Several small studies in humans with diabetic nephropathy (DN) have shown that a prescribed protein-restricted diet of 0.6 g/kg/ day (subjects actually only achieved a restriction of 0.7 g/kg/day) results in a modest reduction in the rate of fall of the glomerular filtration rate (GFR). However, the recent Modified Diet in Renal Disease Study, in which only 3% of the patients had type 2 diabetes and none had type 1 diabetes, failed to show a clear beneflt of protein restriction |6|. The general consensus is to prescribe a protein intake of approximately the adult recommended dietary allowance of 0.8 g/kg/day (approximately 10% of daily calories) in a patient with overt nephropathy. However, it has been suggested that once the GFR begins to fall, further restriction to 0.6 g/kg/day may prove useful in slowing the decline of the GFR in selected patients. On the other hand, nutrition deficiency may occur in some individuals and may be associated with muscle weakness. Protein restriction may help with symptoms of nausea and sickness as renal failure progresses. Protein-restricted meal plans should be designed by a registered dietitian.

DMG ACCORDING TO THE AMERICAN DIABETES ASSOCIATION

11

Total fat If protein contributes 10–20% of the total caloric intake, then 80–90% of calories remain to be distributed between fat and carbohydrate. Less than 10% of these calories should be from saturated fats and<10% from polyunsaturated fats, leaving 60–70% of the total calories from monounsaturated fats and carbohydrates. The recommended percentage of calories from fat is dependent on identified lipid problems and the treatment goals for glucose, lipids and weight. People with a healthy weight and normal lipids are encouraged to follow the recommendations of the National Cholesterol Education Program (NCEP). The NCEP recommends that all individuals over 2 years limit fat intake to<30% of total calories with saturated fat restricted to<10%. The polyunsaturated fat intake should be<10% of calories with monounsaturated fat in the range of 10–15% of calories. If low-density lipoprotein (LDL) cholesterol is the primary concern or if levels are elevated, a further reduction in saturated fat to 7% of total calories and dietary cholesterol to<200 mg/ day (NCEP step II diet) is recommended. Polyunsaturated fats of the Ω-3 series are provided naturally in fish and other seafood and the intake of these foods need not be curtailed in people with diabetes. If obesity and weight loss are the primary concerns, a reduction in dietary fat should be considered. Additional research is needed in order to assess the impact of fat replacements on the total fat and caloric content of the diet. If triglycerides (TGs) and very low-density lipoprotein (VLDL) cholesterol are the primary concerns, one approach that may be tried is a moderate increase in monounsaturated fat intake with<10% of the calories from saturated fats and a more moderate carbohydrate intake. However, in obese individuals, care should be taken to ensure that increased fat does not perpetuate or aggraviate the obesity. In addition, individuals with TG levels>1000 mg/dl (>11.3 mmol/l) require a reduction in all types of dietary fat (<10% of calories) in addition to pharmacological treatment in order to reduce the risk of pancreatitis. Monitoring of glycaemic and lipid status and body weight with any dietary fat modifications is essential in assessing the effectiveness of the nutrition recommendations. Saturated fat and cholesterol A reduction in saturated fat and cholesterol consumption is an important goal in reducing the risk of cardiovascular disease (CVD). Diabetes is a strong independ ent risk factor for CVD over and above the adverse effects of elevated serum cholesterol. Therefore,<10% of the daily calories should be from saturated fats and dietary cholesterol should be limited to<300 mg daily. However, even these recommendations must be incorporated with consideration of an individual’s cultural and ethnic background. Carbohydrates and sweeteners The percentage of calories from carbohydrates will also vary and is individualized based on the individual’s eating habits and glucose and lipid goals. For most of this century, the most widely held belief about the nutritional treatment of diabetes has been that simple sugars should be avoided and replaced with starches. This belief appears to be based on the assumption that sugars are more rapidly digested and absorbed than starches and, therefore, that they aggravate hyperglycaemia to a greater degree. However, there is very little scientific evidence that supports this assumption. Fruits and milk have been shown to have a lower glycaemic response than most starches and sucrose produces a glycaemic response similar to that of bread, rice and potatoes. Although various starches do have different glycaemic responses, from a clinical perspective first priority should be given to the total amount of carbohydrate consumed rather than the source of the carbohydrate.

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Sucrose Scientific evidence has shown that the use of sucrose as part of the total carbohydrate content of the diet does not impair blood glucose control in type 1 or type 2 diabetes. Sucrose and sucrose-containing foods must be substituted for other carbohydrates. In making such substitutions, the nutrient content of concentrated sweets and sucrose-containing foods as well as the presence of other nutrients frequently ingested with sucrose, such as fat, must be considered. Fructose Dietary fructose produces a smaller rise in plasma glucose than isocaloric amounts of sucrose and most starches. In that regard, fructose may offer an advantage as a sweetening agent in the diabetic diet. However, because of the potential adverse effects of large amounts of fructose (i.e. double the usual intake) (20% of calories) on serum cholesterol and LDL cholesterol, fructose may have no overall advantage in the diabetic diet. Although people with dyslipidaemia should avoid consuming large amounts of fructose, there is no reason for recommending that people with diabetes avoid consumption of fruits and vegetables, in which fructose occurs naturally or moderate consumption of fructose-sweetened foods. Other nutritive sweeteners Nutritive sweeteners other than sucrose and fructose include corn sweeteners, such as corn syrup, fruit juice or fruit juice concentrate, honey, molasses, dextrose and maltose. There is no evidence that foods sweetened with these sweeteners have any significant advantage or disadvantage over foods sweetened with sucrose in decreasing the total calories or carbohydrate content of the diet or in improving overall diabetes control. Sorbitol, mannitol and xylitol are common sugar alcohols (polyols) that produce a lower glycaemic response than sucrose and other carbohydrates. Starch hydrolysates are formed by the partial hydrolysis and hydrogenation of edible starches, thus becoming polyols. Although the exact caloric value of sugar alcohols vary, they average approximately 2 kcal/g compared with the 4 kcal/g from other carbohydrates. Evidence to suggest that this can be expected to contribute to a major reduction in total calories or in the total carbohydrate content of the daily diet is limited. Furthermore, excessive amounts of polyols may have a laxative effect. The calories and carbohydrate content from all nutritive sweeteners must be accounted for in a meal plan and have the potential for affecting blood glucose levels. Non-nutritive sweeteners The Food and Drug Administration (FDA) has approved the use of saccharin, aspartame, acesulphame K and sucralose in the USA. The FDA determines an acceptable daily intake (ADI), which is defined as the amount of a food additive that can be safely consumed on a daily basis over a person’s lifetime without any adverse effects and includes a 100-fold safety factor, for all food additives, including non-nutritive sweeteners. The actual intake by individuals with diabetes for all nonnutritive sweeteners is well below the ADI.

DMG ACCORDING TO THE AMERICAN DIABETES ASSOCIATION

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Fibre Dietary fibre may be helpful in the treatment or prevention of constipation and several gastrointestinal disorders, including colon cancer and provides satiety value to the diet and large amounts of soluble fibre have a beneficial effect on serum lipids. People with diabetes would be as amenable to these effects as those without diabetes. Although selected soluble fibres are capable of inhibiting the absorption of glucose from the small intestine, in the amounts likely to be consumed from foods the clinical significance of this effect on blood glucose levels is probably insignificant. Therefore, the recommendations for people with diabetes that are related to fibre and a healthy diet are the same as for the general population. Daily consumption of a diet containing 20–35 g dietary fibre from both soluble and insoluble fibres from a wide variety of food sources is recommended. Sodium People differ in their sensitivity to sodium and its effect on BP. Because it is impractical to assess individual sodium sensitivity, the intake recommendations for people with diabetes are the same as for the general population. Some health authorities recommend no more than 3000 mg/day of sodium for the general popula Table 1.5 A historical perspective of nutrition recommendations Distribution of calories (%) Year

Carbohydrate

Protein

Fat

Before 1921 1921 1950 1971 1986 1994

– 20 40 45 ≤60 *

Starvation diets 10 20 20 12–20 10–20

– 70 40 35 <30 *†

*Based on nutritional assessment and treatment goals. †Less than 10% of calories from saturated fats. Source: American Diabetes Association (2000).

tion, while other authorities recommend no more than 2400 mg/day. An intake of <2400 mg/day of sodium is recommended for people with mild to moderate hypertension while an intake of<2000 mg/day of sodium is recommended for people with hypertension and nephropathy. Alcohol The same precautions regarding the use of alcohol that apply to the general public also apply to people with diabetes. Nutrition and Your Health: Dietary Guidelines for Americans |3| recommends no more than two drinks per day for men and no more than one drink per day for women. The effect of alcohol on blood glucose levels is dependent not only on the amount of alcohol ingested, but also on the relationship to food intake. Alcohol is not metabolized to glucose and inhibits gluconeogenesis and, therefore, hypoglycaemia can result if people treated with insulin or oral glucose-

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lowering agents consume alcohol without food. Hypoglycaemia can occur at blood alcohol levels that do not exceed mild intoxication. However, if used in moderation and with food, blood glucose levels are not affected by the ingestion of alcohol when diabetes is well controlled. Two or less alcoholic beverages (one alcoholic beverage=12 oz (340 ml) beer, 5 oz (142 ml) wine or 1.5 oz (42 ml) distilled spirits) can be ingested with and in addition to the regular meal plan in individuals using insulin. No food should be omitted because of the possibility of alcohol-induced hypoglycaemia. When calories from alcohol need to be calculated as part of the total caloric intake, alcohol is best substituted for fat exchanges (one alcoholic beverage=two fat exchanges) or fat calories. Abstention from alcohol should be advised for people with a history of alcohol abuse or during pregnancy. A reduction in or abstention from alcohol intake is advisable for diabetic individuals with other medical problems such as pancreatitis, dyslipidaemia and in particular elevated TGs or neuropathy. Micronutrients Vitamins and minerals When dietary intake is adequate, there is generally no need for additional vitamin and mineral supplementation for the majority of people with diabetes. Although there are theoretical reasons for supplementing with antioxidants, there is little confirmatory evidence at present that such therapy has any benefits. The only known circumstance in which chromium replacement has any beneficial effect on glycaemic control is for people who are chromium deficient as a result of long-term chromium-deficient parenteral nutrition. However, it appears that most people with diabetes are not chromium deficient and, therefore, chromium supplementation has no known benefit. Similarly, although magnesium deficiency may play a role in insulin resistance, carbohydrate intolerance and hypertension, the available data suggest that routine evaluation of serum magnesium levels is recommended only in patients at high risk of magnesium deficiency. Levels of magnesium should be repleted only if hypomagnesaemia can be demonstrated. Potassium loss may be sufficient for warranting dietary supplementation in patients taking diuretics. Hyperkalaemia sufficient for warranting dietary potassium restriction may occur in patients with renal insufficiency or hyporeninaemic hypoaldosteronism or in patients taking ACE inhibitors. Pregnancy The nutrition recommendations for women with pre-existing and gestational diabetes should be based on a nutrition assessment. Monitoring blood glucose levels, urine ketones, appetite and weight gain can be a guide to developing and evaluating an appropriate individualized nutrition prescription and meal plan and for making adjustments to the meal plan throughout pregnancy in order to ensure desired outcomes. Summary A historical perspective of nutrition recommendations is provided in Table 1.5. Today there is no one ‘diabetic’ or ‘ADA’ diet. The recommended diet can only be defined as a nutrition prescription based on assessment and treatment goals and outcomes.

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MNT for people with diabetes should be individualized, with consideration given to usual eating habits and other life style factors. Nutrition recommendations are then developed and implemented in order to meet the treatment goals and desired outcomes. Monitoring metabolic parameters, including blood glucose levels, glycated haemoglobin, lipids, BP, body weight and renal function, if appropriate, as well as quality of life, is crucial in ensuring successful outcomes. Furthermore, it is essential that ongoing nutrition selfmanagement education and care be provided for individuals with diabetes. Diabetes mellitus and exercise American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S50.

Comment An update and consolidation of current knowledge about the role of physical exer cise in patients with type 1 and 2 diabetes mellitus (DM). Patient evaluation before exercise Before embarking on a physical exercise programme, patients with diabetes should undergo a detailed medical evaluation and diagnostic studies, if appropriate, for detecting clinically significant macrovascular and microvascular complications that may deteriorate with exercise. An assessment would include the following. Cardiovascular system A careful history should be taken in order to determine the presence or absence of cardiovascular symptoms. It is important to remember that symptoms of angina and heart failure may be atypical in diabetes and a high index of suspicion must be maintained. In selected cases where there are symptoms or a high risk of CVD a progressive exercise test can be helpful before recommending a moderate- to high-intensity physical exercise programme. The criteria for patient selection include one of the following: age>35 years of age, type 2 diabetes which has been developing for>10 years, type 1 diabetes for>15 years, the presence of additional coronary artery risk factor(s), the presence of microvascular complications, peripheral vascular disease (PVD) and autonomic neuropathy (Table 1.6). Likewise, patients with non-specific electrocardiogram changes in response to exercise, as well as T wave and ST changes at rest, should undergo a stress gammagraphy scan. Although coronary disease is probable in such cases, the ischaemic response and threshold response to exercise and predisposition to arrhythmia whilst exercising may be determined. PVD Examining for the symptoms and signs of PVD, for example intermittent claudication, atrophy of the subcutaneous tissue, low foot temperature and peripheral cyanosis or pallor. If the physical examination raises any doubt, the ankle brachial pressure index should be estimated using a Doppler examination if necessary.

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Retinopathy Patients with active, proliferative diabetic retinopathy (DR) should be advised to avoid anaerobic exercises, strenuous exercise or exercise involving Valsalva’s manoeuvres (Valsalva’s manoeuvre involves an increase of intrathoracic pressure by forcible exhalation effort against the closed glottis) due to the risk of vitreous haemorrhage or retinal detachment (Table 1.7). Table 1.6 Classification of physical activity intensity, based on physical activity lasting up to 60 min Relative intensity Intensity

Vo2max(%)

Maximal heart rate(%)*

RPE†

Very light Light Moderate Hard Very hard Maximal

<20 20–39 40–59 60–84 >85 100

<35 35–54 55–69 70–89 >90 100

<10 10–11 12–13 14–16 17–19 20

Modified by Haskell and Pollock from Physical Activity and Health: A Report of the Surgeon General. *Maximal heart rate (HRmax)=220—age. (Note: it is preferable and recommended that HRmax be measured during a maximal graded exercise test when possible. †Borg rating of relative perceived exertion (RPE) 6–20 scale. The maximal values are the mean values achieved during maximal exercise by healthy adults. Source: American Diabetes Association (2000). Table 1.7 Considerations for activity limitation in DR (3) Level of DR

Acceptable activities

Discouraged activities

Ocular reevaluation

No DR Mild non-proliferative DR Moderate non-proliferative DR

Dictated by medical status Dictated by medical status

Dictated by medical status Dictated by medical status

12 months 6–12 months

Dictated by medical status

4–6 months

Severe non-proliferative DR

Dictated by medical status

Proliferative DR

Low-impact, cardiovascular conditioning Swimming Walking Low-impact aerobics Stationary cycling Endurance exercises

Activities that dramatically elevate blood Power lifting Heavy Valsalva Activities that substantially increase systolic blood pressure, Valsava manoeuvres, and active jarring Boxing Heavy competitive sports Strenuous activities, Valsava manoeuvres, pounding or jarring Weight lifting Jogging Highimpact aerobics Racquet sports Strenuous trumpet playing

Source: American Diabetes Association (2000).

2–4 months (may require laser surgery)

1–2 months (may require laser surgery)

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Table 1.8 Exercises for diabetic patients with loss of protective sensation Contraindicated exercise

Recommended exercise

Treadmill Prolonged walking Jogging Step exercises Arm exercises Other non-weight-bearing exercise

Swimming Bicycling Rowing Chair exercises

Source: American Diabetes Association (2000).

Nephropathy No specific recommendations have been made for patients with incipient (microalbuminuria>20 mg/min) or established nephropathy (>200 mg/min). As renal failure progresses patients become less capable of exercise because of anaemia, uraemic fatigue and other complications. Such patients should be advised to undertake low to moderately intense activity only. Peripheral neuropathy This causes loss of sensitivity in the feet and, hence, loss of a protection mechanism. Severe polyneuropathy indicates the need to limit intense exercise (Table 1.8). Polyneuropathy is evaluated by physical examination of Achilles reflex, vibratory, proprioceptive and tactile sensitivity using a 10 g monofilament (an inability to detect it indicates loss of protective foot sensitivity). Autonomic neuropathy Limits individual capacity to perform physical exercise and increases the risk of cardiovascular events during exercise. Autonomic cardiac neuropathy may be suspected in patients with a resting tachycardia, postural hypotension and other changes to the autonomic nervous system that may affect the skin, pupils, gastrointestinal tract or genitourinary tract. Exercise thallium scanning of the heart is a non-invasive test for diagnosing the presence and extent of coronary disease in these patients. Preparation for exercise Preparation for safe, agreeable exercise is as important as the exercise itself. Young people with good metabolic control can perform any activity. The middle aged and elderly should be encouraged to undertake physical activity with assessment for the complications listed earlier in selected cases. In addition, diabetics, like non-diabetics, must include a warm-up period before exercising (low-intensity aerobic activity for 5–10 min) and before or after this period a muscle stretching session. This would primarily involve the muscle groups that are going to be exercised and, finally, after exercising, they must include a cooldown (paralleling the warm-up) period. Considerations specific to patients with diabetes include the following:

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1. Aerobic exercise. 2. Protection of their feet (adequate footwear and hosiery) and keeping their feet dry (particularly patients with peripheral neuropathy). Patients should routinely check their feet for possible lesions before and after exercise. 3. Carrying diabetic identification. 4. Adequate hydration before, during and after exercising. 5. Avoidance of overly hot or cold environments. Exercise and type 2 diabetes The benefits are substantial and recent studies have shown the long-term importance of physical exercise programmes in the treatment and prevention of common metabolic disturbances and their complications. Sugar control Carbohydrate metabolism and insulin sensitivity are improved and regular exercise over a 5-year period ensures that the benefits are maintained. Moderate exercise for 30 min five times each week may result in a 10–20% improvement in HbAlc and there is some evidence that regular exercise may delay or prevent the progression of IGT to established type 2 diabetes. Prevention of CVD Insulin resistance is an important risk factor in the development of premature coronary disease and is associated with hypertension, central (abdominal) obesity, hyperinsulinism and an atherogenic lipid profile. Many studies show that such patients have low levels of activity in comparison with controls. Many of the beneficial effects of exercise on cardiovascular risk are probably related to improved sensitiv ity to insulin. Hyperlipidaemia Regular exercise produces an effective reduction in TG and VLDL levels. At present, no improvement in high-density lipoprotein (HDL) or reduction in LDL has been detected in type 2 DM. High BP There is a connection between high BP and insulin resistance in these patients. Exercise lowers the BP in patients with insulin resistance and also in hyperinsulinism patients. Fibrinolysis Many patients with type 2 diabetes have altered fibrinolytic activity plus increased plasminogen activator inhibitor type 1 (PAI-1) levels (the main natural tissue plasminogen activator (tPA) inhibitor). There appears to be a link between physical aerobic exercise and fibrinolysis, but so far there is no clear-cut evidence that exercise improves fibrinolytic activity.

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Obesity Exercise causes weight loss and, above all, helps to keep weight levels constant within a calorie-controlled food diet. Some interesting studies have suggested that there may be a disproportionate effect on abdominal fat loss associated with metabolic changes. Prevention of type 2 diabetes A large body of opinion believes that there is evidence that exercise, amongst other therapies, is helpful in preventing or delaying the onset of type 2 DM. The National Institutes of Health has a substantial, prospective, randomized study under way that aims to clarify this possibility, namely the Diabetes Prevention Programme. Exercise and type 1 diabetes Type 1 DM patients without complications and with good metabolic control can perform any type of exercise at any degree of intensity. However, they should follow certain general guidelines that are designed for assisting in the regulation of blood sugar response to exercise and make it safe. These can be summarized as follows. Metabolic control before exercising 1. Do not exercise if the fasting blood sugar is>250 mg/dl (14 mmol/l) and ketosis is present. In addition, exercise circumspectly if the basic blood sugar is>300 mg/dl (20 mmol/l) without ketosis. 2. Take additional carbohydrates if the blood sugar is less than 100 mg/dl. Blood sugar monitoring before and after exercise 1. Identify when to make changes to the volume of insulin administered or food intake if necessary. 2. Learn how blood sugar responds to different exercise situations. Food intake 1. Consume additional carbohydrates as and when necessary in order to avoid hypoglycaemia. 2. Carbohydrate-rich foods are recommended before and after exercise. Exercise for the elderly With advancing years there is a steady decline in elasticity and muscle mass that is mitigated, to some extent, by engaging in regular exercise. In addition, sensitivity to insulin declines partly owing to the absence of physical activity. Clearly, if this population were to exercise more, chronic vascular disease would be reduced and quality of life improved.

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Conclusion There are clinical benefits in incorporating a regular exercise programme into the management of diabetes. In patients with type 2 diabetes the earlier the exercise programme is started and the longer it is maintained the greater the benefits. Exercise is also beneficial for patients with type 1 diabetes. The aim should be to adjust the treatment (diet and insulin pattern) so that physical activity can be undertaken safely. All diabetic patients must have the chance to benefit from the rewards of physical exercise. Preventive foot care in people with diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S55.

Comment Foot ulcers and amputations are an important cause of morbidity, distress and expense for patients with diabetes. The early recognition and management of risk factors for ulcers and amputations can prevent or delay the onset of these adverse outcomes. The consensus of the ADA has issued certain recommendations concerning diabetic foot management. Risk identification The risk of ulcers or amputations increases in people who have been suffering from diabetes for≥10 years, if they are male and if they have poor metabolic control and also if they have renal, retinal or cardiovascular complications. Foot ulceration is also more likely in patients from lower socioeconomic classes and in the elderly. The likelihood of amputation is increased by the presence of peripheral neuropathy, pressureinduced biomechanical deterioration (calluses, erythema and subcallus bleeding), restricted joint movement, bone deformity or severe nail disease, PVD and a previous history of ulcers or amputation. Foot examination All diabetics should have their feet examined thoroughly, at least initially and thereafter annually, in order to identify the ‘at-risk’ diabetic foot. This examination should include an assessment of peripheral sensation, foot structure, vascular condition and skin integrity. People with one or more risk factors should be evaluated more often in order to assess the development of additional risk factors. Peripheral neuropathy is associated with drying and cracking of the skin particularly around the heel. The resulting fissures commonly become infected. Wasting of the intrinsic muscles of the feet leads to abnormal pressure loading and the development of calluses over pressure points. Clawing of the toes is often seen. Peripheral neuropathy should be evaluated using the 10 g Semmes-Weinstein monofilament. Failure to appreciate the monofilament is associated with a sevenfold increased risk of foot ulceration. Pinprick (Neurotips) and vibration perception thresholds are alternative screening modalities. Screening for PVD should include a detailed history of claudication or ischaemic rest pain. Foot pulses should be assessed by palpation or using Doppler ultrasound. The integrity of the skin should be checked, particularly between the toes, around the heels and underneath the metatarsal heads. The presence of erythema or callus formation may indicate areas of damaged tissue impeding mobility. Severe compromise

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of the peripheral vasculature is associated with atrophy of the skin and dystrophic nail changes that make the foot more vulnerable to ulceration. Prevention of high-risk conditions Symmetrical polyneuropathy is one of the most important predictors of foot ulceration and amputation. Optimal glycaemic control can prevent or delay the onset of neuropathy, but it must be remembered that approximately 20% of patients with new type 2 diabetes already have neuropathy at diagnosis. The diabetic should try to reduce the risk of CVD by giving up smoking and receive appropriate attention to their BP and lipid profiles. Management of high-risk conditions Neuropathy People with neuropathy or evidence of increased plantar pressure can cope satisfactorily with their problems by wearing cushioned shoes or trainers. Patients should be educated about the implications of reduced sensitivity and acquire alternative sensing skills (palpation and visual inspection) in order to locate and resolve any problems that may arise early on. Daily inspection of the feet is essential. People with evidence of increased plantar pressure (erythema, calluses or pressure readings) should wear shoes and insoles that redistribute the pressure. A podiatrist or other health professional with experience of and training in foot care can remove calluses with a scalpel and patients with at-risk feet should receive a regular programme of podiatric care. People with bone deformities (for example hallux valgus, claw toes or Charcot neuroarthropathy) may require bespoke (custom made) shoes from a specialist orthotist. Vascular Patients with PVD should be regularly reviewed in order to assess their symptoms and exercise tolerance. Regular low-intensity exercise (i.e. walking) is of benefit in encouraging the development of collateral vessels. Where the symptoms dictate vascular assessment using duplex scanning or arteriography should be considered in collaboration with an experienced vascular surgeon. Proximal atheromatous lesions suitable for angioplasty or bypass may be identified. Vascular risk factors including glucose control, hypertension and lipid abnormalities should be vigorously treated and aspirin is advised unless contra-indicated. Patient education Diabetic patients with high-risk foot conditions should be told what the foot risk factors are and how to manage them appropriately. Patients who have had problems with their sight, mobility or experienced cognitive difficulties should be monitored at an appropriate institute and will need other people such as family members for assisting with their care. Organizations interested in providing diabetic foot care can be given additional training in the management of high-risk conditions. Other experts may need to be involved in patient education, foot and callus care, shoe adjustments and in foot surgery management.

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Conclusion The prevention, detection and care of foot lesions plus good metabolic control are the cornerstones of diabetic podiatry. Management of dyslipidaemia in adults with diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S57.

Comment High fasting TG, low HDL cholesterol and normal total and LDL cholesterol levels characterize dyslipidaemia in type 2 DM patients. The LDL particle size is altered in diabetes with an increase in small, dense LDL particles that are more susceptible to oxidation leading to atheroma. Major studies, such as the Scandinavian Simvastatin Survival Study or Cholesterol and Recurrent Events project, have demonstrated a reduction in fatal and non-fatal cardiovascular events with an effective reduction in LDL cholesterol. Subgroup analysis of patients with diabetes in these landmark studies has suggested that similar benefits are likely to be achieved in treating lipid disorders in diabetes. Lipoprotein levels can be used to identify three coronary risk categories (Table 1.9). Patients at high and borderline risk should have an annual lipid profile whilst those in the low-risk group should be reassessed every 2 years. Table 1.9 Category of risk based on lipoprotein levels in adults with diabetes Risk

LDL cholesterol (mg/dl) (mmol/l)

HDL cholesterol* (mg/dl) (mmol/l)

TG (mg/dl) (mmol/l)

High Borderline Low

>130 (3.4) 100–129 (2.6–3.4) <100 (2.6)

<35 (0.9) 35–45 (0.9–1.2) >45 (1.2)

>400 (4.5) 200–399 (2.3–4.5) <200 (2.3)

Conversion factors between mg/dl and mmol/l are 0.02586 for cholesterol and 0.01129 for TG. *For women the HDL cholesterol values should be increased by 10 mg/dl. Source: American Diabetes Association (2000). Table 1.10 Treatment decisions based on cholesterol level in adults with diabetes MNT

With CHD, PVD or CVD Without CHD, PVD or CVD

Drug therapy

Starting treatment

LDL goal

Starting treatment

LDL goal

>100

<100

>100

<100

>100

<100

>130*

<100

CHD, coronary heart disease. *For diabetic patients with multiple CHD risk factors (low HDL (<35), hypertension, smoking, a family history of CVD or microalbuminuria or proteinuria) some authorities recommend initiation of drug therapy when their LDL levels are between 100 and 130 mg/dl. Caveats: (1) MNT should be attempted before starting pharmacological therapy and (2) since diabetic men and women are considered to have equal CHD risk, age and sex are not considered as ‘risk factors’. Source: American Diabetes Association (2000).

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The ADA and NCEP recommend that medication should be started only if dietetic measures and greater physical activity have proved unsuccessful. However, they accept that patients with established coronary artery disease or very high LDL levels (>200 mg/dl) should start both measures simultaneously, since the maximum LDL cholesterol reduction achieved with non-pharmacological measures is modest at between 15 and 25 mg/dl. The treatment objectives are summarized in Table 1.10. The aim of the treatment must be taken into account in any dyslipidaemia treatment, i.e. priorities need to be assigned (Table 1.10). Initial treatment for hypertriglyceridaemia should focus on a change in life style, weight reduction, increased physical activity, lower alcohol consumption and target optimized blood sugar control. In cases where fasting TG remains over 400 mg/dl, medication should be started. In cases of severe hypertriglyceridaemia (>1000 mg/dl), a massive restriction in dietary fat to less than 10% of calories plus pharmacological measures must be applied in order to avoid the risk of pancreatitis. However, although fibrates are the isolation to patients with undesirable LDL levels. Within this group, phenofibrate is most effective drugs for reducing TG indices, they should not be administered in Table 1.11 Order of priorities for the treatment of diabetic dyslipidaemia in adults LDL cholesterol lowering* First choice: HMG CoA reductase inhibitor (statin) Second choice: bile acid-binding resin (resin) or fenofibrate HDL cholesterol raising Behavioural interventions such as weight loss, increased physical activity and smoking cessation may be useful Glycaemic control Difficult except for nicotinic acid, which is relatively contra-indicated, or fibrates TG lowering Glycaemic control is the first priority Fibric acid derivative (gemfibrozil or fenofibrate) Statins are moderately effective at high doses in hypertriglyceridaemic subjects who also have high LDL cholesterol Combined hyperlipidaemia First choice: improved glycaemic control plus a high-dose statin Secondchoice: improved glycaemic control plus a statin plus a fibric acid derivative (gemfibrozil or fenofibrate) Third choice: improved glycaemic control plus a resin plus a fibric acid derivative (gemfibrozil or fenofibrate)

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Combined hyperlipidaemia Improved glycemic control plus a statin† plus nicotinic acid† (glycaemic control must be monitored carefully) *The decision for the treatment of high LDL cholesterol before elevated TGs is based on clinical trial data indicating the safety as well as efficacy of the available agents. †The combination of statins with nicotinic acid and, in particular, with gemfibrozil or fenofibrate may carry an increased risk of myositis. Source: American Diabetes Association (2000).

the most effective agent for reducing LDL cholesterol levels. In some studies, high statin doses (80 mg/day of simvastatin or 40 mg/day of atorvastatin) have been moderately effective in reducing the TG levels of patients with a TG of>300 mg/dl. Sometimes, a combination of drugs is required and various options (see the summary in Table 1.11) are available for this purpose. Evaluation and changes in the treatment programme should be performed at 4- to 6-week intervals. The objectives of dyslipidaemia treatment for type 1 diabetes are similar to those for type 2 diabetes. Smoking and diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S63.

Comment Many studies have linked smoking with the onset and progression of microvascular and macrovascular complications in patients with DM. The established prevalence of smokers amongst DM patients is very similar to the incidence of non-diabetic smokers. Smoking is therefore a modifiable risk factor; all health professionals and probably their directing diabetologists are ideally placed for advising diabetic patients who smoke. The ADA has provided guidelines as to how tobacco consumption can be prevented or given up |7| (see Table 1.12). Assessing how to deal with the smoking habit Details of a patient’s smoking pattern should form an essential part of the clinical history record. A few simple questions will provide the doctor with information about the patient’s particular smoking habit, in particular nicotine dependency and help in identifying situations where there may be difficulty in resisting smoking or a temptation to relapse. Table 1.12 Recommendations regarding diabetes and smoking Assessment of smoking status and history • Systematic documentation of a history of tobacco use must be obtained from all adolescent and adult individuals with diabetes. Counsellingon smoking prevention and cessation • All health care providers should advise individuals with diabetes notto initiate smoking. This advice should be consistently repeated to prevent smoking and other tobacco use among children and adolescents with diabetes under age 21 years.

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•

Among smokers, cessation counselling must be completed as a routine component of diabetes care. Every smoker should be urged to quit in a clear, strong and personalized manner that describes the added risks of smoking and diabetes. • Every diabetic smoker should be asked if he or she is willing to quit at this time. If no, initiate brief and motivational discussion regardingthe need to stop using tobacco, the risks of continued use, and encouragementto quit as well as support when ready. If yes, a preference for and initiate either minimal, brief, or intensive cessation counselling and offer pharmacological supplements as appropriate. Effective systems for delivery of smoking cessation • Training of all diabetes health care providers in the Agency for Health Care Policy and Research Guidelines regarding smoking should be implemented. • Follow-up procedures designed to assess and promote quitting status must be arranged for all diabetic smokers. Source: American Diabetes Association (2000).

Treatment of smoking addiction All health professionals must discourage their patients with diabetes from starting to smoke in the first place. Patients who smoke should be informed of the currently available treatments for tobacco addiction. In these patients, treatment must take account of and limit their nicotine dependency. The ideal treatment for nicotine addiction is one combining psychological/behavioural therapy and pharmacology. Much information now supports the idea that the use of nicotine replacement therapy (NRT) in conjunction with behavioural therapy is more effective than NRT alone. In the case of diabetic smokers, the doctor must be aware of special situations that may affect stopping smoking, such as increased calorie intake and weight gain. However, this must not be used as an argument against trying to give up smoking. Pre-conception care of women with diabetes American Diabetes Association. Diabetes Care 2000;23(Suppl 1): S65.

Comment This guide from the ADA seeks to identify the basis for an interactive pre-conception programme in order to give women with diabetes the best opportunity of having a normal pregnancy. Women with diabetes should be informed of the maternal and fetal risks associated with an unplanned pregnancy. Ideally a multidisciplinary team, including diabetes specialists, interns or family practitioners, obstetricians and diabetes educators such as nurses, dieticians and welfare assistants plus other specialists, should be involved in providing appropriate pre-conceptual counselling. However, the patient is the central member of the team with others acting as ‘guides’ for helping her manage the pregnancy and post-natal period. Initial visit See Table 1.13.

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Condition follow-up The patient’s progress in relation to agreed management targets should be assessed at each visit. Outstanding issues should be re-evaluated and the management plan restructured if appropriate. Topics associated with the following should be discussed. Table 1.13 Initial visit

Diabetes type and duration

Medical history and obstetrics Acute complications: infections, ketoacidosis and hypoglycaemia Chroniccomplications: retinopathy, nephropathy, neuropathy and hypertension Diabetes management: insulin regimen and previous orcurrent use of oral hypoglycaemic drugs Concomitant illnesses and medications Menstrual history, pregnancy and contraceptive use Back-up system, includingfamily and family environment Physical examination BP Cardiovascular examination: patients with over 10 years of the illness or at coronary vascular risk Neurological examination, including autonomic function if necessary Examination of lower limbs: evidence of vascular illness, neuropathy, deformity or infection. Pelvic examination includingthe neckofthe uterus (Papanicolaou’s stain test) Ophthalmological examination of the retina through dilated pupils Laboratory evaluation Glycated haemoglobin Basal study of renal function: serum creatinine, microalbuminuria and creatinine clearance Thyroid function: thyroid-stimulating hormone and free thyroxine Other studies as indicated bythe physical examination orclinical history Patient-monitored capillaryglucose measurements, patient familiarity with techniques and quality assurance, insulin regimen and techniques for adjusting insulin doses Educative session Hypoglycaemic and hyperglycaemic events in terms of frequency, severity, signs and symptoms and the way each should be tackled by the patient Nutritional history: calculation of the number of food calories required, changes in weight and food upsets, gastrointestinal problems, exercise and other life style considerations Evaluation of stress factors associated with diabetes and pregnancy Source: American Diabetes Association (2000).

1. Possible fetal and neonatal risks: preventive measures. 2. Possible maternal obstetric complications and the implications in respect of the diabetes. 3. Effective contraceptive measures that should be used pending full a medical assessment and establishment of optimal metabolic control. 4. Adherence to a diet adequately backed up with vitamins, iron and a folic acid supplement and an adequate programme of physical activity. 5. Oral hypoglycaemic drugs should be discontinued in patients with type 2 DM with initiation of insulin therapy in the pre-conceptual period and throughout pregnancy. 6. Training in the use of algorithms for adjusting the insulin dose, remembering that the values in Table 1.14 are considered acceptable.

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7. The patient must be visited every month and weekly telephone contact is a useful option. Visits with other team members will be decided in individual cases. 8. Laboratory determinations: the patient’s HbAlc level should be checked monthly upon commencement of the programme during the lead up to pregnancy and then repeated every 6–8 weeks until conception. Acceptable values range between the upper end of the laboratory reference range and an upper limit of less than three standard deviations from the mean, but this can be adjusted according to the risk of severe neuroglycopenia. In addition, consider possible adjustment of electrolytes, lipids and renal and thyroid function. 9. Fertility studies are recommended if conception does not occur within 1 year offollow-up. Table 1.14 ADA guide

Whole blood 2 h<120 mg/dl (<6.7 mmol/l) Plasma 2 h<135 mg/dl (<7.5 mmol/l)

Glucose before eating

Glucose after eating

70–100 mg/dl (3.9–5.6 mmol/l)

1 h<140 mg/dl (<7.8 mmol/l)

80–110 mg/dl (4.4–6.1 mmol/l)

1 h<155 mg/dl (<8.6 mmol/l)

Source: American Diabetes Association (2000).

Special considerations. See Table 1.15. Table 1.15 Special considerations Hospitalizations Retinopathy High BP

Start of intensive insulin treatment Acute diabetic complications Good sugar control before conception in order to reduce the progression risk Laser photocoagulation, if indicated Aggressive control and monitoring of BP ACE inhibitors (these cannot be used from the second month of pregnancy onwards owing to a reduction in placental flux), methyldopa, hydrallazine and diuretics are anti-hypertensives that can be considered during pregnancy

Nephropathy

Neuropathy

Cardiovascular illness Initial management of pregnancy

Basal studies of renal function at the beginning and at regular intervals thereafter Women with a serum creatinine of≥3 mg/dl or a creatinine clearance of<80 ml/ min must defer pregnancy until renal function is stable with renal transplant Renal function deteriorates by 8–30% during pregnancy and, hence, would not be a contra-indication to pregnancy in patients with less severe nephropathy: pregnancy does not have a long-term deleterious effect on renal function Evidenced bygastroparesis, urine retention, unrecognized hypoglycaemia or postural hypotension could complicate diabetes management during pregnancy Compartmental syndromes may be exacerbated by pregnancy Suggests a high degree of mortality during pregnancy Analytical and echographic confirmation Re-adjust the food plan Weight gain during pregnancy

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Insulin dose adjustment by checking the blood sugar Psychosocial factors and attitudes towards these Source: American Diabetes Association (2000). Diabetic nephropathy American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S69.

Comment DM has become the main cause of end-stage renal failure (ESRF) in the developed world. Early detection and aggressive treatment in order to optimize glycaemic control and effectively treat hypertension and proteinuria may significantly delay or even prevent the development of ESRR The ADA has provided joint recommendations on the detection, prevention and treatment of DN based on expert evaluation of epidemiological studies and clinical trials. Natural history of DN Microalbuminuria is the first clinically detectable sign of DN. Microalbuminuria is the presence of minimal but abnormal albumin losses in the urine (>30 mg/day in a 24-hour urine collection or 20 mg/min in a timedovernight urine) (incipient nephropathy). With disease progression urinary albumin excretion progressively increases (to >300 mg/24 h or 200 µg/min) until dip-stick-positive proteinuria is detectable and the term established nephropathy is used. Following the onset of established proteinuria there is a progressive decline in the glomerular filtrate until ESRF develops. Hypertension is an almost universal feature of progressive DN. Careful studies using 24-hour ambulatory BP measurements have shown abnormally high BPs relative to matched controls at the stage of incipient nephropathy although the actual BP levels do not usually fulfil the conventional criteria for the diagnosis of hypertension. Uncontrolled hypertension hastens the development of ESRF in established nephropathy. Screening for albuminuria A high proportion of individuals with type 2 diabetes will have microalbuminuria or established nephropathy at diagnosis. Hence, urinalysis should be performed rou tinely at diagnosis and annually thereafter in type 2 diabetes. Microalbuminuria develops before 5 years disease duration or before puberty in patients with type 1 diabetes. Hence, screening should begin after puberty or 5 years after development of the disease. Later on and if microalbuminuria is not present, annual screening is recommended. An algorithm for screening for microalbuminuria is shown in Fig. 1.1. Effect of blood sugar control The Diabetes Control and Complications Trial (DCCT), the United Kingdom Prospective Diabetes Study (UKPDS), the Stockholm Intervention Study and the Kumamoto Study have clearly documented that intensive glycaemic control in type 1 and type 2 diabetes lessens the risk of developing microalbuminuria and the progression to established nephropathy. Consequently, the glycaemic control recommendations

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Fig. 1.1 Routine urinalysis at diagnosis. Source: American Diabetes Association (2000).

supplied by the ADA in Standards of Medical Care for Patients with DM |8| must be discussed with every patient with diabetes. BP control Hypertension accelerates the progression of DN. Effective anti-hypertensive treatment is renoprotective and reduces the rate of progressive loss of the GFR. The Standards of Medical Care for Patients with DM advises that the primary objective for the treatment of non-pregnant diabetic patients≥18 years of age should be atargetof<130/85 mmHg. Patients with isolated systolic hypertension (systolic blood pressure (SBP) of ≥180 mm of Hg) should have their SBP lowered to≤160 mmHg or, where patients have an SBP of between 160 and 179 mmHg, their SBP should be lowered by 20 mmHg. If these initial targets are achieved and tolerated, a greater reduction in BP is indicated. Many studies have demonstrated that, in type 1 diabetic patients with incipient or established nephropathy, ACE inhibitors reduce albuminuria and the progression of renal disease as compared to other

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anti-hypertensive agents that achieve a similar degree of BP reduction. ACE inhibitors are believed to reduce proteinuria by specifically relaxing the efferent arteriole of the glomerulus, thereby producing lower intra-glomerular capillary filtration pressure. Thus, in patients with incipient nephropathy, initial treatment with ACE inhibitors is advised. If adequate BP control has not been achieved after 4–6 weeks, additional anti-hypertensive therapy must be provided. ACE inhibitors are also recommended for ‘normotensive’ patients with diabetes and incipient nephropathy. Summary Annual screening for microalbuminuria identifies DN patients at early stages of the condition. Better control of blood sugar levels, aggressive treatment for combating hypertension and ACE inhibitors will reduce the advance of DN. Diabetic retinopathy American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S73.

Comment Two factors make the early recognition and monitoring of this microvascular complication of DM vitally important. The first is its prevalence. Retinopathy is related to diabetes disease duration. After 20 years of diabetes: (1) over 98% of patients with type 1 diabetes will have background DR, (2) 40–50% of patients with type 1 diabetes will have proliferative retinopathy and (3) over half (>60%) of patients with type 2 diabetes will have retinopathy. In the Western world, DR is the commonest cause of blindness in adults of working age. The second factor is the consequences of its prevention and treatment. There is clear evidence from the DCCT and UKPDS trials that has established the importance of good glucose control in preventing the onset and progression of DR. However, since retinopathy is symptomless until complications such as vitreous haemorrhage or macular oedema develop and effective treatment of established disease with laser photocoagulation is available, the detection of early disease with a regular screening programme is an integral part of diabetes care. Early detection 1. Type 1 diabetes. All patients over 10 years but under 30 years of age diagnosed as having type 1 diabetes should undergo full ophthalmic examination using direct ophthalmoscopy through dilated pupils by a trained examiner or mydriatic polaroid or digital retinal photography within 5 years of diagnosis (ideally including at diagnosis). 2. Where type 1 diabetes is diagnosed in patients under 10 years of age evidence suggests that the prepubertal duration and level of control have a significant impact on the risk of developing retinopathy in adolescence or early adult life. Each case must be assessed individually in deciding on when to initiate screening. 3. Patients in whom the onset of diabetes occurs after 30 years of age should be subjected to examination initially and annually thereafter.

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4. Type 2 DM. Type 2 diabetes has a long pre-clinical phase and up to 50% of cases remain undiagnosed in the community. At clinical diagnosis, approximately 30% of patients have developed some degree of retinopathy and in 1% this can be sight threatening; a full ophthalmic examination is mandatory at the diagnosis of type 2 diabetes. Follow-up 1. An annual ophthalmological examination is generally recommended for both types of diabetes. The monitoring frequency is variable and will depend on the absence, presence or need for treatment in each case. Groups with handling skills supervised by an ophthalmologist with retinopathy experience can use a non-mydriatic retinal camera for assisting with ophthalmological examination. 2. Pregnant patients with established diabetes should undergo an ophthalmological examination before conception, during each trimester of pregnancy and following any deterioration in eyesight. It should be remembered that pregnancy per se carries a higher risk of retinopathy development and progression. 3. In cases of macular oedema, severe non-proliferative or proliferative retinopathy, the patient must be referred without dilation to the ophthalmology team used for treating retinopathy. 4. Laser treatment is effective in reducing the risk of vitreous haemorrhage or the progression of macular oedema in patients with sight-threatening retinopathy. Where advanced diabetic eye disease does not respond to photo-coagulation and either vitreous haemorrhage or retinal fibrosis or detachment threatens vision, the patient may benefit from vitreoretinal surgery. Referral to a specialist vitreoretinal surgeon is recommended. Gestational diabetes mellitus American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S77.

Comment The ADA has defmed gestational diabetes mellitus (GDM) as any degree of IGT developing during pregnancy. The definition applies whether insulin or only diet modification is used for treatment and whether or not the condition persists after pregnancy. The condition affects between 1 and 14% of pregnancies although the prevalence varies with the population studied and the diagnostic criteria used. There are maternal and neonatal consequences. Women with GDM are at increased risk of pre-eclampsia and have a higher Caesarean section rate than women with normal glucose tolerance (NGT) during pregnancy. This is largely due to the greater likelihood of delivering a macrosomic infant. Fifty percent of women with GDM subsequently develop type 2 diabetes within 15 years. Neonates are at increased risk of macrosomia (birth weight>4 kg) plus hypoglycaemia, hypocalcaemia, polycythaemia and jaundice during the early neonatal period. Table 1.16 Diagnosis of GDM based on the 100 g or 75 g oral glucose load

Fasting 1h

100 g test mg/dl

mmol/l

75 g test mg/dl

mmol/l

95 180

5.3 10.0

95 180

5.3 10.0

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100 g test mg/dl

mmol/l

75 g test mg/dl

mmol/l

155 145

8.6 7.8

155 N/A

8.6 N/A

Two or more of the venous plasma glucose concentrations must be met or exceeded for the diagnosis. The test should be performed in the morning after an 8- to 14-hour fast and following 3 days of unrestricted diet and exercise. Subjects should remain seated and not smoke. Source: American Diabetes Association (2000).

Diagnosis and screening Risk assessment for GDM should be undertaken at the first pre-natal visit. Women with clinical characteristics consistent with a high risk of GDM (see Table 1.16) should have an assessment of their glucose tolerance as soon as feasible. Clinical features associated with a high risk of GDM 1. 2. 3. 4. 5. 6.

Obesity. A personal or family history of DM. A personal or family history of GDM. A previous large for gestational age baby. A previous unexplained stillbirth. Ethnicities, i.e. Asian subcontinent, Afrocaribbean, Black American, His-panic, Pacific Islanders and indigenous Australians. 7. A history of polycystic ovarian syndrome. High-risk subjects who have NGT at initial testing should be re-tested between 24 and 28 weeks of gestation. Women of average risk should have testing undertaken at 24–28 weeks of gestation. Low-risk status requires no glucose testing, but this category is limited to those women meeting all of the following characteristics. 1. 2. 3. 4. 5. 6.

Age<25 years. Weight normal before pregnancy. Member of an ethnic group with a low prevalence of GDM. No known diabetes in first-degree relatives. No history of abnormal glucose tolerance. No history of poor obstetric outcome. Diagnostic strategies

An FPG level>126 mg/dl (7.0 mmol/l) or a casual plasma glucose>200 mg/dl (11.1 mmol/l) meets the threshold for the diagnosis of diabetes if confirmed on a subsequent day and precludes the need for any glucose challenge. In the absence of this degree of hyperglycaemia, evaluation for GDM in women with average or high-risk characteristics should follow one of two approaches.

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1. One-step approach. Perform a diagnostic OGTT without prior plasma or serum glucose screening. The one-step approach may be cost-effective in high-risk patients or populations (e.g. some Native American groups) but would subject many women at low risk to a time-consuming and unpleasant investigation and would involve high health costs. 2. Two-step approach. Perform an initial screening by measuring plasma or serum glucose concentrations 1 h after a 50 g oral glucose load (glucose challenge test (GCT)) and perform a diagnostic OGTT on that subset of women exceeding the glucose threshold value on the GCT. When the two-step approach is employed, a glucose threshold value>140 mg/dl (7.8 mmol/ l) identifies approximately 80% of women with GDM and the yield is further increased to 90% by using a cut-off of>130 mg/dl (7.2 mmol/l). With either approach the diagnosis of GDM is based on an OGTT. The diagnostic criteria for the 100 g OGTT are derived from the original work of O’Sullivan and Mahan |9| (modified by Carpenter and Coustan |10|) and are shown in Table 1.16. Alternatively, the diagnosis can be made using a 75 g glucose load and the glucose threshold values listed for fasting, 1 h and 2 h (Table 1.16). However, this test is not as well validated as the 100 g OGTT for the detection of at-risk infants or mothers. Therapeutic strategies during pregnancy Monitoring 1. Patients must be taught self-monitored capillary glucose testing and asked to monitor their pre- and post-prandial glucose concentrations using seven-point profiles at least twice weekly. 2. Urinalysis is unreliable due to the lower renal threshold associated with pregnancy and is not recommended. 3. BP and urinalysis for proteinuria should be regularly monitored during antenatal care. 4. Routine fetal ultrasound is used to monitor fetal growth and development. Management 1. Dietary advice should be tailored to the individual anthropometric characteristics of each patient in order to ensure adequate nutrient intake during pregnancy whilst limiting weight gain in those who are overweight or obese. For obese women (BMI>30 kg/m2), a 30–33% calorie restriction (to approximately 25 kcal/kg actual weight per day) has been shown to reduce hyper-glycaemia and plasma TGs with no increase in ketonuria. Restriction of carbohydrates to 35–40% of calories has been shown to decrease maternal glucose levels and improve maternal and fetal outcomes. 2. Moderately intense physical activity programmes lower maternal glucose concentrations in women with GDM. Although the impact of exercise on neonatal complications awaits rigorous clinical trials, the beneficial glucose-lowering effects suggest that women without medical or obstetrical contraindications should undertake a programme of moderate exercise as a part of their treatment for GDM. 3. Treatment with insulin. Insulin therapy should be initiated when diet therapy has failed to achieve metabolic targets: fasting glucose<95 mg/dl (5.3 mmol/l) or post-prandial (2 h post-meal) whole blood levels<120 mg/dl (6.7 mmol/l). Insulin analogues have not been adequately studied in pregnancy and oral hypoglycaemics are not recommended during pregnancy.

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4. GDM is not of itself an indication for Caesarean delivery or for delivery before 38 completed weeks’ gestation. Prolongation of gestation past 38 weeks increases the risk of fetal macrosomia without reducing Caesarean rates, so that delivery during the thirty-eighth week is recommended unless obstetric considerations dictate otherwise. 5. Breast-feeding, as always, should be encouraged in women with GDM. Long-term therapeutic considerations Mothers should have a 75 g OGTT 6-weeks post-partum. If the post-partum OGTT reveals NGT, patients should be monitored with an annual FPG. Women with IFG or IGT must be studied at more frequent intervals and encouraged to maintain a normal weight and take regular exercise. Contraceptives with low doses of oestrogen-progesterone can be used, always provided that this not contra-indicated on medical grounds. Tests of glycaemia in diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl): 80–2.

Comment Blood glucose monitoring is a way of evaluating therapy efficiency and adjusting treatment. Patient SMBG Patient SMBG has been available for 20 years since the introduction of the first generation of blood glucose meters. It is an essential tool in helping motivated patients optimize their diabetic control and is superior to urinalysis. Regular systematic testing before and after meals provides information about blood glucose profiles that the patient can use for adjusting their insulin or dietary regimen. It can also help to ‘troubleshoot’ when, for example, the patient is unsure whether they are hypoglycaemic or during intercurrent illness. However, patients must be taught the correct technique since up to 50% of patientgenerated SMBG results are inaccurate. Maintaining enthusiasm for SMBG is a constant problem in diabetes care since many patients find systematic testing difficult to sustain in the long term. Teaching patients how to use the results in order to improve their diabetic control is an essential component of an intensive regimen and helps patients to use the technique wisely. 1. Daily SMBG is recommended for patients treated with insulin, sulphonylureas and prandial glucose regulators (meglitinides and amino acid analogues). Type 2 diabetic patients should perform SMBG as often as is necessary for achieving their blood glucose targets. 2. The high financial costs and inconvenience to patients entailed in SMBG should not hamper its use. 3. A health professional should evaluate the patient’s testing skills in order to ensure correct SMBG. 4. SMBG facilitates treatment self-monitoring by the patient.

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Blood glucose monitoring by a health professional The use of SMBG and measurement of HbAlc provides essential information in evaluating a patient’s diabetic control. Diabetes educators should evaluate the patient’s ability to perform SMBG accurately by simultaneously performing a laboratory blood glucose test or by using a correctly calibrated glucometer. Urine tests Glycosuria Whilst SMBG has replaced urine glycaemia tests for some patients urinalysis still has an important role in patient monitoring and is preferred over SMBG by some patients. Urinalysis can be helpful in patients with type 2 diabetes who are controlled on diet alone and who have modest fasting and post-prandial hyperglycaemia. Patients should be asked to test their urine fasting and 2 h after their largest meal once or twice a week. Both tests should be negative in order to reflect good glucose control. Urine ketone A urine ketone determination is recommended for patients with type 1 diabetes in the following circumstances: acute illness, stress, blood glucose levels in excess of 300 mg/dl (15 mmol/l), symptoms of ketoacidosis and during pregnancy. Glycosylated protein determination HbA1c The HbA1c concentration is directly proportional to the mean glucose concentration over a 2- to 3-month period, reflecting blood glucose control. It predicts the risk of developing many chronic complications of diabetes. However, allowance must be made for the fact that the values obtained by different laboratories may have been achieved by different methods of determination. HbA1c should be determined for all diabetic patients upon diagnosis and at regular intervals thereafter. A minimum of two determinations a year is recommended for well-controlled patients and more often for those failing to adhere to therapy targets (HbA1c<7%). Glycosylated serum proteins Total glycosylated serum proteins or glycosylated serum albumin measurements correlate to some extent with HbA1c values although the blood glucose reading they provide represents a shorter duration (approximately 14–20 days). Measurement of total glycosylated serum proteins is a simpler and cheaper laboratory technique than HbA1c estimation, but is generally accepted as being less accurate than HbA1c since up to 50% of the measurement is determined by non-glucose-related factors. It should only be used when HbA1c measurement is not available. One of the methods most commonly used is fructosamine analysis.

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Hospital admission guidelines for diabetes mellitus American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S83.

Comment Hospital admission in connection with diabetes is indicated in the following circumstances. 1. The treatment of acute complications of DM. 2. DM onset in children and adolescents. 3. Chronic severe lack of DM control involving monitoring of the patient with a view to determining the aetiology of the problem and changing the treatment accordingly. 4. Severe chronic diabetic complications necessitating intensive treatment or other serious circumstances unconnected with DM, but which appreciably affect DM control or complications. 5. Need for insulin treatment or uncontrolled DM during pregnancy. 6. Implantation of a continuous subcutaneous insulin perfusion pump or other intensive treatments with insulin. These criteria, although accurate, can never replace medical judgement and clinical and psychosocial factors specific to each patient must be taken into account when applying these criteria. There are situations in which the patient’s clinical profile does not fulfil these criteria, but admission is indicated for other reasons. Acute metabolic complications of DM Admission is indicated for the following. 1. Diabetic ketoacidosis: blood sugar in excess of 250 mg/dl (13 mmol/l), blood pH of<7.30 and bicarbonate<15 mEq/l with ketonuria and/or ketonaemia. 2. Non-ketotic hyperosmolar hyperglycaemia: an altered level of consciousness associated with a rise in plasmatic osmolarity in patients with hyperglycaemia. Normally the blood sugar is>600 mg/dl (30 mmol/l) and the plasma osmolarity over 320 mOsm/kg. 3. Hypoglycaemia with clinical neuroglycopenia, i.e. plasma glycaemia of<50 mg/dl where routine treatment fails to give rapid recovery, plus situations where (1) a coma, convulsions or behavioural disturbances occur due to suspected or confirmed hypoglycaemia, (2) although a capable adult is treating the hypoglycaemia, he/she fails to resolve the situation quickly, and (3) hypoglycaemia caused by sulphonylureas. Poorly controlled DM Hospital admission on the grounds of poor chronic metabolic control is only justified in establishing the reasons for poor control and for suggesting solutions to the patient. It should fulfil at least one of the following conditions. 1. Hyperglycaemia accompanied by volume depletion.

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2. Persistent refractory hyperglycaemia associated with metabolic deterioration. 3. Recurrent (>300 mg/dl) refractory basal hyperglycaemia upon treatment of the patient or an HbAlc of≥100% of the normal upper limit. 4. Severe recurrent hypoglycaemic attacks (<50 mg/dl) despite professional preventive intervention. 5. Recurrent diabetic ketoacidosis in the absence of trauma or precipitating infection. 6. Absence from school or work due to psychosocial problems through poor long-term control. Admissionfor DM complications or in other acute medical situations Chronic complications of diabetes may require hospital admission for assessment and treatment. In such cases, the complication per se is the admission criterion. These guidelines must also cover other medical circumstances and treatments that would not warrant hospitalization in non-diabetics and could be treated on an out-patient basis (for instance infections and chemotherapy), but would be regarded as indications for hospital admission in DM patients if (1) the diabetes management cannot be safely undertaken by the patient or their family, (2) rigorous DM control could be instigated with a view to improving outcome (in pregnancy, for example), (3) the main medical problem or treatment may worsen metabolic control (for example with the initiation of steroid therapy) and (4) the DM is liable to cause acute retinal, renal, neurological or cardiovascular complications. Pancreas transplantation for patients with type 1 diabetes American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S85.

Comment Whole organ pancreatic transplantation in patients with type 1 DM has improved patients’ quality of life, eliminated the risks of acute complications and avoided advancement of chronic complications, such as nephropathy and polyneuropathy. It may partially reverse these complications whilst making positive changes to the most intractable diseases of the retina. However, pancreatic transplantation requires lifelong immunosuppression with two main aims: (1) to prevent graft rejection and avoid recurrent destruction of autoimmune B cells and (2) to prevent resorting to complex surgical procedures. Whole organ transplantation is associated with a not inconsiderable morbidity and mortality and should be restricted to patients with established complications, who usually require a renal transplantation at the same time. An established indication for whole organ transplantation is the need for renal transplantation in order to treat end-stage DN in type 1 diabetes. Such patients must meet the requirements for renal transplantation together with additional criteria related to the complexity and duration of double transplant surgery. It is important to remember that the survival of both pancreatic and renal grafts is higher when both organs are transplanted simultaneously. On the other hand, some patients with type 1 diabetes and renal insuffkiency would have to meet three requirements in order to be considered for a whole organ transplant. 1. They would have a history of frequent acute severe metabolic complications requiring medical attention. 2. They would display severe psychological and clinical problems as the result of insulin treatment.

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3. They would display evidence of the failure of insulin treatment in avoiding acute complications, despite strenuous efforts at tailoring it to the subject’s life style. In addition to eligibility for the transplant programme being subject to certain selection criteria, a multidisciplinary evaluation of both medical and psychological conditions must be conducted on the potential transplant candidate. Islet transplantation may offer advantages over whole organ transplantation. Recent advances in the isolation of donor islets and improvements in immunosuppression reported by the Edmonton group have led to renewed optimism regarding the possibility of achieving insulin independence using islet transplantation. From a patient’s perspective the procedure is carried out under sedation while the isolated islets are injected into the hepatic vein under ultrasound guidance and is associated with significantly less morbidity and mortality than whole organ transplantation. However, many centres worldwide are now attempting to reproduce the Edmonton protocols allowing more experience of islet cell transplantation to be gained. Insulin administration American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S86.

Comment Insulin There are three species from which insulin can be obtained. It can be extracted from pork pancreas and purified by crystallization and it may also be obtained from bovine pancreas but beef insulin is less commonly used. Human sequence insulin may be produced by chemical modification of pork insulin or, more commonly, by recombinant DNA technology using Esherichia coli. Porcine insulin differs from human insulin by one amino acid and from bovine insulin by three amino acids. All insulin preparations are to a greater or lesser extent immunogenic with the most marked immunogenic response resulting from the use of beef insulin. Insulin is available in different preparations that are designed for altering the speed of absorption and biological action after injection. The types of insulin available are soluble (fast-acting), analogues (ultra-fast acting) (lispro and Novolog), isophane and lente (medium-acting) and slow (ultralente and protamine zinc insulin [PZI]) insulins. Pre-mixed insulins containing a variable or regular quantity of neutral protamine Hagedorn (NPH) are also commercially available. Insulin is marketed in 100 or 500 U/ml strengths (known as U-100 and U-500). U-500 is used only for rare cases of insulin resistance where the patient needs ex tremely high doses. The U-40 form is also commercially obtainable outside the USA. Storage 1. Unused vials of insulin must be kept in the refrigerator. Their refrigerator life is 2 years. 2. Use of a vial for more than 40 days is inadvisable.

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3. It is a good idea to examine the vial before use in order to detect possible changes. Discard a vial of clear insulin if it becomes cloudy or hazy in appearance since this suggests a degree of denaturing of the insulin protein. Mixing insulins 1. 2. 3. 4. 5. 6.

Follow the standard process for preparing the insulin dose. Do not mix other medications or solvents with insulin. Use pre-mixed insulin if the insulin ratio is appropriate for the patient. Mixtures must be used immediately or stored for future use. A mixture of fast- and medium- or slow-acting insulin must be administered 2–30 min before a meal. Mixtures of fast- and slow-acting insulins are not recommended because the zinc present in slow-acting insulins may retard the ‘kick-in’ of the fast-acting insulin. 7. Phosphate-containing insulins such as NPH must not be mixed with slow-acting insulins because zinc phosphate may precipitate and convert the slow-acting insulin into fast-acting insulin. 8. Any alterations to insulin formulations should involve consultation with the manufacturers if their recommendations do not tally with ADA guidelines. Syringes

1. A range of different syringe capacities (0.25, 0.3, 0.5 and 1 ml) is available. 2. Needles must be kept in specific sheaths in order to avoid possible needle-stick accidents. 3. It is inadvisable to either reuse or share syringes owing to an increased risk ofinfection. Alternatives to the syringe This involves injection by means of injectors that administer insulin after exerting sharp pressure on the skin. 1. This is indicated for people who are needle-phobic or unable to use syringes. 2. It has a faster insulin absorption capacity. 3. Its disadvantages are a high cost and skin microtrauma. There are various types of pens for injecting insulin in cartridge or disposable pen-fill form that are capable of administering insulin in 0.5–1 unit increments. Injection technique It is advisable for patients themselves, other than very young children, to administer their own insulin. Dose preparation 1. First, wash your hands. 2. It is not necessary to swab the injection site with alcohol prior to injection.

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3. Mix the insulins manually (except for the fast-acting ones) in order to resuspend the insulin. 4. When mixing insulins, inject an equal dose of air into the vial to avoid a vacuum effect and draw up fastacting insulin first into the syringe. 5. Check for the presence of possible bubbles to avoid injecting a lower dose. Injection 1. Subcutaneously at an angle of 90° or, in the case of thin people or children, at 45° to avoid injecting into the muscle. 2. Press for a few seconds if there is post-injection bleeding. 3. In a room at an appropriate temperature. 4. Avoid air bubbles in the syringe. 5. Relax the muscles in the injection zone; make sure that they are not tense. 6. Penetrate the skin quickly. 7. Avoid changing syringe direction during penetration. 8. Do not reuse syringes if they are showing signs of wear. 9. Consult your usual specialist if you are getting local reactions at the injection site. Injection site 1. Into the subcutaneous tissue of the upper arm overlying the triceps, the buttocks, the anterior surface and sides of the thighs and abdomen except for a 2 cm radius circle around the navel. 2. It is important to rotate injection sites to prevent lipoatrophy and lipohypertrophy. 3. The absorption areas (faster to slower) are the abdomen-arms, thighs and buttocks. 4. Exercise increases insulin absorption and lipohypertrophy delays it. Patient’s contribution 1. Administration of fast-acting insulin analogues 5 min or immediately before eating and regular insulin 30 min beforehand. 2. Self-monitoring of capillary blood sugar is important. 3. Continue to administer insulin in the case of acute illness despite vomiting or difficulty in ingesting. 4. Hypoglycaemia: insulin excess is the commonest cause of hypoglycaemia as well as a lowcarbohydrate meal or skipping a meal. It is important to always carry 15 g of carbohydrates and to instruct close family and friends in the use of glucagon. Continuous subcutaneous insulin infusion American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S90.

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Comment Both CSII and multiple daily insulin injection therapy are effective methods in improving the control of diabetes, the aim of which is to achieve virtually normal blood glucose levels and to improve life style flexibility. The use of CSII requires the assistance of trained professionals, careful patient selection, the monitoring of each patient and a programme of ongoing education. The insulin pumps prescribed by the doctor under these conditions are part of the treatment and should be covered by welfare structures. This type of intensive therapy is not suitable for all diabetic patients. Early experience with the use of pumps in the 1980s was not always positive. In many instances CSII was associated with a deterioration in glycaemic control and an increased risk of ketoacidosis due, in part, to inappropriate patient selection. However, with improved patient selection and, together with educational support from pump manufacturers, CSII has become more popular in recent years with over 75 000 pump users in the USA and over 25 000 in Germany. It is important that patients who are considered for CSII should be highly motivated, willing to cooperate with the medical team and know how to manage the business of daily diabetes care. In addition, they must prove that they have the skills needed for using more sophisticated equipment than the ‘pen’ and, based on an ability to interpret capillary blood glucose results, make appropriate treatment adjustments. Various reasons for recommending treatment with CSII can be identified from the support team standpoint. These include the following. 1. 2. 3. 4. 5.

An inability to achieve good control with multiple insulin doses a day. Patients suffering many unavoidable ‘hypos’ with conventionally administered insulin. Patients with very variable work and/or meal times. Optimized glucose control in women both before gestation and/or during pregnancy. The patients’ own desire to have fewer restrictions than with multiple-dose insulin.

The success or failure of CSII therapy often depends on the correct choice of patient, his/her needs and reliance on a specialized support team for providing back-up in an emergency or simply for giving advice. For the patient to be able to understand, assimilate and manage the control of this type of therapy he/she needs to be involved in a treatment education programme that is appropriate for pump therapy and to be provided with the technical knowledge and handling capabilities essential for the achievement of adequate autocontrol. Role of fat replacers in diabetes medical nutrition therapy American Diabetes Association. Diabetes Care 2000; 23(Suppl 1): S96.

Comment The ADA recommends reducing fat intake, in particular saturated fat (to less than 10% of total calories). The availability of fat-substituting ingredients has led to the production of foods that are low in fat and calories, fat-free foods and low-calorie fast foods.

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The ideal fat substitute is defined as a safe compound that has the (same) organoleptic properties as fat but a signifkantly lower number of calories. Fat substitutes are classified into three categories according to the nutrients from which they have been prepared. 1. Carbohydrate derivatives: these are made from cereals, vegetables, starches and fibres, such as polymers/hydrocolloids (dextrins and maltodextrins) plus bulking agents such as polyols (sorbitol, maltitol, isomaltose, manitol, xylitol and a variety of hydrolysed starches). 2. Protein derivatives: these are prepared by modifying proteins such as egg white. 3. Fat derivatives: these are synthesized from vegetable TG substitutes. The purpose of these fat substitutes is to reduce the caloric value of 9 kcal/g of fat whilst retaining its creaminess and flavour. Some of these ingredients are only partially absorbed and, hence, lower the number of calories. The FDA approved a non-calorific ingredient called Olestra as a food additive in 1996. The information currently available provides reasonable assurances that fat substitutes are non-harmful. A low calorie intake in diabetes at the expense of fat can lead to over-ingestion of substitutes. Consumption of these products may result in a higher carbohydrate allocation and may be a factor in poor metabolic control. Some fat substitute-containing foods yield less than 20 calories or<5 g of carbohydrates per portion. Since the impact of these on metabolic control is slight, they can be regarded as ‘free foods’. Fat substitute foods may help people with diabetes to reduce their overall intake of saturated fats and lessen the prevalence of dyslipidaemia in type 2 diabetes. However, people with type 2 diabetes need to know how to use these products sensibly in order to avoid compromising their metabolic control. References 1. 2.

3. 4. 5. 6.

7. 8. 9. 10.

American Diabetes Association. Translation of the diabetes nutrition recommendations for health care institutions (position statement). Diabetes Care 2001; 24(Suppl 1): S48–50. Franz MJ, Horton ES, Bantle JP, Beebe CA, Brunzell JD, Coulston AM, Henry RR, Hoogwerf BJ, Stacpoole PW. Nutrition principles for the management of diabetes and related complications (technical review). Diabetes Care 1994; 17:490–518. US Department of Agriculture, US Department of Health and Human Services. Nutrition and Your Health: Dietary Guidelines for Americans, 4th edn. Hyattsville, MD. USDA’s Human Nutrition Information Service; 1995. US Department of Agriculture. The Food Guide Pyramid. Hyattsville, MD. USDA’s Human Nutrition Information Service; 1992. American Diabetes Association and The American Dietetic Association. The First Step in Diabetes Meal Planning. Alexandria, VA. American Diabetes Association; 1995. Levey AS, Adler S, Caggiula AW, England BK, Greene T, Hunsicker LG, Kusek JW, Rogers NL, Teschan PE. Effects of dietary protein restriction on the progression of advanced renal disease in the Modification of Diet in Renal Disease Study. Am J Kidney Dis 1996; 27:652–63. Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes (technical review). Diabetes Care 1999; 22: 1887–98. American Diabetes Association. Standards of medical care for patients with diabetes mellitus (Position Statement). Diabetes Care 2001; 24(Suppl 1): 533–43. O’Sullivan JB, Mahan CM, Charles D, Dandrow RV. Screening criteria for high-risk gestational diabetes patients. Am J Obstet Gynecol 1973; 116:895–900. Carpenter MW, Coustan DR. Criteria for screening for gestational diabetes. Am J Obstet Gynecol 1983; 144: 768–73.

2 Criteria for diagnosing diabetes

The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes M M Gabir, R L Hanson, D Dabelea, G Imperatore, J Roumain, et al. Diabetes Care 2000; 23(8): 1108–12. BACKGROUND. The 1997 American Diabetes Association (ADA) and the 1985 and 1999 World Health Organization (WHO) criteria for diabetes and hyperglycaemia differ. It remains unclear whether these diagnostic criteria are appropriate in terms of individuals identified as abnormal and their prognosis. This study compared the classification of people by these two different criteria and compared fasting and post-load plasma glucose concentrations in the prediction of diabetes. The frequency of diabetes by the three sets of criteria was compared in 5023 adult Pima Indians who were not taking hypoglycaemic drugs. The fasting plasma glucose (FPG) and 2-hour post-load plasma glucose (2-h PG) concentrations and categories of impaired glucose regulation or diabetes among non-diabetic subjects were evaluated as predictors of diabetes as defined by the 1999 WHO criteria. The frequencies of diabetes were 12.5% by the 1997 ADA criteria, 14.6% by the 1985 WHO criteria and 15.3% by the 1999 WHO criteria. The incidence of diabetes was strongly related to higher FPG and 2-h PG values, each of which had very similar predictive powers. Impaired glucose tolerance (IGT) was more common than impaired fasting glucose (IFG) (15 versus 5%), but the 5-year incidence of diabetes was higher for IFG than IGT (37 versus 24%). The prevalence and incidence of diabetes are somewhat lower with the ADA criteria than with the 1985 or 1999 WHO criteria. The intermediate categories of glycaemia differ substantially. IFG defines a smaller number of people who are at higher risk of developing diabetes than those with IGT. More people at high risk of diabetes could be identified by using either IFG or IGT as recommended by the 1999 WHO criteria or by using FPG concentrations alone, but with a lower cut-off value.

Comment In 1997, the ADA |1| recommended using fasting plasma blood glucose values for diagnosing diabetes mellitus (DM). They further proposed that it should have wider clinical application (screening) and should identify patients at risk of microvascular complications (comparable to that of 2-hour post-overload plasma © Clinical Publishing Services Ltd

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Table 2.1 The number of subjects diagnosed with diabetes and the percentage of the total distribution by FPG and 2-h PG concentrations and the WHO and ADA diagnostic groups in 5023 Pima Indians at baseline 2-h PG (mmol/l) FPG (mmol/l)

<7.8

7.8–11.0

>11.1

Total

n WHO-1985 WHO-1999

3499 (69.7) Normal Normal

537 (10.7) IGT IGT

60 (1.2) Diabetes Diabetes

4096 (81.5) ADA=Normal

n WHO-1985 WHO-1999

93 (1.9) Normal IFG

126 (2.5) IGT IFG+IGT

79 (1.6) Diabetes Diabetes

298 (5.9) ADA=IFG

n WHO-1985 WHO-1999

14 (0.3) Normal Diabetes

21 (0.4) IGT Diabetes

85 (1.7) Diabetes Diabetes

n WHO-1985 WHO-1999

2(<0.1) Diabetes Diabetes

8(0.2) Diabetes Diabetes

499 (9.9) Diabetes Diabetes

<6.1

6.1–6.9

7.0–7.7

≥7.8

629 (12.5) ADA=Diabete s

The data are n values with percentages in parentheses. ADA, classification by ADA (1997) criteria for an FPG value only; WHO-1985, classification by WHO (1985) criteria; WHO-1999, classification by WHO (1999) criteria. Source: Gabir et al. (2000).

blood glucose values if the fasting plasma blood glucose threshold was reduced from 7.8 to 7 mmol/1). Since the introduction of the modified ADA criteria there has been considerable debate about the clinical significance of these changes. This article evaluates possible differences between the ADA 1997 diagnosis criteria and the diagnosis criteria amended by the WHO in 1999 |2|, where an oral glucose tolerance test (OGTT) is still being advocated for diagnosing diabetes and glucose intolerance. The different diagnostic criteria were applied to a group of 5000 Pima Indians who were then followed prospectively in order to determine which of the criteria best predicted the development of diabetes. Whilst all the tests were in the diagnosis of established diabetes |3|, they identified different patient populations with lesser degrees of glucose tolerance. Reliance on IFG alone would identify a small group of patients with a high future risk of developing type 2 diabetes. However, a significant number of patients at risk of type 2 diabetes and increased cardiovascular risk would only be identified using the WHO criteria for IGT following an OGTT. Other recently published trials have found similar poor concordance of these different diagnostic criteria in patients with abnormal glucose tolerance. As an example, the Hoorn Study |4|, which was a populationbased survey of almost 2500 men and women aged 50–75 years, recently reported comparative data. In this prospective trial OGTTs were performed and cardiovascular risk factors were deter

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Table 2.2 The number of subjects and percentage in each category of glucose according to the ADA and WHO diagnostic categories Classification

ADA

WHO-1985

WHO-1999

Normal IGT IFG Diabetes

4096 (81.5) − 298 (5.9) 629 (12.5)

3606(71.8) 684 (13.6) − 733 (14.6)

3499 (69.7) 663 (13.2)* 219 (4.4)* 768 (15.3)

The data are n values with percentages in parentheses. ADA, classification by ADA (1997) criteria for an FPG value only; WHO-1985, classification by WHO (1985) criteria; WHO-1999, classification by WHO (1999) criteria. *Includes 126 individuals with IFG and IGT. Source: Gabir et al. (2000).

mined in 2378 subjects without known diabetes. The subjects were categorized according to both sets of diagnostic criteria. Although the prevalence of diabetes was similar for both the 1985 WHO and ADA criteria, 47 out of 120 (39.2%) subjects who were diagnosed with diabetes according to the 1997 ADA criteria were not classified as having diabetes using the 1985 WHO criteria. Similarly, 195 out of 285 (68. 4%) subjects diagnosed with IFG by the 1997 ADA criteria were classified as having normal glucose tolerance by the 1985 WHO criteria. The overall agreement between the criteria was poor. Subjects who were diagnosed as having diabetes by either set of criteria had an adverse cardiovascular risk profile, which was between the cardiovascular risk profiles of concordant normal and concordant diabetic subjects. In 1999 the Diabetes epidemiology: Collaborative analysis of diagnostic criteria in Europe (DECODE) study |5| evaluated 20 population-based epidemiological trials in terms of the sensitivity and specificity of different screening strategies for diabetes. This large meta-analysis concluded that, if FPG values are used alone, approximately one in three patients with a non-diabetic FPG value but a diabetic 2-h PG value would not be diagnosed using ADA criteria alone. Furthermore, IFG and IGT do not identify the same people and the risk profile of people with IFG depends on 2-h PG concentrations. These and other studies have demonstrated that these changes in the diagnostic criteria will include a new group of individuals as having diabetes, while others may be left undiagnosed if FPG values are used as the only diagnostic criteria. One major problem is that, if FPG values are used as the only diagnostic criteria in screening for diabetes, approximately one-third of diabetic individuals will be left undiagnosed. Furthermore, this is the group of diabetic patients that have the highest mortality from cardiovascular disease (CVD) and stroke and the group with the worst cardiovascular risk profile compared to individuals with elevated FPG values alone. This observation raises the need for continued use of the OGTT in selected groups. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2000; 23(Suppl 1): S4–19.

Definition of DM DM is a group of metabolic illnesses that is characterized by hyperglycaemia and caused by impaired insulin secretion, insulin action or both. Chronic hyperglycaemia in diabetes is associated with long-term

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damage, dysfunction and the failure of various organs, in particular the eyes, kidneys, nerves, heart and blood vessels. Various pathogenic factors are involved in diabetes development. They range from autoimmune destruction of the pancreatic β cells and consequent insulin deficiency to anomalies resulting from resistance to insulin activity. DM dassification system Type 1 diabetes Immunomediated diabetes 1. Autoimmune destruction of the pancreatic β cells is determined by a combination of predisposing genetic factors and environmental factors. 2. Autoimmunity markers include islet cell antibodies, insulin antagonistic antibodies, glutamic acid decarboxylase antibodies (e.g. GAD,,) and tyrosine phosphatase antibodies (e.g. IA-2 and IA-2B). These autoantibodies are present in 85–90% of patients at disease onset. 3. Strongly human leucocyte antigen (HLA)-related through the existence of predisposing or protective HLA-DR/DQ alleles. 4. The degree of pancreatic β cell mass destruction is variable, although once the condition is at the advanced stage insulin secretion is minimal or non-existent, as reflected by low to undetectable Cpeptide levels. 5. It normally starts in infancy or youth, although it may materialize at any time in life. 6. It associates with other autoimmune diseases (e.g. Graves’ disease, Hashimoto’s thyroiditis, Addison’s disease and pernicious anaemia). Idiopathic diabetes 1. No autoimmunity symptoms. 2. Most sufferers are of African or Asiatic origin (the populations in which it was first detected). 3. Different degrees of insulin deficiency (including fluctuating insulinopenia). 4. Unassociated with HLA. Type 2 diabetes 1. Its range is variable from a predominance of insulin resistance and relative insulin deficiency to mainly impaired insulin secretion combined with insulin resistance. 2. Frequently associated with obesity (particularly central-type obesity). 3. Considerable genetic predisposition (higher than for type 1 diabetes).

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47

Fig. 2.1 Blood sugar problems: aetiological stages and types. *Including after presentation in the form of ketoacidosis, these patients may revert after a short time to normal blood sugar levels withoutthe needforongoingtreatment(ie “honeymoon” remission period). **In isolated cases, patients who fall into these categories, (eg Vacor toxicity, type 1 diabetes materialising during pregnancy) could require insulin for their survival. Source: Expert Commitee on the Diagnosis and Classification of Diabetes Mellitus (2000).

Other specific types ofdiabetes These would include genetic defects, drug-induced diabetes, exocrine diseases of the pancreas, endocrine complaints and genetic diabetes-related syndromes (see Table 2.3). Diabetes during pregnancy This is defmed as any degree of glucose intolerance from the commencement of pregnancy or diagnosed during pregnancy. Early diagnosis and treatment is important as diabetes is linked to escalating maternal and perinatal complications. Table 2.3 Aetiologic classification of DM I

II III

Type 1 A B Type 2 insulin

diabetes* (β-cell destruction usually leading to absolute insulin deficiency) Immune mediated Idiopathic diabetes* (may range from predominantly insulin resistance with relative deficiency to a predominantly secretory defectwith insulin resistance) Other specific types A Genetic defects of β-cell function 1 Chromosome 12, HNF-1α (MODY3) 2 Chromosome 7, glucokinase (MODY2)

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3

B

C

D

E

F

4 5 Genetic defects in insulin action 1 2 3 4 5 Diseases of the exocrine pancreas 1 2 3 4 5 6 7 Endocrinopathies 1 2 3 4 5 6 7 8 Drug- or chemical-induced 1 2 3 4 5 6 7 8 9 10 11 Infections 1 2

Chromosome 20, HNF-4α (MODY1) Mitochondrial DNA Others Type A insulin resistance Leprechaunism Rapson-Mendenhall syndrome Lipoatrophic diabetes Others Pancreatitis Trauma/pancreatectomy Neoplasia Cystic fibrosis Hemochromatosis Fibrocalculous pancreatopathy Others Acromegaly Cushing’s syndrome Glucagonoma Phaeochromocytoma Hyperthyroidism Somatostatinoma Aldosteronoma Others Vacor Pentamidine Nicotinic acid Glucocorticoids Thyroid hormone Diazoxide β-adrenergic agonists Thiazides Dilantin α-interferon Others Congenital rubella Cytomegalovirus

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3 G

IV

49

Others

Uncommon forms of immune-mediated diabetes 1 2

‘Stiff-man’ syndrome Anti-insulin receptorantibodies 3 Others H Other genetic syndromes sometimes associated with diabetes 1 Down’s syndrome 2 Klinefelter’s syndrome 3 Turner’s syndrome 4 Wolfram’s syndrome 5 Friedreich’s ataxia 6 Huntington’schorea 7 Laurance-Moon-Biedl syndrome 8 Myotonic dystrophy 9 Porphyria 10 Prader-Willi syndrome 11 Others Gestational diabetes mellitus (GDM)

*Patients with any form of diabetes may require insulin treatment at some stage of their disease. Such use of insulin does not of itself classify the patient. Source: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2000).

After pregnancy (6 weeks or more post-partum) the patient must undergo diabetic re-categorization as follows: normal, IFG, IGT or persistent diabetes. In most cases glucose metabolism returns to normal once the baby has been born. Women with a low risk of developing diabetes during pregnancy do not need to be screened (under 25 years of age, of normal weight, no family history of diabetes and not belonging to high-risk ethnic groups). If the risk of developing diabetes during pregnancy is not high, the expectant mother should be screened between weeks 24 and 28 of the pregnancy. For highrisk populations, the type of screening could consist of just one test (OGTT), although the normal procedure is a two-stage screening. The first would involve measuring blood glucose 1 h after administering 50 g of oral glucose. The second would entail performing an OGTT in order to confirm the diagnosis for women over the pre-established blood glucose cut-off point. IGT and IFG These represent a stage that is midway between normal glucose metabolism and diabetes.

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1. IFG: this is defined by the presence of blood glucose levels of≥110 mg/dl (6.1 mmol/l), but<126 mg/dl (7.0 mmol/l). 2. IGT: blood glucose after a 75 g OGTT of≥140 mg/dl (7.8 mmol/l), but< 200 mg/dl (11.1 mmol/l). Outside pregnancy they imply heightened risk of future diabetes and CVD. They are associated with insulin resistance syndrome. Table 2.4 Criteria for the diagnosis of DM 1.

or 2. or 3.

Symptoms of diabetes plus casual plasma glucose concentration≥200 mg/dl (11.1 mmol/l). Casual is defined as any time for day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. FPG≥126 mg/dl (7.0 mmol/l). Fasting is defined as no caloric intake for at least 8 h. 2-h PG≥200 mg/dl (11.1 mmol/l) during an OGTT. The test should be performed as described by WHO (2), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

In the absence of unequivocal hyperglycaemia with acute metabolic decompensation, these criteria should be confirmed by repeat testing on a different day. The third measure (OGTT) is not recommended for routine clinical use. Source: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2000). Table 2.5 Criteria for testing for diabetes in asymptomatic, undiagnosed individuals 1. 2.

Testing for diabetes should be considered in all individuals at age 45 years and above and, if normal, it should be repeated at 3-year intervals. Testing should be considered at a younger age or be carried out more frequently in individuals who: • are obese (≥120% desirable body weight or a BMI≥27 kg/m2) • have a first-degree relative with diabetes • are members of a high-risk ethnic population (e.g. African-American, Hispanic American, Native American, Asian American, Pacific Islander) • have delivered a baby weighing>9 lb or have been diagnosed with GDM • are hypertensive (≥140/90 mmHg) • have an HDL cholesterol level≥35 mg/dl (0.90 mmol/l) and/or triglyceride level≥250 mg/dl (2.82 mmol/l) • on previous testing, had IGT or IFG

The OGTT or FPG test may be used to diagnose diabetes; however, in clinical settings the FPG test is greatly preferred because of ease of administration, convenience, acceptability to patients, and lower cost. Source: Expert Committee on the Diagnosis and Classification of Diabetes Mellitus (2000).

Diagnostic criteria The new revised criteria are shown in Table 2.4. Estimation of the prevalence and incidence of diabetes in epidemiological studies must be based on a FPG value of≥126 mg/dl (7.0 mmol/l), as it is a simpler and cheaper test to perform. However, the estimated prevalence using an FPG value alone is less than for a combination of an FPG value and an OGTT.

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51

The decision was taken to revise the criteria for diagnosing diabetes on the grounds that the FPG cut-off point (7.8 mmol/l) was not equivalent to the 2-h PG cutoff point (200 mg/dl or 11.1 mmol/l) as far as the appearance of microvascular and macrovascular complications was concerned. Various epidemiological studies of diverse populations in different countries and racial groups (Pima Indians, Pacific populations and the National health and nutrition examination study [NHANES III]) have shown that the basal blood glucose cut-off point closest to 200 mg/dl after an OGTT cut-off point for the complications risk was 126 mg/ dl (7.0 mmol/ l). Ultimately, this basal blood glucose cut-off point was adopted for diagnosing diabetes. From this point onwards, the prevalence of microvascular complications rises exponentially. Screening for diabetes in supposedly healthy individuals Screening for type 1 DM outside research programmes is inadvisable in view of the absence of safe, effective therapies for preventing or delaying illness onset. In the case of type 2 DM, on the other hand, it is important to identify undiagnosed patients who have a significantly higher risk of contracting coronary and peripheral vascular disease. Screening must therefore be considered for high-risk populations (Table 2.5). References 1. 2.

3.

4.

5.

Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20:1183–97. World Health Organization. Definition, diagnosis and classification of diabetes mellitus and its complications: report of a WHO Consultation. Part 1. Diagnosis and classification of diabetes mellitus. Geneva. World Health Organization; 1999. Gabir MM, Hanson RL, Dabelea D, Imperatore G, Roumain J, Bennett PH, Knowler WC. Plasma glucose and prediction of microvascular disease and mortality: evaluation of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes. Diabetes Care 2000; 23(8):1113–18. De Vegt F, Dekker JM, Stehouwer CD, Nijpels G, Bouter LM, Heine RJ. The 1997 American Diabetes Association criteria versus the 1985 World Health Organization criteria for the diagnosis of abnormal glucose tolerance: poor agreement in the Hoorn Study. Diabetes Care 1998; 21(10):1686–90. DECODE. Is fasting glucose sufficient to define diabetes? Epidemiological data from 20 European studies. The DECODE-study group. European Diabetes Epidemiology Group. Diabetes Epidemiology: collaborative analysis of diagnostic criteria in Europe. Diabetologia 1999; 42(6):647–54.

Part II Clinical trials

Clinical trials

Introduction This section of the book reviews the design of important multicentre clinical trials that are aimed at preventing the onset of type 2 diabetes or its complications, in particular diabetic nephropathy. Early studies in the UK including the Whitehall (5-year follow-up) and Bedford (10-year follow-up) studies looked at whether life style intervention was effective in reducing the onset of type 2 diabetes. The results were disappointing, with no benefit observed from a carbohydrate-restricted diet. Treatment with tolbutamide or phenformin also had no effect on the conversion of impaired glucose tolerance (IGT) to type 2 diabetes. More recently the Swedish Malmohus study (10 years) reported that the conversion rate was reduced from 29% in the control group to 13% in a group told to limit their intake of carbohydrates and lipids and to reduce weight when overweight. A further Swedish study, the Malmo study (6 years and ongoing) is investigating a combination of dietary intervention and a strenuous exercise programme. In this study the conversion rate decreased from 29% in the control group to 11% in the diet plus exercise group. In contrast to the UK trials, positive results were obtained for tolbutamide in the Malmohus study. No subjects in the tolbutamide plus diet group developed type 2 diabetes compared with 29% of the controls. The Da Qing trial in China also reported that diet and exercise interventions in those with IGT limited the development of type 2 diabetes. A total of 577 subjects were classified (using World Health Organization criteria) as having IGT. The subjects were randomized to either a control group or to one of three active treatment groups: diet only, exercise only or diet plus exercise. The cumulative incidence of diabetes in the controls over a 6-year follow-up period was 67.7%, as compared with 43.8% in the diet group, 41.1% in the exercise group and 46.0% in the diet plus exercise group (P<0.05). These recent trials, together with the rising global burden of type 2 diabetes, have re-focused attention on methods of prevention of type 2 diabetes. A section of Chapter 3 describes three important intervention trials that are currently ongoing in order to evaluate further the benefits of life style intervention in preventing type 2 diabetes. Publication of the results is anticipated in early 2002. Chapter 4 summarizes important clinically based trials in type 1 and type 2 diabetes. Several papers focus on newer oral hypoglycaemic agents such as the postprandial glucose regulators repaglinide and nateglinide or insulin-sensitizing agents such as rosiglitazone or pioglitazone. Important results that help to clarify where these agents fit into the therapeutic approach to the management of type 2 diabetes are summarized. Other approaches using anti-obesity pharmacotherapy in treating type 2 diabetes are highlighted in Chapter 4. The issue of postprandial glucose control and its clinical significance remains a subject of debate and this controversy is highlighted in several clinical papers in this chapter. This interest has developed from

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the epidemiological associations with postprandial hyperglycaemia and long-term cardiovascular risk that have been highlighted in the Diabetes epidemiology: Collaborative anlysis of diagnostic criteria in Europe (DECODE) and other studies. Newer prandial glucose regulators and analogue insulins also allow postprandial glucose control to be specifically targeted for the first time. Insulin therapy forms the major final section of Chapter 4. The increasing range of insulins for clinical use and the diverse methods of administration are highlighted in papers looking at continuous subcutaneous insulin and inhaled and oral preparations in treating type 1 and type 2 diabetes. This is undoubtedly a field of clinical research that will bear fruit in the next few years, thereby allowing the prospect of needle-free insulin administration.

3 Clinical trials in the process of development

The Irbesartan Type 2 Diabetic Nephropathy Trial: study design and baseline patient characteristics R A Rodby, R D Rohde, W R Clarke, L G Hunsicker, D A Anzalone, et al. for the Collaborative Study Group. Nephrol Dial Transplant 2000; 15:487–97 BACKGROUND. The Collaborative Study Group has initiated the Irbesartan Type 2 Diabetic Nephropathy Trial (IDNT), which is studying the effect of the angiotensin II receptor antagonist irbesartan on the progression of renal disease and mortality in type 2 diabetic patients with overt nephropathy and hypertension. Here we report on the study design and baseline patient characteristics. The inclusion criteria were hypertensive type 2 patients aged 30–70 years with a baseline 24-hour urinary protein excretion of>900 mg and a serum creatinine of 90–265 µomol/l (1.0–3.0 mg/dl) in women and 110–265 (Omol/l (1.2–3.0 mg/dl) in men. The patients were randomized to one of three treatment arms comprising irbesartan, amlodipine and placebo, with every attempt made to achieve similar blood pressure (BP) levels in all treatment arms. A total of 1650 patients were enrolled using approximately 225 clinics worldwide. The primary outcome measure is the time to the event of the composite end-point of doubling of serum creatinine, end-stage renal disease or death. The secondary outcome measure is the time to the composite end-point of fatal or non-fatal cardiovascular events. The average length of patient follow-up is expected to be approximately 36 months. The baseline characteristics of the study subjects are age 59 years, duration of diabetes 15 years, height 168 cm (5 ft 6 in), weight 87 kg (192 lb), body mass index (BMI) 31 kg/m2, BP 156/85 mmHg, serum creatinine 150 µomol/l, creatinine clearance 66 ml/ min and 24-hour urine protein 4.0 g/day.

Comment In 1993, the Collaborative Study Group |1| reported a renoprotective effect of the angiotensin-converting enzyme (ACE) inhibitor captopril in type 1 diabetic patients with established diabetic nephropathy. Over a 4-year follow-up period captopril reduced the risk of doubling of serum creatinine, reduced the risk of dialysis from end-stage renal failure and reduced the risk of death by approximately 50% as compared with placebo. The benefits of blockade of the renin-angiotensin-aldosterone axis in providing renal protection in diabetes have subsequently © Clinical Publishing Services Ltd

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Fig. 3.1 Multicentre, randomized, double-blind, placebo-controlled, parallel group comparative trial. Source: Porush et al. (1999).

been confirmed in other trials in patients with microalbuminuria. The question arises as to whether similar benefits would be obtained with type 2 diabetes mellitus (DM) patients using a specific angiotensin II receptor blocker rather than an ACE inhibitor. The renoprotective effects of ACE inhibitors are partly explained by their ability for lowering circulating angiotensin concentrations. Angiotensin II has vasoconstrictor effects at the efferent arteriole of the renal glomerulus that cause an increase in glomerular capillary pressure. ACE inhibitors are thought to cause dilatation of the efferent arteriole, thereby reducing glomerular pressure and, hence, proteinuria improves. Dihydropyridine calcium channel blockers such as nifedipine and amlodipine relax both the afferent and efferent glomerular arterioles and are likely to have different effects to ACE inhibitors on glomerular haemodynamics. Recent studies such as the Appropriate Bloodpressure Control in Diabetes (ABCD) |2| and Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) |3| trials have also cast doubt on the safety of dihydropyridine calcium channel blockers in patients with diabetes relative to agents that block the renin-angiotensin system.

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57

The IDNT is a multicentre, randomized, double-blind study that is designed for comparing the effects of a renoprotective angiotensin receptor blocker (ARB) with a dihydropyridine calcium channel blocker (amlodipine) (see Fig. 3.1). The trial includes a placebo arm in which patients also receive anti-hypertensive therapy, but the choice of drug therapy cannot include ARBs, ACE inhibitors or calcium channel blockers. The primary end-points of the study are renal and are similar to the Collaborative Group Study in 1993, namely the time to the event of the composite end-point of doubling of serum creatinine, end-stage renal disease or death. Importantly, given the increasing literature supporting a cardioprotective role for ACE inhibitors, the IDNT trial also includes secondary outcome measures including the time to the composite end-point of fatal or non-fatal cardiovascular events. Two hundred and twenty-five centres were recruited for this study and randomization began in March 1996 and was completed by December 1998, the total number of patients being 1650. The results are expected by May 2001 and there is to be a 2– 4-year (average 3 years) follow-up. Five hundred and twenty patients were 90% allocated to each study arm with a view to detecting a 26% reduction in the primary objective. The results of this study will also provide an answer to the recent concerns about whether calcium antagonists can be used safely for type 2 diabetes, comparing the efficiency of irbesartan and amlodipine via an equivalent BP check. The disadvantage of this study is that the patients would need more than one anti-hypertensive agent in order to obtain acceptable BP control. In any comparison with primary agents ‘dilution’ is therefore a possibility. Determinants of elevated urinary albumin in the 4937 type 2 diabetic subjects recruited for the DIABHYCAR Study in Western Europe and North Africa M Marre, M Lievre, D Vasmant, Y Gallois, S Hadjadj, et al. Diabetes Care 2000; 23(Suppl 2): B40–8. BACKGROUND. Whether ACE inhibition is benefical in type 2 diabetic patients with micro- or macroalbuminuria remains unknown. In this article, the authors report on the characteristics of patients who have been randomized to an ongoing clinical trial comparing the ACE inhibitor ramipril with placebo.

The main selection criteria were as follows: men or women aged≥50 years with type 2 diabetes treated with oral anti-diabetic drugs, with or without hypertension, with a plasma creatinine level<150 µomol/l and with persistent micro- or macroalbuminuria as assessed centrally by two successive urine samples containing a urinary albumin concentration of≥20 mg/l. The patients’ characteristics were studied by comparing patients who were randomized to those who were not. Of 25 455 patients screened for urinary albumin excretion, 4937 were randomized. Compared with the non-randomized patients, the randomized patients were older, more often men, more obese, had higher systolic/diastolic BP and plasma glucose, smoked more tobacco, drank more alcohol and had complications more frequently. All the abovementioned items appeared as independent determinants for randomization into the study using a logistic regression analysis, with the exception of alcohol intake. The physical, biological and behavioural characteristics create a poor renal and cardiovascular prognosis for the type 2 diabetic patients randomized to the Non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular event and ramipril (DIABHYCAR) Study because of micro- and macroalbuminuria.

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Comment The DIABHYCAR study is a multicentre, randomized, parallel group, placebo-controlled study that is intended to evaluate the effect of 1.25 mg of ramipril per day on the cardiovascular morbidity and mortality of patients with normal or high BP in conjunction with type 2 DM and microalbuminuria or proteinuria. This study started solely with general practitioners in France in early 1995 but, subsequently, in 1997, was extended to 15 more countries owing to enrolment problems. Recruitment in these countries was divided between general practitioners and diabetes specialists. Patients were assigned randomly to ramipril or placebo treatment. The primary outcome of the trial is the time to the first occurrence of cardiovascular death including sudden death, non-fatal myocardial infarction, stroke or congestive cardiac failure or the need for haemodialysis or renal transplantation. A 2000-patient 90% power sample was allocated to each branch of the study, the aim being to detect a 20% reduction in the primary end-points. A total of 4937 patients enrolled for this study. Monitoring through to 31 March 2001 was planned. Angiotensin II enzyme conversion inhibitors are thought to protect the kidneys of diabetic patients suffering from nephropathy. Hence, they are recommended as a first-line therapy for such patients. However, there is still some debate as to whether this renal protection is due to the haemodynamic effect on BP or whether it occurs independently of this effect. In this study, the chosen dose of 1.25 mg of ramipril per day is advantageous in that it does not have any effect on BP and, hence, provides clinical evidence of the effkiency of ramipril independently of the effect on BP. Primary analysis of recruited patients has identified independent predictors for micro- or macroalbuminuria in type 2 diabetic patients, in whom such factors generated greater renal and cardiovascular risk characteristics. It is therefore vital to search for an effective treatment for reducing this risk. The Diabetes Prevention Program: baseline characteristics of the randomized cohort The Diabetes Prevention Program Research Group. Diabetes Care 2000; 23:1619–29. BACKGROUND. The Diabetes Prevention Program (DPP) is a 27-centre, randomized clinical trial designed for evaluating the safety and efficacy of interventions that may delay or prevent the development of diabetes in people at increased risk of type 2 diabetes. The eligibility requirements were impaired glucose tolerance (IGT) plus a fasting plasma glucose (FPG) value of 5.3–6.9 mmol/l. The 3234 participants are distributed in three treatment groups: intensive life style modification, standard care plus metformin and standard care plus placebo. Their baseline characteristics are described in this paper. The DPP has successfully randomized a large cohort of participants with a wide distribution of age, obesity and ethnic and racial backgrounds who are at high risk of developing type 2 diabetes. The study will examine the effects of interventions on the development of diabetes.

Comment The increase in the prevalence of type 2 diabetes resulting from widespread adoption of the Westernized life style together with demographic changes resulting from population ageing presents health services with major health challenges worldwide. Effective strategies for delaying the onset or preventing type 2 diabetes are urgently needed. The DPP trial is the largest ongoing trial evaluating the effectiveness of various life style and pharmacological interventions in preventing the progression of IGT to type 2 diabetes. In order to help guide clinical management, such large-scale studies must try to recruit patients from a representative population and to use interventions that are achievable and, from a pharmacological perspective, safe.

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Tissue insulin resistance, which principally affects skeletal muscle, adipose tissue and the liver, is a fundamental abnormality in the pathogenesis of type 2 diabetes. Glucose tolerance is initially maintained by increased insulin production from the pancreas but, in susceptible subjects, insulin secretion gradually declines leading to progressive hyperglycaemia. Interventions that improve the tissue sensitivity to insulin may delay the onset of B cell failure. Life style intervention with weight loss and regular exercise is a potent means of improving insulin resistance. The DPP trial will evaluate whether an intensive life style modification programme will alter the natural evolution of progressive glucose intolerance in type 2 diabetes. Metformin is an oral hypoglycaemic agent, the principle mechanism of action of which is to reduce hepatic glucose output and increase skeletal muscle glucose uptake. These are early abnormalities in the pathogenesis of type 2 diabetes and the DPP trial will address whether early metformin therapy has the potential for delaying type 2 diabetes. The initial trial design of the DPP also included an arm in which patients were randomized to troglitazone, a thiazolidinedione class of drug. The thiazolidinediones are a new class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Their mode of action suggests potential benefit in preventing the progression of IGT to established diabetes but, because of concerns about hepatotoxicity, troglitazone was withdrawn worldwide in April 2000 and can no longer be included in this study. This article identifies the baseline characteristics for the army of randomized patients included in this study, i.e. the DPR It is one of the most important studies under way on type 2 diabetes prevention and patients with IGT. The large sample size—3234 patients—makes this study a multicentre one carried out exclusively in the USA. The sample is composed of different ethnic groups that are representative of the population of the country. This characteristic of the study is very important if the effect of this preventive programme on different ethnic groups is to be assessed. The project took at least 3 years and pursued three lines of inquiry: drastic life style changes, metformin without life style changes and placebo without life style changes. This structure will help to contrast the efficacy of metformin administration and life style intervention. The STOP-NIDDM trial: an international study on the efficacy of an α-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design and preliminary screening data. The Study to Prevent Non-insulin-dependent Diabetes Mellitus J L Chiasson, R Gomis, M Hanefeld, R G Josse, A Karasik, et al. Diabetes Care 1998; 21:1720–5. BACKGROUND. This report describes the rationale and design and the preliminary screening data of the Study to Prevent Non-insulin-dependent Diabetes Mellitus (STOP-NIDDM trial), which is an international study on the efficacy of the cc-glucosidase inhibitor acarbose in preventing or delaying the development of type 2 diabetes in a population with IGT. As of 1 March 1997, 4424 subjects had been screened and data were available for 3919 (88.5%) subjects. Of these subjects, 1200 (30.6%) had glucose intolerance and of the subjects with glucose intolerance, 521 (13.3%) had previously undetected type 2 diabetes and 679 (17.3%) had IGT. Of the IGT population, 412 (60.7%) subjects were eligible for the study This population had the following characteristics: the mean age was 54.8 years, 52% of the subjects were female, 53% had more than one risk factor for type 2 diabetes, >90% had a family history of diabetes, 78.2% had a BMI of≥27 kg/m2, 47.5% had high BP, 51.2% had dyslipidaemia and 22.8% of the women had a history of gestational diabetes. According to the World Health Organization’s criteria patients with IGT and having an FPG concentration≥5.6 mmol/l were randomized to receive either acarbose (100 mg three times daily) or placebo for a median follow-up period of 3.9 years. Screening of a high-risk population yields one

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eligible subject per every ten volunteers screened. This study should definitely answer the question of whether acarbose can prevent or delay the progression of IGT to type 2 DM.

Comment IGT is an established risk factor for type 2 diabetes. IGT is defined by a blood/ plasma glucose value 2 h after a 75 g glucose load that was clearly abnormal, but was not associate with a risk of micro-angiopathy in those with non-diabetic fasting blood glucose (FBG)/FPG levels. IGT is common, having a prevalence of 2– 25% in adults depending on the population studied. The risk factors for IGT include age, obesity (total and central), a family history of type 2 diabetes, physical inactivity and triglyceride levels. There are three main clinical issues that make IGT an important clinical entity. 1. It is a risk factor for type 2 diabetes with 20–50% of individuals developing type 2 diabetes over 10 years. 2. It is a risk factor for cardiovascular disease (CVD). 3. It is a component of the metabolic syndrome. This article details the clinical and biochemical characteristics of the sample included in the STOP-NIDDM trial together with those of the at-risk population analysed with a view to sample selection. This is a well-designed, multicentre, randomized, double-blind, placebo-controlled study that is designed for assessing whether treatment with the α-glucosidase inhibitor acarbose will delay or prevent progression of patients with IGT to type 2 diabetes. The STOP-NIDDM trial, which is one of the most important type 2 DM prevention studies in hand, has recruited a sample of approximately 400 patients. The people included in the survey were identified as having IGT and a FBG in excess of 100 mg/dl (5.6 mmol/l) by screening, i.e. a situation carrying a high diabetes and CVD development risk. The patients were treated with 100 mg of acarbose or placebo three times a day for a minimum period of 3 years. The primary outcome is the development of type 2 diabetes as diagnosed using a 75 g oral glucose tolerance test (OGTT) according to the new diagnostic criteria. Secondary outcomes are changes in BP, lipid profile, insulin sensitivity, cardiovascular events and morphometric profile. It is hoped that this study will answer the question of whether acarbose can prevent or delay the progression of IGT to type 2 DM. Prevention of type 2 diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study in Finland. Study design and 1-year interim report on the feasibility of the life style intervention programme J Eriksson, J Lindstrom, T Valle, S Aunola, H Hamalainen, et al. Diabetologia 1999; 42:793–801. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance J Tuomilehto, J Lindstrom, J G Erikkson, T T Valle, H Hamalainen, et al. N Engl J Med 2001; 344:1390–2. BACKGROUND. The aim of the Diabetes Prevention Study (DPS) is to assess whether an intensive diet-exercise programme delays or prevents type 2 DM in subjects with IGT. The sample, which comprised 523 overweight (mean BMI of 31 kg/m2) subjects (172 men) with a mean age of 55 years, was randomized to intervention (intensive life style modifications) or control (subjects only received general information about the life style changes necessary) groups. Each subject in the intervention group received individual counselling aimed at reducing their weight and their intake of total and saturated fat

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and increasing their intake of dietary fibre together with physical activity. The first paper describes the interim results after the first year of the programme and confirms the efficacy and feasibility of the life style intervention programme. It is intended that subjects will be followed for 6 years but the results of a mean of 2.3 years follow-up have recently been reported in a paper in the New England Journal of Medicine. The weight loss achieved in the intervention group at the end of year 1 was 4.2±5.1 kg and that at the end of year 2 was 3.5 ±5.5 kg as compared with 0.8±3.7 and 0.8±4.4 kg, respectively, in the controls. The cumulative incidence of diabetes after 4 years was 11% in the intervention group and 23% (P<0.001) in the controls amounting to a 58% reduction in the risk of developing diabetes.

Comment The development of type 2 diabetes is preceded by a long period (years) of IGT. The predictors of progression include fasting and post-challenge glucose levels, ethnicity (Hispanics, Mexican-Americans, Pimas and Narauans) and obesity, as assessed by BMI, waistrhip ratio or waist circumference |4|. Identifying patients with IGT using an OGTT allows interventions that may delay or even prevent progression to established diabetes to be tested. Previous studies investigating the effectiveness of life style intervention in reducing conversion of IGT to type 2 diabetes have shown variable results |5|. Early studies in Bedford and Whitehall in the UK failed to show benefit from a diet restricting carbohydrate intake to<120 g/day. More recently, both the Malmohus and Malmo Prevention Projects from Sweden reported that dietary life style modification reduced the conversion rates from 29 and 29% in subjects receiving no advice to 13 and 11%, respectively, in the intervention groups. The Malmohus trial also reported benefit from treatment with tolbutamide, a first-generation sulphonylurea. Similar benefits were reported in the Da Qing trial, which was carried out in 577 Chinese subjects with IGT who received advice about diet, exercise or both |6|. At 6 years the cumulative incidence of diabetes was 67.7% in the control group, 43.8% in the diet group, 41.1% in the exercise group and 46.0% in the combined diet and exercise group. The Fasting Hyperglycaemia Study from Oxford, UK |7|, failed to show benefit from 1 year of reinforcement of diet and exercise programmes in altering body weight, glucose control or insulin sensitivity, perhaps because the achieved life style change was not sufficiently pronounced. Interestingly more patients withdrew from the intensive life style modification programme than from the controls, raising some doubts about the feasibility of achieving widespread effective life style change in unselected at-risk patients. These articles detail the design of the DPS, the characteristics of the sample subjects included and the results of a mean of 2.3 years. This study aims to prevent type 2 DM in obese subjects with IGT by making them change their life styles. The intervention is intensive and individualized to each patient’s needs, which may account for the positive outcome. Such being the case, the DPS study has demonstrated that an individualized life style modification programme has a significant effect in reducing the progression of IGT to type 2 diabetes. It will be important to continue to follow-up this cohort in order to establish whether the results obtained at 3 years in the context of a clinical trial can be maintained in the longer-term in view of the known difficulties in maintaining life style changes over many years.

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References 1 2

3

4

5 6

7

. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study group. The effect of angiotensinconverting enzyme inhibition of diabetic nephropathy. N Engl J Med 1993; 329:1456–62. . Estacio RO, Jeffers BW, Hiatt WR, Biggerstaff SL, Gifford N, Schrier RW. The effect of nisoldipine as compared with enalapril on cardiovascular outcomes in patients with non-insulin-dependent diabetes and hypertension. New Engl J Med 1998; 338:645–52. . Tatti P, Pahor M, Byington RP, Di Mauro P, Guarisco R, Strollo G, Strollo F. Outcome results of the Fosinopril versus Amlodipine Cardiovascular Events randomized Trial (FACET) in patients with hypertension and NIDDM. Diabetes Care 1998; 21:597–603. . Edelstein SL, Knowler WC, Bain RP, Andres R, Barrett-Connor EL, Dowse GK, Haffner SM, Pettitt DJ, Sorkin JD, Muller DC, Collins VR, Hamman RF. Predictors of progression from impaired glucose tolerance to NIDDM: an analysis of six prospective studies. Diabetes 1997; 46:701–10. . Melander A. Review of previous impaired glucose tolerance intervention studies. Diabetic Med 1996; 13(3) (Suppl 2): S20–2. . Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care 1997; 20:537–44. . Dyson PA, Hammersley MS, Morris RJ, Holman RR, Turner RC. The Fasting Hyperglycaemia Study 11. Randomized controlled trial of reinforced healthy-living advice in subjects with increased but not diabetic fasting plasma glucose. Metabolism 1997; 40: 50–5.

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Comparison of acarbose and metformin in patients with type 2 diabetes mellitus who are insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study BWillms, DRuge. DiabeticMedl999; 16:755–61. BACKGROUND. This study aimed to compare the efficacy and safety of acarbose and metformin when added to sulphonylurea therapy in diabetic patients who were insufficiently controlled with sulphonylureas alone. The authors carried out a 12-week, single-centre, placebo-controlled study with 89 patients. The primary end-point, glycosylated haemoglobin (HbA1c), decreased from baseline in all groups after 12 weeks. The decrease was greater in the two groups receiving active therapy compared with placebo (acarbose −2.3± 0.32%, metformin −2.5±0.16% and placebo −1.3±0.34%). There was no significant difference between acarbose and metformin (P=0.65). The differences between both active therapies and placebo were statistically significant (acarbose P<0.01 and metformin P<0.004). Reductions in body weight were seen in all three groups over the treatment period and were greatest in the acarbose group (median weight reductions: acarbose 3.5 kg, metformin 1.0 kg and placebo 1.4 kg). There were no significant differences in the incidence of gastrointestinal side-effects between the three groups and all regimens were generally well tolerated. The results of the study demonstrate the equivalence of acarbose and metformin in improving metabolic control in patients who are insufficiently controlled with diet and sulphonylureas.

Comment This study compared the efficacy and safety of acarbose and metformin for type 2 diabetes mellitus (DM) patients in whom control by sulphonylureas was inadequate. The patients were found to have improved blood glucose with both treatments. An earlier comparison of the efficacy of these two treatments on diet-only patients had yielded similar results. This study is useful in that it recruited patients who had more severe metabolic disturbance and who had inadequate glycaemic control on sulphonylurea therapy and is notable for its correct design and the authors’ intention to treat (ITT) analysis. © Clinical Publishing Services Ltd

Despite the different mechanisms of action of the two drugs, interestingly both achieved an equally significant reduction in HbA1c and in the patients’ postprandial glucose figures relative to the placebo.

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In conclusion, this study has established that acarbose and metformin are equally effective for patients with more advanced diabetes. A randomized, double-blind trial of acarbose in type 2 diabetes shows improved glycaemic control over 3 years R R Holman, C A Cull, R C Turner. Diabetes Care 1999; 22:960–4. BACKGROUND In order to determine the degree to which a-glucosidase inhibitors, with their unique mode of action of primarily reducing post-prandial hyperglycaemia, offer an additional therapeutic approach in the long-term treatment of type 2 diabetes, the authors studied 1946 patients who were previously enrolled in the UK Prospective Diabetes Study (UKPDS). Analysis by ITT showed that patients allocated to acarbose as compared with placebo had 0.2% significantly lower median HbA1c at 3 years (P<0.001). The HbA1c difference at 3 years in patients remaining on their allocated therapy was 0.5% lower median HbA1c (8.1 versus 8.6%) (P<0.0001). Acarbose appeared to be equally efficacious when given in addition to diet alone, in addition to monotherapy with a sulphonylurea, metformin or insulin or in combination with more complex treatment regimens. Acarbose significantly improved glycaemic control over 3 years in patients with established type 2 diabetes.

Comment This is an important study for evaluating the effect of involving acarbose on blood glucose control in the treatment of established type 2 DM. The condition had previously been treated with diet treatment, monotherapy or combined treatment. The quality of the results obtained in this study is endorsed by its being performed as part of the UKPDS, by an adequate study design and the conclusion of an ITT analysis. The reduction in blood glucose persisted throughout the 3-year term of the study. Interestingly, the reductions in HbA1c were achieved independently of the type of pre-established antidiabetic therapy, thereby suggesting that acarbose can be administered with an assurance of blood glucose reduction and in conjunction with any other treatment for diabetes. A major problem with acarbose is its gastrointestinal side-effect profile. A lower proportion of patients in this report were taking acarbose at 3 years as compared with placebo (39 versus 58%) (P<0.0001), the main reasons for non-compliance being flatulence (30 versus 12%) (P<0.0001) and diarrhoea (16 versus 8%) (P< 0.05). Careful titration of acarbose is needed in view of the increased non-compliance rate seen secondary to the known side-effects. Improved post-prandial glycaemic control with insulin aspart in type 2 diabetic patients treated with insulin A M Rosenfalck, P Thorsby, L Kjems, K Birkeland, A Dejgaard, et al. Acta Diabetol 2000; 37(1):41–6. BACKGROUND. The effect of an injection of the rapid-acting insulin analogue aspart immediately before a meal on postprandial blood glucose control was compared with that of human insulin Actrapid® injected immediately or 30 min before a test meal in insulin-treated type 2 diabetic patients with residual β cell function. Immediate pre-meal administration of the rapid-acting insulin analogue aspart improved post-prandial glucose control compared to Actrapid® injected immediately before the meal, but showed similar control compared to Actrapid® injected 30 min before the meal. These results indicate that the improved glucose control previously demonstrated with insulin aspart compared to

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human insulin Actrapid® in healthy subjects and type 1 diabetic patients also applies to insulin-treated type 2 diabetic patients.

Comment Insulin aspart is a monomeric insulin analogue that is created by substituting proline with aspartic acid at position 28 of the B chain of the insulin molecule. This substitution has the effect of weakening the selfassociation of insulin, thereby allowing faster absorption from the injection site. In comparison with conventional soluble insulin, which takes 30–45 min to begin working, absorption of insulin aspart begins 5– 15 min after injection, thereby allowing immediate pre-meal dosing, which many patients find more convenient. This study compares the effect of insulin aspart administered immediately before meals with Actrapid® insulin administered immediately or 30 min before meals on postprandial glucose in type 2 diabetes patients who had residual pancreatic function. Twenty-five patients were given a standard test meal preceded by two subcutaneous injections per patient over a 3-day period. One injection of the trial insulins was administered 30 min before the test and the second was administered immediately before the meal, as defmed by the test protocol. The authors reported significantly better postprandial glucose control when pre-meal insulin aspart was compared with immediate pre-meal Actrapid®, with a smaller post-meal glucose excursion and a lower postprandial glucose peak. There were no differences in the postprandial glucose control parameter between premeal insulin aspart and Actrapid® given 30 min before the meal. In conclusion, injection of insulin aspart improved the postprandial blood glucose profile of type 2 diabetic patients as compared with immediate pre-meal injection of Actrapid® insulin. There were no detectable differences between the aspart insulin and Actrapid® when the latter was administered 30 min before meals. Rapid absorption of the aspart insulin appears to be the reason for the improved control over post-meal blood glucose. The difference between the insulin curves for aspart insulin and Actrapid® insulin, an effect that disappeared over a 2-hour period, suggests that the aspart insulin has a more ‘physiological’ profile for treating type 2 DM. The timing of insulin secretion is extremely important in regulating postprandial blood glucose. Similar results have been reported in trials of patients with type 1 diabetes |1|, thereby suggesting that insulin analogues offer improved postprandial glucose control compared with human soluble insulin. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial V Fonseca, J Rosenstock, R Patwardhan, A Salzman. JAMA 2000; 283(13):1695–702. BACKGROUND. In order to evaluate the efficacy of metformin-rosiglitazone combination therapy in patients with type 2 diabetes who were inadequately controlled with metformin alone, the authors carried out a randomized, double-blind, placebo-controlled trial from April 1997 to March 1998. Three hundred and forty-eight patients aged 40–80 years with a mean fasting plasma glucose (FPG) level of 12. 0 mmol/l (216 mg/dl), a mean HbA1c level of 8.8% and a mean body mass index (BMI) of 30.1 kg/m2 were randomized. The patients’ HbA1c levels, FPG levels, insulin sensitivity and β cell function improved significantly with metformin-rosiglitazone therapy in a dose-dependent manner. The mean levels of HbA1c decreased in the metformin-rosiglitazone group as did the mean FPG levels compared with the metformin-placebo group. Dose-dependent increases in the patients’ body weight and total and low-

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density lipoprotein (LDL) cholesterol levels were observed. The proportion of patients reporting adverse experiences was comparable across all groups.

Comment Metformin works by reducing hepatic glucose output and gluconeogenesis and by increasing peripheral glucose uptake. The effect on the hepatic glucose output is predominant. It also has anorectic properties and is not associated with weight gain in long-term use. Rosiglitazone, on the other hand, modifies insulin resistance in adipose tissue and skeletal muscle by combining with the nuclear transcription factor that is activated by the gamma receptor peroxisome proliferator. It thus promotes the synthesis of glucose transporter proteins in various tissues and stimulates adipocyte differentiation. These different but complementary mechanisms of action suggest that combination therapy in overweight patients with type 2 diabetes may be beneficial. The study was a multicentre, randomized, double-blind, placebo-controlled study conducted on an outpatient basis over a 26-week period. Patients were assigned Table 4.1 Reductions in combination treatment patients’ HbA1c and FPG levels relative to patients receiving metformin plus placebo (all P<0.001)

Metformin plus 4 mg rosiglitazone Metformin plus 8 mg rosiglitazone Source: Fonseca et al. (2000).

HbA1c %

FPG mmol/l

mg/dl

−1.0 −1.2

−2.2 −2.9

39.8 52.9

2.5 g of metformin per day plus placebo or 4 mg of rosiglitazone per day or 8 mg of rosiglitazone per day. Combination of rosiglitazone with metformin resulted in a dose-dependent improvement in the patients’ HbA1c levels, FPG levels (see Table 4.1), insulin sensitivity and β cell function. The improvements in the clinical end-points were dose dependent and became significant after 4 weeks of treatment, reaching a maximally effective plateau from week 18 onwards. The proportion of patients reporting side-effects was comparable across all groups. There was a significant increase in the patients’ total cholesterol, high-density lipoprotein (HDL) cholesterol and LDL cholesterol, despite the total cholesterol/ HDL cholesterol ratio remaining unaffected. However, rosiglitazone therapy was associated with a modest weight gain relative to the control group, but without changes in the patients’ waist to hip ratios and slight reductions in their haematocrits and haemoglobin concentrations during weeks 12–18, which recovered spontaneously in the course of the study. Other studies have confirmed that rosiglitazone therapy causes fluid retention, resulting in oedema in 5% of treated patients and may contribute to a mild dilutional fall in haemoglobin concentration. Rosiglitazone has also been shown to cause a redistribution of body fat stores, with a reduction in intraabdominal fat and increased subcutaneous fat. Improvements in β cell function have also been a consistent fmding with the glitazone drugs. Data from rodent models of diabetes treated with rosiglitazone have suggested that the drug may preserve islet cell anatomy and alter the expected progressive decline in β cell function. Uncontrolled data from human trials also suggest that the improved β cell function associated with glitazone therapy may lead to long-term stabilization of glycaemic control for at least 3 years.

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Fig. 4.1 Change in HbA1c levels at week 26 in patients taking metformin hydrochloride and rosiglitazone maleate combined compared with patients taking metformin alone. Source: Fonseca et al. (2000).

Consequently, a combination of metformin and rosiglitazone can be regarded as an effective low-risk treatment for reducing hyperglycaemia in overweight type 2 diabetic patients whose main problem is insulin resistance. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes E S Horton, C Clinkingbeard, M Gatlin, J Foley, S Mallows, et al. Diabetes Care 2000; 23(11):1660–5. BACKGROUND. In order to evaluate the efficacy and tolerability of nateglinide and metformin alone and in combination in type 2 diabetic patients who were inadequately controlled by diet, focusing on changes in their HbA1c levels, FPG levels and mealtime glucose excursions, the authors performed a randomized, double-blind study where patients received 24-weeks’ treatment with 120 mg nateglinide before meals (n=179), 500 mg metformin three times a day (n=178), combination therapy (n=172) or placebo (n=172). At the study end-point, the patients’ HbAlc levels were reduced from baseline with nateglinide and metformin, but were increased with placebo (-0.5, -0.8 and +0.5%, respectively) (P≤0. 0001). The changes in the FPG values followed the same pattern (−0.7, −1.6 and+0.4 mmol/l, respectively) (P<0.0001). Combination therapy was additive (HbA1c −1.4% and FPG−2.4 mmol/l) (P<0.01 versus monotherapy). There was a greater reduction in meal-related glucose excursions after Sustacal challenge with nateglinide monotherapy than with metformin monotherapy or placebo. All regimens were well tolerated. Nateglinide and metformin monotherapy each improved overall glycaemic control but by different mechanisms. Nateglinide decreased mealtime glucose excursions, whereas metformin primarily affected the patients’ FPG levels. In combination, nateglinide and metformin had complementary effects, improving the patients’ HbA1c levels, FPG levels and postprandial hyperglycaemia.

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Fig. 4.2 Mean change in HbA1c levels overtime in patients taking metformin hydrochloride alone compared with patients taking metformin and rosiglitazone maleate combined. Source: Fonseca et al. (2000).

Comment Nateglinide is a derivative of D-phenylalanine (N-(trans-4-isopropylcyclohexyl carbonyl)-D-phenylalanine) that acts by directly stimulatin g insulin release from pancreatic β cells via the inhibition of K+-sensitive ATP channels. The resulting depolarization of the extracellular membrane and higher intracellular calcium triggers insulin release by exocytosis. The stimulation of insulin secretion depends on the circulating blood glucose levels and reverses rapidly when the blood glucose levels decline |2|. This type of action lowers the risk of hypoglycaemia. Recent studies have shown that postprandial hyperglycaemia may be linked to higher general mortality and to death through coronary disease. Other authors have suggested that postprandial blood glucose may contribute towards and be a better long-term blood glucose predictor than fasting plasma blood glucose |3|. As the illness progresses, most type 2 diabetic patients usually require combined therapy for controlling both fasting and postprandial hyperglycaemia. Current treatments generally do not tackle the problem of postprandial hyperglycaemia Various studies evaluating the effects of nateglinide on type 2 diabetic patients have confirmed that nateglinide improves blood glucose control by reinstating the early insulin secretion phase, thereby lowering HbA1c levels at the expense of a reduction in postprandial blood glucose levels |4|. Similarly, good results have been obtained by combining nateglinide with other anti-diabetics such as metformin. This regime was well tolerated and offered a good safety margin whilst not raising the percentage of’hypos’ any more than other oral anti-diabetics would have done. In view of treatment selectivity vis-à-vis postprandial hyperglycaemia, the authors suggested nateglinide as a prime choice of anti-diabetic monotherapy for type 2 diabetic patients with virtually normal fasting plasma blood glucose indices and for elderly patients with intolerance to other anti-diabetic agents and also as a combined therapy.

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Fig. 4.3 Change in FPG concentrations at week 26 in patients taking metformin hydrochloride and rosiglitazone maleate combined compared with patients taking metformin alone. Source: Fonseca et al. (2000).

In the study the authors noted that nateglinide primarily reduced postprandial blood glucose excursions, while metformin basically reduced fasting blood sugar. On the other hand, the degree of HbA1c reduction is higher when a combination of both drugs is employed. In view of the additional benefits it offers, combination of both drugs would be a good alternative for the treatment of diabetic patients for whom optimal control has not been achieved by monotherapy. Use of insulin aspart, a fast-acting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes P Raskin, R A Guthrie, L Leiter, A Riis, L Jovanovic. Diabetes Care 2000; 23(5):583–8. BACKGROUND. This was a multicentre, randomized, open-label, 6-month study in 882 subjects, with a 6-month extension period in 714 subjects with type 1 diabetes. The subjects were administered insulin aspart immediately before meals or regular human insulin 30 min before meals and basal neutral protamine Hagedorn (NPH) insulin was taken as a single bedtime dose in the majority of subjects. The mean postprandial blood glucose levels (mg/dl) were significantly lower for subjects in the insulin aspart group compared with subjects in the human insulin group after breakfast (156 versus 185), lunch (137 versus 162) and dinner (153 versus 168) when assessed after 6 months of treatment. The mean HbA1c values (%) were slightly but significantly lower for the insulin aspart group (7.78%) than for the regular human insulin group (7.93%) (P=0.005) at 6 months. Similar postprandial blood glucose and HbA1c values were observed at 12 months. Adverse events and overall hypoglycaemic episodes were similar for both treatment groups.

Comment Insulin aspart (lasp) is a human insulin analogue that is important for its pharmacokinetic characteristics, as it ‘kicks in’ faster and is shorter acting. The difference between this and earlier studies with lasp |1, 5, 6| is

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Fig. 4.4 Mean FPG concentrations overtime in patients taking metformin hydrochloride alone compared with patients taking metformin and rosiglitazone maleate combined. Source: Fonseca et al. (2000).

that it includes a large number of type 1 diabetics whose life styles have not undergone specific changes (basically diet and physical activity). It compares the glycaemic control of two groups of patients subjected to intensified conventional treatment with multiple doses of insulin (pre-prandial (soluble or lasp) insulin and basic insulin (NPH) in one or two doses depending upon how the established blood sugar control targets are achieved). Both groups were found to have undergone a reduction in their HbA1c values, with the lasp group achieving significantly lower levels. This better metabolic control was obtained by adjusting the basic insulin dose, but more particularly through better postprandial blood sugar control unaccompanied by a high number of hypoglycaemic events. Although similar numbers of patients experienced severe hypoglycaemia requiring outside assistance, there were fewer episodes of severe nocturnal hypoglycaemia in the lasp group (4 versus 8%) (P<0.013). This observation has been reported in other trials using short-acting insulin analogues |7| and probably reflects the shorter duration of action of analogues, which results in reduced overlap with night-time NPH insulin relative to human insulin. This study is also noteworthy in that it compares treatment with lasp and treatment with soluble insulin administered 30 min before meals, something that, despite American Diabetes Association assertions, rarely happens in daily life. Therapy focused on lowering post-prandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group

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Fig. 4.5 Adjusted mean changes from baseline in HbA1c, FPG and glucose areas underthe curve (AUCs) after Sustacal® challenge (ITT population). All parameters were significantly reduced from baseline (P≤0.0001) in the active treatment groups. All values were significantly reduced compared with placebo (P≤0.0001) except for the glucose AUC with metformin monotherapy(non-significant). *P≤0.01, **P≤0.001, ***P≤0.0001. Open bars, placebo; lightgrey bars, nateglinide; dark grey bars, metformin; black bars, nateglinide plus metformin. Source: Horton et al. (2000). E J Bastyr III, C A Stuart, R G Brodows, S Schwartz, C J Graf, et al. Diabetes Care 2000; 23(9): 1236–41. BACKGROUND. The aim of this study was to compare the overall efficacy of combination therapies focused on FPG or postprandial blood glucose in type 2 diabetes patients who were insufficiently controlled with oral sulphonylurea agents alone. A total of 135 patients were randomly assigned for 3 months to one of three combination regimens with glyburide (G) that addressed either postprandial blood glucose with insulin lispro (L+G), pre-meal blood glucose with metformin (M+G) or fasting blood glucose (FBG) with bedtime NPH insulin (NPH+G). At the end-point, the patients’ HbA1c was significantly lower with all three therapies (P=0.001) and was significantly lower for the L+G therapy (7. 68%) as compared with either the NPH+G or M+G therapies (8.51 and 8.31%, respectively) (P=0.003 and P=0.025, respectively). The patients’ FBG at the end-point was significantly lower for the NPH+G (8. 49 mmol/l) therapy as compared with either L+G or IVI+G therapies (10.57 and 9.69 mmol/l, respectively) (P=0.001 and P=0.029, respectively). The mean 2-hour postprandial glucose after a test meal was significantly lower for the L+G therapy (10.87 mmol/l) versus the NPH+G and IVI+G therapies (12.21 and 12.72 mmol/l, respectively) (P=0.052 and P=0.009, respectively). The overall rate of hypoglycaemia (episodes per 30 days) was low and not statistically significant between groups (P=0.156). These data support the importance of lowering postprandial blood glucose in optimizing overall glycaemic control and, thus, improving long-term outcomes.

Comment In recent years, studies highlighting the importance of postprandial hyperglycaemia in the development of micro- and macrovascular complications and the mortality attributable to these causes have been appearing. Clearly, treatment aimed at reducing 2-hour postprandial blood sugar may help in reducing the

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Fig. 4.6 (a) The comparison of the observed HbA1c levels atthe end-point was statistically significantly lower for the L +G therapy versus the M+G or NPH+G therapies. (b) The comparison of the observed FBG levels atthe end-point was statistically significantly lower for the NPH+G therapy versus the M+G or L+G therapies. (c) The 2-hour postprandial blood glucose after the test meal was significantly lower for the L+G therapy versus the M+G or NPH+G therapies. (d) The 2-hour postprandial glucose excursion after the test meal was significantly lower for the L+G therapy versus the M +G or NPH+G therapies. Source: Raskin et al. (2000).

incidence of chronic complications, but this study also shows that treatment that targets a reduction in postprandial hyperglycaemia has a greater effect on HbA1c levels. The differences obtained between the group treated with bedtime NPH insulin/glyburide or glyburide and metformin compared to the group

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treated with glyburide and lispro insulin were 1% over the 7.7–8.5% HbA1c range. The problem of channelling treatment towards correcting postprandial hyperglycaemia when treatment with sulphonylureas is unsuccessful is that the treatment will be complex and involve three insulin injections a day, probably using a rapid-acting insulin analogue owing to its action profile. However, one point that should be borne in mind is that HbA1c reductions over this range in the UKPDS were responsible for an up to 35% reduction in the incidence of microvascular complications |8|. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. US Study Group of Insulin Glargine in Type 1 Diabetes R E Ratner, I B Hirsch, J L Neifing, S K Garg, T E Mecca, et al. Diabetes Care 2000; 23(5):639–43. BACKGROUND. Insulin glargine (21A-Gly-30Ba-L-Arg-30Bb-L-Arg-human insulin) is a biosynthetic insulin analogue with a prolonged duration of action compared with NPH human insulin. This study compared insulin glargine with NPH human insulin in subjects with type 1 diabetes who had been previously treated with multiple daily injections (MDIs) of NPH and regular insulin. This was a multicentre, randomized, parallel-group study in which the subjects were randomized to receive premeal regular insulin and either insulin glargine (at bedtime) or NPH insulin (at bedtime for patients on once-daily therapy and at bedtime and in the morning for patients on twice-daily therapy) for up to 28 weeks. A total of 534 well-controlled type 1 diabetic subjects (mean HbA1c 7.7% and mean FPG 11.8 mmo/ l) were treated. A small decrease in the patients’ HbAlc levels was noted with both insulin glargine (−0. 16%) and NPH insulin (−0.21%) (P>0.05). Significant reductions in the patients’ median FPG levels from baseline (−1.67 versus −0.33 mmol/l with NPH insulin) (P-0.0145) and a trend for a reduction in capillary FBG levels were achieved with insulin glargine. After the 1-month titration phase significantly fewer subjects receiving insulin glargine experienced symptomatic hypoglycaemia (39.9 versus 49.2%) (P=0.0219) or nocturnal hypoglycaemia (18.2 versus 27.1%) (P= 0.0116) with a blood glucose level of<2.0 mmol/l as compared with subjects receiving NPH insulin. Lower FPG levels with fewer episodes of hypoglycaemia were achieved with insulin glargine as compared with once-or twice-daily NPH insulin as part of a basal bolus regimen in patients with type 1 diabetes.

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Fig. 4.7 Percentage of subjects reporting at least one episode of symptomatic, nocturnal or severe hypoglycaemia confirmed by a blood glucose level<2.0 mmol/l (month 2 to the endpoint). Source: Ratner et al. (2000).

Comment Intensive insulin therapy that is aimed at obtaining strict blood glucose control has proved an effective way of preventing patients with DM from developing or experiencing a deterioration in microvascular complications. One of the hazards of intensive insulin therapy is an increased incidence of hypoglycaemia. One standard approach involves administering fast-acting insulin with main meals and using a mediumacting NPH insulin for providing nocturnal basal insulin. Bedtime NPH insulin, particularly when used with pre-meal regular insulin, can be associated with a risk of nocturnal hypoglycaemia plus rebound fasting hyperglycaemia. In addition, the variability in the absorption of NPH insulin may be associated with difficulty in controlling fasting hyperglycaemia resulting from the dawn phenomenon. In order for good metabolic control to be achieved, it is important to start from the correct fasting glucose. Insulin glargine is an insulin analogue that is produced from recombinant DNA. The change in the amino acid sequence alters the iso-electric point, thereby reducing insulin glargine solubility at physiological pH and, via hexamer formation, slowing down the dissociation to monomers. Thus, after subcutaneous administration insulin glargine has a more delayed, longer lasting effect that is ‘peakless’ compared with NPH insulin. Various studies have shown that insulin glargine therapy administered once a day is able to reduce fasting plasma glycaemia and the number of nocturnal hypos |9, 10|. This study investigated whether insulin glargine would be associated with fewer hypoglycaemic episodes when used as a basal insulin compared with the conventionally used NPH insulin regimen. Table 4.2 Glycaemic control (change from baseline to the end-point)

GHb (%) n Means±SEM

Insulin glargine

NPH

P

256 −0.16±0.05

262 −0.21±0.05

0.4408

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Capillary FBG (mmol/l) n Means±SEM FPG(mmol/l) n Medians (ranges)

Insulin glargine

NPH

P

244 -1.12±0.15

258 −0.94±0.14

0.3546

261 −1.67 (−20.1 to 15.3)

265 −0.33 (−24.3 to 15.4)

0.0145

75

Source: Ratner et al. (2000).

As far as safety and side-effects are concerned, insulin glargine did not stimulate anti-insulin antibody levels, but merely caused a slight deterioration in local reactions. These results suggest that insulin glargine may be a new basal insulin therapy, in particular for type 1 diabetics undergoing intensive therapy in order to achieve optimal metabolic control, thanks to a better nocturnal blood glucose profile and lower fasting blood sugars. Repaglinide in type 2 diabetes: a 24-week, fixed-dose efficacy and safety study L Jovanovic, G Dailey III, W C Huang, P Strange, B J Goldstein. J Clin Pharmacol 2000; 40(1):49–57. BACKGROUND. In this 24-week, multicentre, double-blind, randomized, fixed-dose trial, 361 patients with type 2 diabetes received daily pre-prandial treatment with placebo (n=75), 1 mg of repaglinide (i?=140) or 4 mg of repaglinide (n=146). By a last-observation carried-forward calculation, 1 mg or 4 mg repaglinide treatment decreased the patients’ mean FPG values (by -47 mg/dl or -49 mg/dl, respectively) while the placebo group had increased FPG values (by 19 mg/dl). The changes in the patients’ HbA1c from baseline values at the end of the study for the repaglinide treatment groups ranged from 1.8 to 1.9 percentage points lower than the placebo group. There were no episodes of severe hypoglycaemia. Nearly all hypoglycaemic symptom episodes had blood glucose levels above 45 mg/dl. Repaglinide was well tolerated in a pre-prandial fixed-dose regimen of 1 mg or 4 mg assigned without adjustment for clinical parameters.

Comment This article describes a study aimed at evaluating the efficacy and safety of fixed doses of 1 and 4 mg of repaglinide over a prolonged period of approximately 6 months (24 weeks). The study design was good, being multicentre, randomized, double-blind and referenced to a (placebo) control group and used an adequate sample (361 patients with type 2 diabetes). The result highlights are as follows. 1. Efficacy. At a dose of 1 and 4 mg, repaglinide generated much better fasting blood sugar and HbA1c levels than the placebo. These differences in blood sugar control became apparent within 2 weeks of starting therapy and were sustained throughout. Another important fact is that repaglinide, despite having a rapid onset of action and a short half-life with pre-prandial administration, also lowered FBG levels.

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Fig. 4.8 Changes in the mean FPG values at each visit week (all patients) relative to the baseline (week 0). Baseline FPG values: placebo, 246 mg/dl; 1 mg repaglinide, 250 mg/dl; 4 mg repaglinide, 241 mg/dl. Number of patients providing data at baseline: placebo, n=74; 1 mg repaglinide, n=135; 4 mg repaglinide, n=143. Number of patients providing data at week 24: placebo, n=30; 1 mg repaglinide, n=104; 4 mg repaglinide, n=98. Source: Jovanovic et al. (2000).

2. Safety. The investigators monitored cardiac and thyroid function (as both have potassium ATPdependent channels, as have pancreatic β cells). No changes were noted in either electrocardiogram or thyroid function indicating the high specificity of the drug for the potassium canals of pancreatic β cells. However, more cardiovascular events were observed in the 4 mg repaglinide group, but this finding is of doubtful clinical significance. The placebo group had a higher drop-out rate in contrast to the average 80% longer trial exposure time of the group treated with repaglinide, which allowed a longer time for the development of the cardiovascular events. Regarding safety, despite using a fixed dose, there were no episodes of severe hypoglycaemia during the trial. An important disadvantage of this trial worth highlighting was that no comparable group was randomized to conventional sulphonylurea therapy in order to compare its efficacy and hypoglycaemia incidence. In conclusion, the findings of this fixed dose study of repaglinide confirmed the efficacy and safety observed in other shorter trials. Both doses improved blood glucose control as compared to the placebo group and were well tolerated.

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Fig. 4.9 Changes in the mean HbA1c values at each visit week (all patients) relative to the baseline (week 0). Baseline HbA1c values: placebo, 8.6%; 1 mg repaglinide, 8.9%; 4 mg repaglinide, 8.7%. Number of patients providing data at baseline: placebo, n=74; 1 mg repaglinide, n= 136; 4 mg repaglinide, n=145. Number of patients providing data at week 24: placebo, n=30; 1 mg repaglinide, n=106; 4 mg repaglinide, n=101. Source: Jovanovic etal. (2000). Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes H Hanaire-Broutin, V Melki, S Bessieres-Lacombe, J PTauber. Diabetes Care 2000; 23(9): 1232–5. BACKGROUND. In order to compare the efficacy of two intensified insulin regimens, namely continuous subcutaneous insulin infusion (CSII) and MDIs, by using the short-acting insulin analogue lispro in type 1 diabetic patients, a total of 41 C-peptide-negative type 1 diabetic patients on intensified insulin therapy were included in an open-label, randomized, cross-over study comparing two 4-month periods of intensified insulin therapy with lispro: one period by MDIs and the other by CSII. The basal insulin regimen had to be optimized in 75% of the patients during the MDI period (mean number of NPH injections per day=2.65). Their HbA1c values were lower when lispro was used in CSII than in MDIs (7.89±0.77 versus 8.24±0.77%) (P<0.001). Their blood glucose levels were lower with CSII (165±27 versus 175±33 mg/dl) (P< 0.05). The SD of all the blood glucose values (73±15 versus 82±18 mg/dl) (P< 0. 01) was lower with CSII. The frequency of hypoglycaemic events, which was defined as blood glucose levels of < 60 mg/dl, did not differ significantly between the two modalities (CSII 3.9±4.2 per 14 days versus MDIs 4.3 ± 3.9 per 14 days). The mean insulin doses were significantly lower with CSII than with MDIs (38.5±9.8 versus 47.3±14.9 U/day, respectively) (P<0.0001). When used with external pumps versus

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MDIs, lispro provides better glycaemic control and stability with much lower doses of insulin and does not increase the frequency of hypoglycaemic episodes.

Comment The Diabetes Control and Complications Trial (DCCT) confirmed beyond doubt the relationship between blood glucose control and the risk of development and progression of microvascular complications. Intensive insulin therapy for patients with type 1 DM has become an important objective in managing these patients. Table 4.3 Patient characteristics n Sex (M/F) Age (years) Weight (kg) BMI (kg/m2) Duration of diabetes (years) HbAlc (%) Daily insulin dose (U/day)

41 21/20 43.5±10.3 (21.0–65.4) 68.2±10.0 (47–87) 24.0±2.4 (18.7–28.5) 20.0111.3 (4.0–42.0) 8.39±0.87 (6.8–10.0) 43.6+13.5

The data are n values or means±SDs (range). Source: Hanaire-Broutin et al. (2000). Table 4.4 HbA1c, capillary blood glucose measurements and daily insulin doses

HbA1c (%) Mean glycaemia (mg/dl) Mean SD of BG values (mg/ dl) Patients with BG level<60 mg/dl Total insulin dose (U/day) Basal insulin dose (U/day) Bolus insulin dose (U/day)

CSII regimen

MDI regimen

P

7.89±0.77 165±27 73±15

8.24±0.77 175±33 82±18

<0.001 <0.05 <0.01

3.9+4.2

4.3±3.9

NS

38.5±9.8 20.8±5.8 17.7±6.6

47.3±14.9 27. 5±8.8 19.8±8.4

0.0001 <0.03 <0.04

The data are means±SDs. HbA1c was measured at the end of each period of treatment. Capillary daily blood glucose measurements, the SDs of the blood glucose values, the number of hypoglycaemic events and the insulin doses were measured during the last 14 days of each treatment period. Source: Hanaire-Broutin et al. (2000).

Two types of treatment are available: intensive insulin therapy using MDIs or CSII by means of infusion pumps. The authors of this study compared the effect of lispro insulin in both types of treatment (MDIs and CSII) on the same group of type 1 diabetic patients following a crossed, open protocol. Forty-one type 1 diabetic patients whose ages ranged between 21 and 65 years were studied. Regardless of which treatment and insulin they had been taking earlier, they were subjected to intensive treatment with

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Fig. 4.10 Randomized cross-over open-label design comparing two methods of intensified insulin therapy (CSII and MDIs) using insulin lispro. Source: Hanaire-Broutin et al. (2000).

lispro insulin for 4 months and, in random allocation, were subsequently treated with a continuous lispro insulin pump for a further 4 months. The patients’ general practitioners monitored them on a bimonthly basis. Both the HbA1c and capillary blood glucose measurements recorded throughout the study were better for patients treated with CSII. Patients treated with MDIs were able to achieve the study objectives in respect of their glycaemic targets by means of a 32% higher insulin dosage than that of CSII. In most cases a third dose of NPH insulin had to be administered in order to optimize their blood glucose profiles without any weight gain or increases in blood pressure (BP). The larger quantity of insulin administered may have been responsible for these patients experiencing as many hypos as patients treated with an infusion pump. Overall, by the end of the study, the HbA1c values were better, insulin doses were lower, hypos occurred less often and most patients preferred treatment with the lispro continuous infusion insulin pump. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Lancet 2000; 355:253–9. BACKGROUND. Three thousand, five hundred and seventy-seven people with diabetes included in the Heart Outcomes Prevention Evaluation (HOPE) study aged 55 years or older who had a previous cardiovascular event or at least one other cardiovascular risk factor, no clinical proteinuria, heart failure or low ejection fraction and who were not taking angiotensin-converting enzyme

(ACE) inhibitors were randomly assigned ramipril (10 mg/day) or placebo and vitamin E or placebo according to a 2×2 factorial design. The combined primary outcome was myocardial infarction (Ml), stroke or cardiovascular death. Overt nephropathy was a main outcome in a substudy. The study was stopped 6 months early (after 4.5 years) by the independent data safety and monitoring board because of a consistent benefit of ramipril compared with placebo. Ramipril lowered the risk of the combined primary outcome by 25%, Ml by 22%, stroke by 33%, cardiovascular death by 37%, total mortality by 24%, revascularization by 17% and overt nephropathy by 24%. After adjustment for the changes in systolic (2.4 mmHg) and diastolic (1.0 mmHg) BPs, ramipril still lowered the risk of the combined

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primary outcome by 25% (P=0.0004). Ramipril was beneficial for cardiovascular events and overt nephropathy in people with diabetes. This treatment represents a vasculoprotective and renoprotective effect for people with diabetes.

Comment Patients with DM have a high risk of cardiovascular mortality and morbidity and the presence of other added risk factors increases the likelihood of CVD. Epidemiological evidence suggests that patients with type 2 diabetes who have not had vascular disease have a similar cardiovascular risk to non-diabetic subjects who have suffered an MI |11|. The HOPE study is a landmark clinical trial with adequate inherent statistical power for assessing whether the addition of ramipril (an ACE) inhibitor) or vitamin E to the medical treatment currently being administered to high-risk DM patients can prevent cardiovascular and renal complications. In the final evaluation, the results of the HOPE study showed a significant reduction in the primary variable. The authors pointed out that approximately 45% of patients discontinued treatment at the end of the study. These results may therefore underestimate the true benefit that might have been gained if the completion levels had been higher, suggesting that 15 patients with high-risk DM should be treated with ramipril for an average of 4.5 years in order to prevent any cardiovascular event from materializing. In this study, 10 mg of ramipril, a dose that is known to be BP effective, was administered. However, on completion of the study, patients in the ramipril group registered a slightly lower BP than those in the placebo group. However, the reduction in cardiovascular events was better than would have been expected from the average BP difference observed in both groups, indicating that the improved benefits offered by ramipril extends to aspects other than BP reduction alone. The MICRO-HOPE substudy (Microalbuminuria, Cardiovascular and Renal Outcomes) showed that ramipril significantly lowered the risk of the combined microvascular evaluation variable (full nephropathy, dialysis and laser therapy) in DM patients. In conclusion, these results provide clear evidence of the great benefits that are to be derived from ACE inhibition in DM patients. Cardiovascular risk reduction unconnected with BP decline suggests that other mechanisms associated with ACE inhibition have some additional role in cardiovascular event prevention. Metabolic and immunological effects of insulin lispro in gestational diabetes L Jovanovich, S llic, D Pettitt, K Hugo, M Gutierrez, et al. Diabetes Care 1999; 22(9):1422–7. BACKGROUND. The authors compared the metabolic and immunological effects of insulin lispro and regular human insulin in 42 women>18 years of age diagnosed with gestational diabetes mellitus (GDM) by an oral glucose tolerance test at 14–32 weeks of gestation. Their insulin antibodies and HbA1c levels were determined at enrolment and 6 weeks later. The anti-insulin antibody levels were similar in the two groups. Insulin lispro was not detectable in cord blood. During a meal test, the AUCs for glucose, insulin and C-peptide were significantly lower in the insulin lispro group. The mean fasting and postprandial glucose concentrations and end-point HbA1c levels were similar in the two groups. Insulin lispro may be considered a treatment option for women with gestational diabetes.

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Comment The pharmacokinetic characteristics of insulin lispro make it a suitable treatment for patients with GDM because the main problem is one of postprandial hyperglycaemia. However, its use during pregnancy has not yet been approved. This study evaluated the effects of insulin lispro and regular insulin. Fewer hypoglycaemic events were recorded for the first group, but the perinatal, anti-insulin antibody and metabolic control complications were similar for both groups. Consequently, the authors suggested that insulin lispro is a valid, effective, safe alternative for use during pregnancy. Table 4.5 Maternal HbA1c levels (%)

Regular human insulin Insulin lispro P value The data are means±SDs. Source: Jovanovich et al. (1999).

At enrolment

6 weeks later

Difference from baseline

5.24±0.09 5.47±0.09 0.0801

5.16±0.12 5.12±0.11 0.7508

0.07 (2.8%) 0.35 (5.7%) 0.0018

Table 4.6 Maternal and fetal outcomes Insulin lispro group

Regular human insulin group

n 19 22* Caesarean section delivery 7 (36.8) 6 (27.3) Gestational week at delivery 38.8±0.3 38.8+0.2 Neonatal parameters Length (cm) 49.8 ±0.5 49.5±0.3 Weight (g) 3098±202 3169+78 Percentile rankt 10–25 6 6 25–50 6 8 50–75 4 6 75–90 3 2 Apgar score (1 min) 8.3±0.2 7.5+0.4 9.0+0 8.7+0.2 Apgar score (5 min) The data are n values, n values with percentages in parentheses or means ± SEMs. *0ne woman participated in the meal test only. †Specific for sex, gestational age and ethnicity. No differences were statistically significant. Source: Jovanovich et al. (1999). Optimized basal bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients: no favourable effects on glycaemic control, physiological responses to hypoglycaemia, well-being or treatment satisfaction M M Janssen, FJSnoek, N Masurel, R P Hoogma, W L Deville, et al. Diabetes Care 2000; 23:629–33.

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BACKGROUND. In order to investigate the effects of a multiple injection regimen with a mixture of 75% lispro and 25% intermediate-acting insulin (lispro high mixture (lispro HM)) before meals on glycaemic control, physiological responses to hypoglycaemia, well-being and treatment

satisfaction, the authors studied 35 type 1 diabetes patients. After an 8–10-week run-in period, the patients were randomized to lispro HM or human regular insulin therapy for 12–14 weeks. Multiple injection therapy with lispro HIVI rather than human regular insulin before meals did not offer advantages regarding glycaemic control, the frequency of hypoglycaemia, well-being or treatment satisfaction. In addition, this regimen caused an attenuation of the adrenaline and autonomic symptom responses to hypoglycaemia.

Comment This article compares the effects of a treatment involving multiple injections of a fixed mixture (lispro HM) of 75% lispro insulin and 25% NPL insulin (lispro with a protamine base having kinetics similar to those of NPH) before meals and NPL at bedtime against a treatment comprising multiple injections of ordinary insulin before meals and NPH at bedtime over a 12–14-week period of treatment. The first phase involved initial monitoring, treatment and instruction until such time as certain blood glucose profile optimization targets were achieved during the first 8–10 weeks of the study. This randomized study, although interesting, focused on a relatively small patient sample (n=35). The points to be assessed by the study were blood glucose control, hypo frequency and the physiological response to hypoglycaemia and, secondly, patient feelings of well-being and satisfaction with both treatments. The following conclusions emerged from the study. 1. There were no differences in the patients’ HbA1c levels in the lispro HM treatments when compared to ordinary insulin plus NPH, despite the fact that the patients’ postprandial capillary blood sugars were significantly lower with lispro HM. Possible author explanations were that both groups had previously achieved optimal blood glucose control during the early part of the study and that the mixed lispro plus NPL dose ought not to be fixed but tailored to the individual for better control. However, other published studies have found that, when postprandial blood glucose is improved, better blood glucose control is observed |12|. This contrasts with the findings of this study. 2. There were no differences in patient hypo frequency, satisfaction and feelings of well-being in both treatments. 3. Similarly, treatment with lispro HM and neutral protamine lispro (NPL) at bedtime attentuated the patients’ adrenaline response and autonomic symptoms (investigated via euglycaemic-hypoglycaemic clamp in the first 19 patients enrolled). One possible explanation for this phenomenon could be delayed effects of NPL accumulation during the night. In conclusion, there are no advantages to treatment with multiple injections of lispro HM before meals as opposed to treatment with ordinary insulin in terms of blood glucose control, hypo frequency and patient feelings of well-being and satisfaction. Furthermore, the response of adrenaline and autonomic symptoms to hypoglycaemia was attenuated. More studies are needed in order to define the application of fixed versus flexible doses of lispro plus NPL and, thus, optimize lispro treatment for patients with type 1 diabetes. Use of insulin pump therapy at night-time only for children of 7–10 years of age with type 1 diabetes

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F R Kaufman, M Halvorson, C Kim, P Pitukcheewanont. Diabetes Care 2000; 23:579–82. BACKGROUND. Because of age-related developmental and cognitive issues, children <10 years of age may not be able to wear an insulin pump safely when they are not under direct parental supervision. The purpose of this study was to determine whether insulin pump therapy at night-time only, when children are at home, could improve their FBG and night-time blood glucose levels without adverse effects. A randomized, cross-over design was used for comparing night-time-only pump usage from dinner and throughout the night, combined with a pre-breakfast injection of intermediate-acting NPH and rapid-acting lispro insulin, with three insulin injections per day. Compared with baseline levels, the use of the pump resulted in a significant decrease in the mean average (P<0.001), breakfast (P<0.0001) and 3.00 a.m. (P<0.003) blood glucose levels. Night-time-only insulin pump therapy may be a viable alternative that young children can use for improving glycaemia when they are not capable of independently managing an insulin pump.

Comment Despite the innumerable advantages of the insulin continuous infusion pump for type 1 diabetic patients, its use in paediatrics is inadvisable owing to the risks that misuse of this technique might have on the diabetic child. However, with parental supervision, use of the insulin infusion pump could be helpful to children with poor diabetic control. This study evaluated use of the pump at night for children experiencing nocturnal hypoglycaemias and hyperglycaemias whilst they are at home and in the direct care of their parents. Ten diabetic children aged between 7 and 10 years used the insulin continuous infusion pump during their evening meal and throughout the night for 4 weeks and this treatment was compared with conventional treatment without a pump. During the day, the pump was withdrawn and the child resumed their normal activities and insulin regimen. The results of the study showed that the children had much improved diabetic control throughout the period that they were using the nightly insulin continuous infusion pump. The incidence of hypoglycaemias and the overall insulin doses were lower. Once the fear of nocturnal hypoglycaemias had declined, the quality of life also improved. Nevertheless, the use of insulin continuous infusion pumps is not recommend ed for child diabetics until the youngsters acquire an adequate grasp of how this technique works and how to manage it independently and self-sufficiently. Oral insulin administration and residual β cell function in recent-onset type 1 diabetes: a multicentre randomized controlled trial LChaillous, H Lefevre, CThivolet, C Boitard, N Lahlou, et al. Lancet 2000; 356:545–9. BACKGROUND. The authors investigated whether oral administration of recombinant human insulin could protect residual β cell function in recent-onset type 1 diabetes and enrolled 131 autoantibody-positive diabetic patients aged 7–40 years within 2 weeks of diagnosis (no ketoacidosis at diagnosis, weight loss<10% and polyuria for<6 weeks). They were randomly assigned 2.5 or 7.5 mg oral insulin daily or placebo for 1 year in addition to subcutaneous insulin therapy. Their serum C-peptide concentrations were measured in the fasting state and after stimulation in order to assess their β cell function. The baseline C-peptide and HbA1c concentrations were similar in the three groups. The HbA1c concentrations or measurements of fasting (means at 12 months 0.18, 0.17 and 0.17 nmol/l) or stimulated

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C-peptide concentrations (glucagons stimulated 0.39, 0.37 and 0.33 nmol/l) were similar in the placebo, 2. 5 and 7.5 mg insulin groups, respectively. No differences were seen in the time-courses or titres of antibodies to insulin, glutamic acid decarboxylase or islet antigen 2. At the doses used in this trial, oral administration of insulin initiated at the clinical onset of type 1 diabetes did not prevent the deterioration of β cell function. Table 4.7 Baseline characteristics of the participants

Demography Age (years)* M/F HLA type DR3 DR4

Placebo (n=45)

Oral insulin 2.5 mg (ii=42)

Oral insulin 7.5 mg(n=44)

19.8(8.4) 31/14

18.4(7.7) 16/26†

18.1(8.2) 29/15

28 (63%) 32 (71%)

20 (47%) 23 (55%)

27 (61) 29 (66%)

Clinical Body-mass index (kg/m2)* Weight loss (%)* Duration of polyuria (weeks)* pH* Haemoglobin Alc (%)* Subcutaneous insulin dose (IU/kg daily)* C-peptide concentrations (nmol/l)* Fasting Glucagon stimulated Meal stimulated Antibodies ICA Positive Median (range) titre Insulin antibodies Positive Mean (SD) % binding GAD antibodies Positive Mean (SD) index IA2 antibodies Positive Mean (SD) index *Mean (SD). †P<0.01 versus placebo group. Source: Chaillous et al. (2000).

20.1(3.3) 6.3 (3.6) 2.5 (1.6) 7.35(0.08) 11.0(2.9) 0.73(0.35)

20.3(4.1) 6.2 (3.4) 3.1 (2.4) 7.36(0.04) 12.1(2.6) 0.84(0.41)

20.2(3.6) 6.3 (3.9) 3.6(2.1)† 7.34(0.06) 12.0(2.7) 0.82(0.32)

0.20(0.17) 0.44(0.37) 0.66(0.51)

0.20(0.17) 0.44(0.34) 0.74(0.49)

0.19(0.12) 0.41(0.24) 0.57(0.41)

40 (90%) 20 (0–640)

36 (85%) 18 (0–640)

41 (93%) 20 (0–320)

12 (27%) 1.5(1.4)

33 (79%) 1.9(4.1)

38 (87%) 1.7 (2.5)

36 (79%) 56 (44)

33 (79%) 52 (39)

38 (87%) 50 (40)

32 (70%) 41 (48)

26 (62%) 49 (49)

26 (60%) 47 (51)

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Comment The autoimmune process in type 1 DM has led to immunological intervention via clinical trials focusing on strategies for dealing with the early stages of the illness. Oral administration of autoantigens may retard progressive destruction of β cells in non-obese mice. Oral administration of recombinant human insulin in the doses used in this study at the onset of type 1 DM did not arrest the deterioration of β cell function during the first year of type 1 DM. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study. A randomized trial. Arterial Disease Multiple Intervention Trial M B Elam, D B Hunninghake, K B Davis, R Garg, C Johnson, et al. JAMA 2000; 284(10):1263–70. BACKGROUND. Current guidelines do not recommend the use of niacin in patients with diabetes because of concerns about adverse effects on glycaemic control. However, this is based on limited clinical data. The objective of this study was to determine the efficacy and safety of lipid-modifying dosages of niacin in patients with diabetes. Niacin use significantly increased HDL cholesterol and decreased triglycerides (TGs) and LDL cholesterol in participants with and without diabetes (P<0.001 for niacin versus placebo for all). The glucose levels of participants with and without diabetes were modestly increased by niacin. The levels of HbA1c were unchanged from baseline to follow-up in participants with diabetes treated with niacin. There were no significant differences in niacin discontinuation, niacin dosage or hypoglycaemic therapy in participants with diabetes assigned to niacin versus placebo. This study suggests that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin therapy may be considered as an alternative to statin drugs or fibrates for patients with diabetes in whom these agents are not tolerated or fail to correct their hypertriglyceridaemia or low HDL cholesterol levels sufficiently.

Comment This substudy from the Arterial Disease Multiple Intervention Trial (ADMIT) evaluated the safety and efficacy of an intermediate release formulation of niacin in patients with diabetes. The ADMIT trial is an ongoing, prospective, placebo-controlled study that is aimed at evaluating the safety and efficacy of a combination of HDL cholesterol-raising antioxidant vitamins and low-dose warfarin therapy in subjects with diagnosed peripheral arterial disease. One hundred and twenty-five out of 468 ADMIT enrolees met the criterion for diabetes, which was defined as a history of diabetes or a level of HbA1c higher than 7% at the first study visit. Patients were administered 3 g of intermediate-release niacin or the maximum tolerated dose. The authors showed that niacin is equally effective in modifying lipid levels in patients with and without diabetes. HDL cholesterol increased by 29%, TGs and LDL cholesterol decreased by 23 and 8%, respectively and glucose increased in participants with and without diabetes (by 8.7 and 6.3 mg/dl, respectively). All these effects were significantly different from placebo. The HbA1c levels were not significantly modified in patients with diabetes. The authors concluded that this formulation of niacin given at this dose was safe in patients with diabetes and that this therapy may be considered as an alternative to statin drugs or fibrates in patients with diabetes in whom these agents are not tolerated or in whom they fail to correct the HDL cholesterol or TG levels. These results are interesting, although they do not provide cardiovascular events or mortality data (the end-point for which risk factor modification is aimed). Current guidelines in the management of diabetes discourage the use of niacin. These authors showed that niacin did

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Fig. 4.11 Trial profile. Source: Chaillous et al. (2000).

not worsen glycaemic control in patients with treated diabetes and, therefore, is a second-line safe treatment to consider in cardiovascular risk factor modification therapy. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study

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Fig. 4.12 Mean fasting, glucagon-stimulated and meal-stimulated C-peptide concentrations. The error bars show SEs. P<0.05 versus placebo group. Source: Chaillous et al. (2000). J S Skyler, W T Cefalu, I A Kourides, W H Landschulz, C C Balagtas, et al. for The Inhaled Insulin Phase II Study Group. Lancet 2001; 357:331–5.

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BACKGROUND. Seventy-three patients with type 1 DM were studied in an open-label, proof of concept, parallel-group, randomized trial. Patients in the experimental group received pre-prandial inhaled insulin plus a bedtime subcutaneous ultralente insulin injection. Patients in the control group received their usual insulin regimen of two to three injections per day. The changes in the HbA1c levels and in fasting and postprandial glucose concentrations and the occurrence and severity of hypoglycaemia were similar between groups. Inhaled insulin was well tolerated and had no effect on pulmonary function. This proof of concept study shows that pre-prandial insulin can be given by inhalation in individuals with insulin-deficient type 1 diabetes as a less invasive alternative to conventional pre-prandial insulin injections.

Comment One of the problems of endogenous insulin product substitution is how it should be administered. As insulin is a large molecule, it cannot be absorbed in whole peptide form by the gastrointestinal mucosa and, to date, conventionally the only way of administering it has been by subcutaneous injection. The inhalation method has been the most important method of non-invasive administration of peptides or proteins. The insulin peaks obtained after inhalation are as fast and transitory as those obtained after injection of fast-acting analogue insulin and longer lasting and the variability between individuals is comparable to that of insulin injection. Absorption is significantly increased in smokers. One of the problems of insulin inhalation is that its bioavailability is between 10 and 30%. This randomized, open, parallel study compared the blood glucose control of patients with type 1 diabetes undergoing intensified treatment. The test group were given three doses of fast-acting insulin by inhalation and NPH insulin just before going to bed and the control group received its normal treatment of two or three insulin injections a day. The conclusion drawn by this study was that the overall blood glucose control quantified in terms of HbA1c levels after 3 months’ treatment was similar using regular inhaled insulin to that obtained via subcutaneous injection. There is virtually no difference between the postprandial blood glucose checks obtained by inhalation immediately after a meal and those obtained with normal insulin injected 30 min before meals. From the standpoints of safety and general satisfaction with the treatment, the inhalation method was found to be reliable and patients claimed to be generally satisfied with inhaled insulin. The unresolved problems associated with this manner of administration concern the equipment used for inhalation and the greater dose of insulin required with this method in order to achieve the desired effects, which represents a considerable cost |13|. This mode of treatment would also need to be compared with insulin analogues that are known to have a more positive effect on postprandial glycaemia. Another concern relates to whether any long-term effects on pulmonary function will emerge from continued use. Efficacy and safety of recombinant human nerve growth factor in patients with diabetic polyneuropathy: a randomized controlled trial S C Apfel, S Schwartz, B T Adornato, R Freeman, V Biton, et al. JAMA 2000; 284:2215–21. BACKGROUND. In order to evaluate the efficacy and safety of a 12-month regimen of rhNGF (recombinant human nerve growth factor) in patients with diabetic polyneuropathy, a total of 1019 men and women aged 18–74 years with either type 1 or type 2 diabetes and a sensory polyneuropathy that was attributable to diabetes were studied. Patients were randomly assigned to receive 0.1 (Jg/kg of rhNGF or placebo by subcutaneous injection three times per week for 48 weeks. The patients were assessed at

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baseline, 12 weeks, 24 weeks and 48 weeks. This phase 3 clinical trial failed to demonstrate a significant beneficial effect of rhNGF on diabetic polyneuropathy.

Comment Nerve growth factor (NGF) is a protein that selectively encourages the survival of the small nerve fibres of the peripheral nervous system. Both experimental animals and patients with diabetes have been found to have lower levels or impaired retrograde transport of NGF mitochondrial RNA (mRNA) from the target tissue to the neuronal body. This suggests that NGF plays some part in diabetic polyneuropathy pathogenesis. Phase 2 studies have shown that treatment with rhNGF has resulted in a significantly greater improvement in the signs and symptoms of diabetic polyneuropathy than placebo. The aim of this multicentre, randomized, controlled, double-blind study was to evaluate the efficacy and safety of rhNGF administration. One thousand, one hundred and nine patients with DM and secondary sensitive peripheral polyneuropathy were included in the trial and the effect of administration on associated signs and symptoms was investigated using the change in neuropathy impairment score for the lower limb as the prime objective after a 12-month period. The other variables studied were quantitative sensitivity tests, quality-of-life tests, nerve conduction studies and the appearance of new foot ulcers. This study found no significant differences in polyneuropathy development between the two treatment groups and stabilization was evident in both. Doubts were raised as to whether the advanced age of the test subjects compared to the previous phase 2 study, the rhNGF doses used, the short follow-up time, the degree of neuropathy affecting the patients under investigation and even the use of a foot examination as a neuropathy improvement index might be contributing factors. The fact that no major side-effect was detected after 0.1 mg/kg of rhNGF had been administered three times a week for 12 months indicated that the treatment was safe. Effects of simvastatin and atorvastatin administration on insulin resistance and the respiratory quotient in aged dyslipidemic non-insulin-dependent diabetic patients G Paolisso, M Barbagallo, G Petrella, E Ragno, M Barbieri, et al. Atherosclerosis 2000; 150(1):121–7. BACKGROUND. One hundred and ninety-five patients with type 2 diabetes (mean age 67±4.8 years) underwent a randomized, single-blind study for investigating the effect of statin administration on their insulin resistance and respiratory quotient (Rq). All patients were randomized to three groups after a 4week run-in period: placebo (n=67), 10 mg/day of simvastatin (n=61) or 5 mg/day of atorvastatin (n=67). Each treatment period lasted 8 weeks. Insulin resistance was assessed by the homeostasis model assessment (HOMA) index at the beginning, after the run-in and at the end of the study, while ftq values were evaluated by indirect calorimetry. Statins versus placebo significantly lowered the plasma total, LDL and HDL cholesterol and TG concentrations and improved insulin resistance, Rq and metabolic control. Atorvastatin had a greater effect than simvastatin on the plasma TG concentration (−26.3 versus −19.7%) (P<0.03), the HOMA index (−13.1 versus −9.1%) (P<0.05), Rq (5.9 versus 3.1%)(P<0.05) and HbA1c levels (−11.2 versus

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Fig. 4.13 Changes in the HOMA index (top) and adjusted Rq (bottom) after 8-weeks placebo, simvastatin (10 mg/day) and atorvastatin (5 mg/day) administration. The difference versus placebo is *P<0.005. Rq was adjusted for age and BML Source: Paolisso et al. (2000). −7.1%) (P<0.05). In conclusion the study demonstrated that statin administration was useful in controlling dyslipidaemia in non-insulin-dependent diabetes mellitus (NIDDM) patients and for

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Table 4.8 Change (%) in plasma lipids and HbA1c levels at the end of each treatment period*

FP triglycerides (mmol/l) FP total Cholesterol (mmol/l) FP LDL-cholesterol (mmol/l) FP HDL-cholesterol (mmol/l) HbA1c (%) Physical activity (METs) Body weight change (kg)

Placebo

Simvastatin

P†

Atorvastain

1.6±0.8 1.8±0.6 2.7±0.3 1.2±0.3 0.3±0.4 3.2±0.3 −0.7±0.4

−19.7±2.8 −19.1±4.1 −19.6±5.5 9.1±3.1 −7.1±0.4 3.5±0.2 −0.6±0.7

0.3 0.1 0.13 0.24 0.05 0.02 0.03

−26.3±3.1 −19.4±3.8 −20.5±4.1 8.7±2.8 −11.2±0.3 3.0±0.2 −0.7±0.8

*All results are means±SDs. FP, fasting plasma. †The differences between simvastatin and atorvastatin are reported as P values. The differences versus placebo are P<0.001. Source: Paolisso et al. (2000). improving their metabolic control. With regard to this latter aim, atorvastatin seems to be more powerful than simvastatin.

Comment Epidemiological studies have established that the incidence of coronary disease and mortality in diabetic patients is two or three times higher than in the general population. One of the most important factors contributing to cardiovascular disease (CVD) in patients with type 2 diabetes is their adverse lipoprotein profile. Increased plasma TGs and low HDL cholesterol concentrations together with increased small dense LDL particles are typically seen in patients with type 2 diabetes. Similar adverse lipid profiles are seen in the metabolic syndrome though it remains uncertain whether they contribute to the pathogenesis of this syndrome or develop as a consequence of insulin resistance. Insulin resistance in type 2 diabetes is associated with the failure of basal insulin levels suppressing lipolysis adequately. The resulting increased concentrations of non-esterified fatty acids (NE-FAs) stimulate hepatic gluconeogenesis and inhibit peripheral glucose uptake in peripheral tissues, both of which would tend to worsen insulin resistance. In addition, raised NEFAs have been shown to impair β cell function and reduce insulin secretion. This paper studied the effect of statins on insulin resistance, Rq, LDL and HDL cholesterol and lipoproteins on metabolic control. Insulin resistance was measured via the HOMA index and Rq values were evaluated by indirect calorimetry. The statins were found to cause a significant reduction in LDL cholesterol, HDL cholesterol and TGs and to improve insulin resistance and metabolic control relative to the placebo group. The results suggest that, of the two statins, atorvastatin dealt more effectively with the TG plasma concentration, HOMA index, Rq and HbA1c levels. Multivariate analysis suggested that the improvement in insulin resistance correlated with the fall in TG levels and this may account for the improved effectiveness of atorvastatin compared with simvastatin in this trial. In summary, statin treatment in type 2 diabetes resulted in improved insulin resistance with a small effect on glycaemic control. Atorvastatin may be more effective than simvastatin because of its greater effectiveness in lowering serum TGs.

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Sildenafil in the treatment of erectile dysfunction in men with diabetes: a randomized, controlled trial. Sildenafil Diabetes Study Group M S Rendell, J Rajfer, P A Wicker, M D Smith. JAMA 1999; 281:421–6. BACKGROUND. In order to assess the efficacy and safety of oral sildenafil citrate in the treatment of erectile dysfunction in men with diabetes, a multicentre, randomized, double-blind, placebo-controlled, flexible dose-escalation study conducted from May through to November 1996 was carried out with a total of 268 men (mean age 57 years) with erectile dysfunction (mean duration 5.6 years) and diabetes (mean duration 12 years). Seventy-four (56%) out of 131 patients in the sildenafil group reported improved erections compared with 13 (10%) out of 127 patients in the placebo group (P< 0.001). The incidence of cardiovascular adverse events was comparable for both groups (3% sildenafil and 5% placebo). Oral sildenafil is an effective and well-tolerated treatment for erectile dysfunction in men with diabetes.

Comment Various studies have demonstrated a higher prevalence of impotence in diabetic patients and shown that this is happening at a younger age. Sildenafil citrate is an orally acting selective type 5 phosphodiesterase inhibitor (PDE 5) (the predominant isoenzyme in the corpus cavernum). It is the most recent advance in the treatment of erectile dysfunction. This multicentre, placebo-contrasted, randomized, double-blind study involving flexible dose escalation was designed for assessing the efficacy and safety of sildenafil in treating impotence in diabetic males. The effectiveness of the treatment with sildenafil, as evaluated in the domestic context using the International Index of Erectile Function (IIEF) |14|, included a validated questionnaire containing 15 questions that patients were required to complete both before treatment and then in the twelfth week. At the end of the study, 93% of the sildenafil group were taking the highest dose permitted in the study (100 mg). Treatment with sildenafil resulted in a statistically significant improvement in erectile function in terms of all three efficacy variables. The relevant questions in the IIEF questionnaire were question 3 (about the ability to obtain an erection in order to have sexual intercourse) and question 4 (about the ability to sustain an erection after penetration) plus a question on general effectiveness, regardless of age, how long the erectile dysfunction had been occurring and the duration of the subjects’ diabetes. It is particularly important for DM patients to be evaluated for cardiovascular function; if the patients are correctly chosen, the side-effects are minimal. Also excluded from this study were patients suffering from proliferating diabetic retinopathy (DR) owing to the possible presence of masked theoretical and potential effects through slight cross-reactivity with the type 6 PDE of the retina. It would probably be useful to conduct comparative studies on DM patients with erectile dysfunction in order to contrast the different types of available treatment such as intracavernous alprostadil (Caverject®), intra-urethral alprostadil (MUSE®) and sildenafil (Viagra®) |15|. A comparison of glyburide and insulin in women with gestational diabetes mellitus O Langer, D L Conway, M D Berkus, E M Xenakis, O Gonzales. N Engl J Med 2000; 343:1134–8. BACKGROUND. Women with GDM are rarely treated with a sulphonylurea drug because of concern about teratogenicity and neonatal hypoglycaemia. The authors studied 404 women with singleton pregnancies and gestational diabetes that required treatment. The women were randomly assigned to

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receive glyburide or insulin according to an intensified treatment protocol between 11 and 33 weeks of gestation. The mean pre-treatment blood glucose concentration as measured at home for 1 week was 114 mg/dl (6.4 mmol/l) in the glyburide group and 116 mg/dl (6.5 mmol/l) in the insulin group (P=0.33). The mean concentrations during treatment were 105 mg/dl (5.9 mmol/l) in the glyburide group and 105 mg/dl (5.9 mmol/l) in the insulin group (P=0.99). There were no significant differences between the glyburide and insulin groups in the percentage of infants who were large for gestational age, who had macrosomia, who had lung complications, who had hypoglycaemia, who were admitted to a neonatal intensive care unit or who had fetal anomalies. The cord serum insulin concentrations were similar in the two groups and glyburide was not detected in the cord serum of any infant in the glyburide group. Glyburide is a clinically effective alternative to insulin therapy in women with gestational diabetes.

Comment The use of oral hypoglycaemic drugs during pregnancy is inadvisable owing to their teratogenic effect and possible fetal hypoglycaemia. Consequently, patients with type 2 DM being treated with these drugs are usually transferred to insulin therapy during the pre-conceptual period. However, gestational diabetes is diagnosed during the second trimester when embryogenesis has occurred and the risk of teratogenicity has passed. In this study, randomly selected women with GDM were given either glyburide or insulin. Both treatments were effective in controlling gestational diabetes although eight women (4%) in the glyburide group had to be transferred to insulin therapy. A concern related to the use of a long-acting sulphonylurea such as glyburide is that the drug could cross the placental barrier and lead to prolonged stimulation of fetal (3 cells. Importantly, concentrations of glyburide were not detected in the cord blood of newborn infants of mothers taking glyburide and the cord serum insulin concentrations were similar in both groups. It is also reassuring that the rates of neonatal hypoglycaemia were similar between the glyburide- and insulin-treated groups. Glyburide is emerging as a new clinically effective alternative in the treatment of gestational diabetes although further long-term studies are awaited in order to confirm its safety. Appropriate insulin regimens for type 2 diabetes: a multicenter, randomized, cross-over study R Taylor, R Davies, C Fox, M Sampson, J U Weaver, L Wood. Diabetes Care 2000; 23:1612–18. BACKGROUND. The aim of this study was to compare the rates of hypoglycaemia, the levels of metabolic control achieved and patient satisfaction and quality of life in patients with type 2 diabetes on once-daily ultralente insulin administration with those in patients with type 2 diabetes on twice-daily NPH insulin administration. A cross-over study was performed involvmg five centres and 79 patients with type 2 diabetes. The HbA1c levels were lower with NPH insulin therapy during each of the 6-month periods (9.7 ±0.2 versus 9.1±0.3 and 9.8±0.2 versus 9.0±0.3 mmol/l) (both P<0.01) and hypoglycaemic episodes requiring third-party assistance occurred almost entirely with ultralente insulin (14 versus 1). The treatment satisfaction scores increased more with NPH insulin as compared with once daily ultralente insulm.

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Fig. 4.14 Mean±SEM HbA1c levels in the two groups during run-in and at the end of each 6-month treatment period. Dashed line, ultralente insulin first; solid line, NPH insulin first. The arrow indicates the time of cross-over between the insulin regimens. *P<0.05, **P<0.01, ***p<0.001. Source: Taylor et al. (2000).

Comment The UKPDS results confirmed a clear relationship between chronic microvascular complications and glycaemic control in patients with type 2 diabetes. It is important to discover the best insulin regimen for type 2 diabetic patients in order to achieve optimal glycaemic control with the lowest risk of hypoglycaemia. This randomized, multicentre, cross-over study, which was structured in 6-months phases, included 70 patients with type 2 diabetes who completed the study. Its aim was to evaluate metabolic control, the number of hypos and patient satisfaction with two types of insulin treatment: one dose of ultralente insulin before an evening meal as opposed to two doses of intermediate-acting insulin. The treatment involving two doses of intermediate-acting insulin achieved significantly lower HbA1c levels over a 6-month period (see Fig. 4.14). The two groups did not differ in terms of their basal blood glucose figures. The group treated with ultralente insulin had a larger number of hypoglycaemic episodes (220 as opposed to 71) (P=0.08) and severe hypoglycaemic attacks (14 versus 1) (P<0.01). Although it is widely held that patients would prefer a single dose to a multiple one, this study showed that the patient were happier with better control. In this case, control was significantly better in the group given two doses of intermediateacting insulin. Despite the improvement in blood glucose control achieved with a twice-daily insulin regimen, together with lower TG and LDL cholesterol levels, the treatment was accompanied by weight gain, although BP remained unaffected. To conclude, it is important to remember that, although a regimen must be tailored for each patient, treatment with two doses of intermediate-acting insulin as opposed to treatment with a single dose of ultralente insulin achieved better blood glucose control, improved patient satisfaction and caused fewer hypoglycaemic episodes.

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The efficacy of octreotide in the therapy of severe non-proliferative and early proliferative diabetic retinopathy: a randomized controlled study M B Grant, R N Mames, C Fitzgerald, K M Hazariwala, R Cooper-DeHoff, et al. Diabetes Care 2000; 23:504–9. BACKGROUND. This pilot study examined the ability of octreotide in retarding the progression of DR and delaying the need for panretinal photocoagulation (PRP) in patients with advanced stages of retinal disease. The incidence of ocular disease progression was only 27% in patients treated with octreotide as compared with 42% in patients with conventional diabetes management. Thyroxine replacement therapy was administered in order to maintain a euthyroid state for all octreotide-treated patients and seven out of twelve control patients. Our results suggest that octreotide treatment in euthyroid patients may retard the progression of advanced DR and may delay the time to laser surgery.

Comment The aim of this study was to evaluate octreotide’s ability for retarding progressive DR and the need for PRP in patients in the advanced stages of DR. The method was a 15-month prospective study of 23 patients with type 1 or 2 DM who were diagnosed as having severe non-proliferative DR or premature proliferative DR, who were randomly distributed between conventional diabetes treatment only (control) (n=12) or treatment with octreotide (200–500 (µg/ day) subcutaneously four times per day or continuous infusion (n=11). Endocrine monitoring was performed at 3-monthly intervals and levothyroxine was started in all octre-otide-treated patients and seven out of twelve controls in order to maintain a euthyroid state (octreotide inhibits thyroid-stimulating hormone (TSH) secretion). The results showed that only one out of 22 eyes from the patients treated with octreotide reached highrisk proliferative DR that required laser photocoagulation, as compared with nine out of 24 eyes in the control patients. The decreased incidence of progression requiring laser surgery was statistically significant if the events were considered independently (P<0.006). The incidence of ocular disease progression was only 27% in patients treated with octreotide as compared with 42% in patients with conventional diabetes management. This treatment effect on whether the retina worsened approached statistical significance using repeated measures analysis (P=0.0605). The endocrine management was similar between treatment groups. Although growth hormone and in particular insulin-like growth factor 1 (IGF-1) have been implicated as growth factors in the development of proliferative DR for many years, previous intervention studies evaluating the benefits of somatostatin or its analogues in the treatment of DR have yielded inconclusive results |16–18|. This study is novel in that it involved treatment with levothyroxine in order to maintain normal thyroid hormone levels during the early treatment phase. Various studies have indicated TSH inhibition with shortterm administration of somatostatin or its analogues, but long-term administration does not affect thyroid hormone concentrations. The authors postulated that hypothyroidism affects the anti-proliferative effect of somatostatin through unknown mechanisms. The results showed a similar degree of inhibition of IGF-1 in patients undergoing treatment with octreotide plus lerothyroxine-4 (LT4) or with the first medication only. This suggested that the level of hormone suppression did not influence the results. These preliminary results should be interpreted with caution in view of the small patient numbers and difficulties in providing adequate placebo control for somatostatin administration. However, the interesting results suggested that more studies should be conducted in order to confirm these preliminary fmdings and,

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if con-firmed, understand how thyroid hormone may influence the clinical effectiveness of octreotide therapy. Flexible prandial glucose regulation with repaglinide in patients with type 2 diabetes P Damsbo, T C Marbury, V Hatorp, P Clauson, P G Muller. Diabetes Res Clin Pract 1999; 45:31–9. BACKGROUND. Repaglinide is a novel, rapid-acting prandial glucose regulator. In order to investigate the effect of 1 mg of repaglinide before each meal in maintaining glycaemic control in type 2 diabetic patients who either miss a meal or have an extra meal, 25 patients were randomized to either a fixed-meal regimen of three meals per day or one of two mixed-meal regimens consisting of repeating patterns of two, three or four meals per day over a 20-day period. Their overall glycaemic control was assessed by their weekly serum fructosamine concentrations and thirteen-point and 37-point serum glucose profiles. The mean fructosamine concentrations decreased significantly to normal values during the treatment period (P<0.05). Repaglinide was well tolerated and no hypoglycaemic events were reported. The serum cholesterol levels in both the fixed-meal and mixed-meal groups were significantly reduced (P<0.05), as were the TG levels in the mixed-meal group (P<0.05). It was concluded that mealassociated treatment with repaglinide was well tolerated irrespective of the number of meals consumed per day. Thus, since missing or postponing a meal is a realistic scenario for many individuals, repaglinide offers an oral anti-diabetic treatment that can be adjusted in order to suit each individual’s life style.

Comment Recently diagnosed type 2 diabetes is characterized by marked postprandial hyperglycaemia that is associated with small or moderate increases in FPG levels. The UKDPS trial showed that the use of longacting sulphonylureas such as glibenclamide is associated with an increased risk of hypoglycaemia in the first year after diagnosis because such agents lower both fasting and postprandial glucose concentrations. Metabolic control in recently diagnosed patients would ideally involve matching insulin secretion to their glucose excursions after meals using a short-acting, rapid-onset, potent insulin secretagogue. Repaglinide is a prandial glucose regulator of the meglitinide group of oral hypoglycaemic drugs. Although it stimulates insulin secretion from the β cell, its binding properties to the sulphonylurea receptor are different from conventional sulphonylureas, thereby giving it different pharmacodynamic and kinetic properties. It has a rapid onset of action that is measured in minutes and a short duration of action with a plasma half-life of approximately 1 h. These characteristics may have clinical benefit in providing improved postprandial glucose control and a lower risk of between-meal hypoglycaemia as compared with longer acting sulphonylureas. This study evaluated the metabolic control obtained in patients treated with different daily doses of repaglinide, which were varied according to whether they ate three meals a day or only ate once or even had supper after dinner and before going to bed. In all cases the patients were given 1 mg of repaglinide before each meal, so that the daily dosage varied from 2 to 4 mg/day. The results did not reveal signifkant differences in the metabolic control of those patients administered different drug doses according to their daily intake or any alterations in their basal glucose concentrations or blood glucose profiles during the day. In fact, after food intake their blood sugar readings reverted to their initial values after each meal and stabilized. No major hypoglycaemias were observed depending on the

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drug dose administered. A moderate weight loss was observed in these patients, another possible factor in metabolic control. It is concluded that repaglinide could be a useful drug in treating recently diagnosed type 2 overweight diabetic patients who have difficulty in maintaining strict diet control. Efficacy, safety and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes BWBode, PStrange. Diabetes Care 2001; 24:69–72. BACKGROUND. The aim of this study was to compare the efficacy, safety and pump compatibility of insulin aspart and buffered regular human insulin in patients with type 1 diabetes undergoing continuous CSII therapy. Insulin aspart and buffered regular human insul’m were both effective in controlling the patients’ average daily blood glucose levels and HbA1c (6.9±0.6 and 7.1± 0.6%) levels. Possible obstructions and set leakages were reported infrequently in both groups. There were no differences between the two insulins in the occurrence of hyperglycaemic events (blood glucose>19 mmol/l) or in the number and type of adverse events.

Comment Treatment using CSII attempts to administer insulin is such a way as to imitate physiological secretion. It is possible to set a basal rate on insulin infusion in order to provide glucose control between meals and overnight and then give supplemental boluses just prior to meals in order to provide postprandial insulin for dealing with the glucose load following eating. Traditionally, soluble insulin has been used in CSII, but, since soluble insulin forms hexamers in solution that delay absorption, the newer rapid-acting insulin analogues may offer advantages in pump therapy. The administration of insulin analogues such as insulin lispro or insulin aspart, which have a faster onset and shorter duration, has the advantage that administration of the insulin bolus can be done immediately before meals. It has further been shown that, with lispro insulin, there is an improvement in overall control and glycaemic excursions when compared with regular insulin used in CSII pumps. The pharmacokinetics of lasp, which starts to act 5–10 min after administration, achieve a peak at 45 min that lasts for 1–3 h, thereby suggesting that it may be a useful type of insulin for treatment with insulin pumps. This article is the first to evaluate the safety and efficacy of lasp and compare it with normal insulin in insulin pump treatment in a random study of 28 patients over a period of 6 weeks. The study concluded that insulin aspart is safe in CSII therapy and that its use was not associated with treatment-related side-effects. No overall advantages were identified with insulin aspart as compared with buffered regular insulin, but the short duration and small patient recruitment would suggest the study was underpowered for detecting small but clinically signifkant differences. Larger comparative trials are needed in order to evaluate the advantages and disadvantages of insulin aspart in CSII therapy fully. Pioglitazone hydrochloride monotherapy improves glycemic control in the treatment of patients with type 2 diabetes: a 6-month randomized, placebo-controlled, dose-response study S Aronoff, S Rosenblatt, S Braithwaite, J W Egan, A L Mathisen, et al. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23(11):1605–11.

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BACKGROUND. In order to evaluate the efficacy and safety of four doses (7.5, 15, 30 and 45 mg/day) of pioglitazone monotherapy in the treatment of patients

with type 2 diabetes, 408 patients were randomized in this multicentre, double-blind, placebocontrolled, clinical trial. Patients treated with 15, 30 or 45 mg pioglitazone had significant mean decreases in their HbA1c and FPG levels. There were significant decreases in their mean TGs and significant increases in their mean HDL cholesterol. Pioglitazone monotherapy significantly improved glycaemic control while producing beneficial effects on serum lipids in patients with type 2 diabetes with no evidence of drug-induced hepatotoxicity.

Comment Pioglitazone is a new oral anti-diabetic drug belonging to the thiazolidinediones group that reduces resistance to insulin by improving insulin action on adipose, hepatic and skeletal muscle. The present study is the first multicentre, large-scale trial aimed at determining the metabolic effects of pioglitazone as a monotherapy for type 2 diabetic patients. The authors concentrated on improving metabolic control in individuals treated with pioglitazone and obtained dose-dependent reductions in their HbA1c levels ranging from 2.35% in the case of the group treated with 45 mg/day to 0.94%. Their basal plasma glucose levels ranged from −74.5 mg to −23.9 mg/dl relative to the basal values. Interestingly the subset of patients who were naive to previous drug therapy had the greater benefit in terms of HbA1c (−2.55% as compared with placebo) and FPG (−79.9 mg/dl as compared with placebo) reductions. Significant improvements in the lipid profiles of the patients were also reported with a decline in their TG levels and higher HDL cholesterol. Although their LDL cholesterol remained unchanged, their HDL/LDL ratios improved. This improved lipid profile may offer the added benefit of reducing the rate of cardiovascular complications in longer term treatment. This hypothesis needs to be assessed in cardiovascular end-point studies using the thiazolidinedione drugs, but if evidence of vascular protection is obtained this new class of oral hypoglycaemic drug would represent a major therapeutic advance in type 2 diabetes. As far as adverse reactions were concerned, the authors reported oedema and discrete reductions in the patients’ haemoglobin and haematocrit levels, but not to the extent that would necessitate the withdrawal of the medication. In agreement with many other trials of the glitazone drugs weight gain (averaging 2.8 kg in the group on the maximum dose) was seen with active treatment. This was proportional to the improvement in blood glucose control, which may account for some of the weight gain, but recent studies have also suggested that treatment with the glitazones is associated with a redistribution of body fat between compartments. There was a reduction in intra-abdominal fat depots and an increase in subcutaneous fat and this redistribution may contribute to the improved lipid profile associated with pioglitazone therapy. The results of the study thus showed that pioglitazone is well tolerated and that it is an effective treatment for type 2 diabetics. Conclusion DM, in particular the most prevalent classification of type 2 diabetes, is an important health problem that is confronting both developed and, in particular, developing countries today. Future predictions of a global

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diabetes epidemic, with a projected 300 million people with diabetes within the next 15–20 years, emphasize the worldwide impact this disease is likely to have. Much of the morbidity and mortality of diabetes results from its associated chronic macrovascular and microvascular complications: 70% of patients with type 2 diabetes will die from CVD. Diabetes remains the commonest cause of blindness in people of working age and it has become the commonest indication for renal replacement therapy in the USA and many European countries. The quality of life of patients with diabetes is diminished by the development of complications rather than the burdens imposed by the monitoring and treatment of the disease. Type 2 diabetes has a long pre-clinical phase during which patients’ glucose tolerance changes from normal through impaired glucose tolerance (IGT) and impaired fasting glucose to established diabetes. The evolution of these changes predisposes patients to complications before a clinical diagnosis has been made, a point eloquently made by the data from the UKPDS in which 50% of newly presenting middle-aged patients with type 2 diabetes had one or more complications at the time of clinical diagnosis. The prevention of type 2 diabetes is therefore an attractive therapeutic option and various studies on this subject are currently in progress. Three of these, which are mentioned in this chapter, employ various strategies, such as the use of metformin or acarbose or simply a change in life style in order to try and prevent the progression of subjects with IGT to diabetes. Clearly, the result of these important multicentre studies will inform us about effective strategies for the prevention of diabetes. The Finnish Diabetes Prevention Study has recently reported its findings after a mean follow-up of 3.2 years. At randomization the intervention group received individualized counselling aimed at reducing their weight, total intake of fat and intake of saturated fat and increasing their intake of fibre and physical activity. They achieved an average weight loss of 4.2±5.1 kg compared with 0.8±3.7 kg in the control group at 1 year with the benefit persisting throughout the study. The cumulative incidence of diabetes after 4 years was 11% in the intervention group and 23% in the control group, which was a reduction in the risk of diabetes of 58% (P<0.001). Publication of the results of the Diabetes Prevention Program and the Study to Prevent Noninsulin-dependent Diabetes Mellitus are expected in early 2002 and should be of great interest. It is now established that glycaemic control is an important risk factor in the development and progression of the complications of diabetes. Recent clinical trials have also provided valuable information about the inter-relationship between modifiable risk factors such as glucose control, BP and serum lipids. Consequently, improved guidelines dealing with all of these inter-related risk factors are needed in order to influence the primary prevention of diabetes. . Emerging evidence is highlighting the importance of the postprandial period and its relation to long-term macrovascular risk. Changes occurring in glycaemia, lipidaemia or oxidative stress may be involved and need to be considered in a comprehensive assessment of the metabolic consequences of diabetes. It follows that drugs designed specifically for improving post-prandial metabolic control, whether these are newgeneration oral hypoglycaemic agents such as acarbose or nateglinide or newer insulin analogues, should be studied in well-controlled clinical trials in order to evaluate their short-term efficacy. The studies summarized in Part II confirm the clinical effectiveness of these agents and suggest some advantages in terms of a lower risk of hypoglycaemia with repaglinide and nateglinide. It is important to highlight the need for long-term ‘hard end-point’ clinical trials in order to determine whether treating postprandial hyperglycaemia will reduce the risk of CVD and other diabetes-related complications. Such studies are under way with nateglinide in the Nateglidine and Valsartan in impaired glucose tolerance outcomes research (NAVIGATOR) trial that is currently being set up. The emerging clinical data with newer oral hypoglycaemic agents are opening up new combinations of therapy for type 2 diabetes. Previous treatment algorithms are likely to need revision as experience and

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clinical trial data guide their use in clinical practice. Several papers reviewed in this chapter support the use of combination therapy. For example, the use of metformin with a glitazone is a logical combination, particularly for the overweight patient with type 2 diabetes and now has an evidence base from which to recommend its use. Similarly, combination of metformin with netaglinide is also shown to be effective. These newer combinations may find a place earlier in the management of type 2 diabetes, possibly being introduced soon after diagnosis when p cell function is reasonably well preserved and optimal efficacy can be expected. Future clinical intervention trials need to test this suggestion. CSII therapy is experiencing a renaissance in the management of selected patients with type 1 or type 2 diabetes. Currently there are over 75 000 CSII pump users in the USA and 25 000 pump users in Germany. The results of the DCCT trial, in which approximately 50% of intensively treated patients used pump therapy, together with significant improvements in pump technology partly explain the increased use of CSIL In addition, improved selection of patients who may be suitable for CSII has reduced the risk of diabetic ketoacidosis and infusion site infection. Improved stability of glucose control with, importantly, a lower risk of hypoglycaemia, are the potential benefits of CSII when used by a well-trained and motivated patient. CSII therapy is shown to benefit from the use of newer analogue insulins and these are now widely used in diabetes centres that run CSII programmes. The results of the Study Group for the Development of Pump Therapy in type 1 diabetes (p. 92) confirmed the benefits of the analogue insulin lispro, which produces more stable glucose control with a reduced risk of hypoglycaemia. The report on the use of insulin lispro in gestational diabetes is similarly reassuring to clinicians who are faced with the dilemma of a patient established on an analogue insulin who becomes pregnant. It is exciting to see the pace of developments in insulin delivery systems. Two main methods of inhaled insulin are showing promise, i.e. dry powder preparations and aerosolized insulin preparations. Both systems aim to deliver microscopic particles of insulin to the alveolar surface where systemic absorption can occur. Advances in inhaler technology have allowed more accurate dosing of insulin, which had been a practical problem associated with insulin inhalation. The time-course of action of inhaled insulin is similar to injected analogue insulins, thereby suggesting they may be of use as a meal-related insulin as part of a basal bolus insulin regimen. Long-acting inhaled preparations are not available and these would still require patients to administer subcutaneous insulin each day. The proof of concept trial reported in this chapter provides the first published data supporting clinical effectiveness in type 1 diabetes. Ongoing studies are also evaluating the use of inhaled insulin in type 2 diabetes and further publications in this field are expected in the next year. Several problems remain in the development of inhaled insulin. Its bioavailability remains low and is approximately 10% in most preparations. This has implications as far as cost is concerned. There are also problems with increased insulin absorption in smokers, which may prevent its use in a significant minority of patients with diabetes who smoke. The impact of lung diseases such as asthma and chronic obstructive pulmonary disease on insulin absorption also needs further study. Nowadays, much clinical and experimental evidence supports the use of ACE inhibiting drugs in improving cardiovascular outcomes for patients with diabetes. One such landmark trial is the HOPE study and MICRO-HOPE substudy, the results of which are highlighted in this chapter. A total of 3577 people with diabetes were included in the HOPE study cohort. In order to be eligible, patients had to be aged 55 years or older and to have had a previous cardiovascular event or at least one other cardiovascular risk factor. The exclusion criteria were clinical proteinuria, heart failure or a low ejection fraction. The reductions in MI by 22% (range 6–36%), strokeby 33% (range 10–50%), cardiovascular death by 37% (range 21–51%), total mortality by 24% (range 8–37%), revascularization by 17% (range 2–30%) and overt nephropathy by 24% (range 3–40%) (P=0.027) were impressive, in particular since the reported differences

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in BP between the two groups were small. Ramipril and probably other ACE inhibitors can be considered as offering renal and cardiovascular protection to type 2 diabetes patients with pre-existing cardiovascular risk. Whilst the use of ACE inhibitors is well established in the treatment of hypertension, heart failure, DN and now vascular risk reduction, the role of the newer angiotensin II (AII) receptor blocking drugs is less clearly defined. This drug class also blocks the renin-angiotensin-aldosterone axis, but achieves this by directly blocking the AII receptor. In contrast to the ACE inhibitors no direct effects on kinins are seen and this probably accounts for the lack of cough as a significant side-effect of AII receptor blocking drugs. There is therefore considerable interest in the results of an important study, Programme for Ibesartan Mortality and morbidity Evaluation (PRIME). This study encompasses two trials: the Irbesartan Diabetic Nephropathy Trial (IDNT), which evaluates the renal and cardiovascular effect of blocking AII receptors with irbesartan in patients with type 2 diabetes and nephropathy and the Irbesartan Microalbuminuria Intervention Trial, which studies type 2 patients with microalbuminuria. The results of these trials have recently been published. In the IDNT trial 1715 hypertensive patients with nephropathy due to type 2 diabetes were randomized to irbesartan (300 mg daily), amlodipine (10 mg daily) or placebo with a target BP of 135/85 mmHg or less in all groups. Over 2.6 years of follow-up treatment with irbesartan was associated with a 20% reduction in the risk of death and end-stage renal failure and a doubling of serum creatinine as compared with the placebo group (P=0.02) and a 23% reduction in the amlodipine group (P=0.006). There was a 24% reduction in the rate of rise of serum creatinine in the irbesartan group. Renal losartan protection trial (RENALL) is a second large multicentre trial comparing a different angiotensin receptor II blocking drug: losartan versus placebo in patients with type 2 diabetes and established nephropathy. In the RENALL study a total of 1513 patients were enrolled in a randomized controlled trial of losartan and placebo. Both were taken in addition to conventional anti-hypertensive treatment (calcium-channel antagonists, diuretics, alpha-blockers, beta-blockers and centrally acting agents) for a mean of 3.4 years. Losartan reduced the incidence of a doubling of the serum creatinine concentration by 25% and end-stage renal disease by 28%, both of which were statistically significant. Taken together the IDNT and RENALL trials provide strong evidence for a renoprotective effect of A II receptor blocking drugs although the lack of cardiovascular benefit in either trial is disappointing. These data pose a problem for the clinician since many patients with type 2 diabetes are already established on ACE inhibition therapy at the onset of overt nephropathy. The question of whether such patients should be switched to an angiotensin receptor blocker (ARB) remains unanswered, but some preliminary data from the Candesartan and Lisinopril Microalbuminuria Study |19| suggest that a combination of ACE inhibitors and ARB may have added benefit. Further trials are needed in this area. Irbesartan has also been studied in type 2 patients with microalbuminuria in a study related to the IDNT trial called IRMA 2 (Irbesartan microalbuminuria type 2 diabetes trial) |20| . A total of 590 hypertensive patients with type 2 diabetes and microalbuminuria were studied in a 2-year controlled trial comparing 150 mg or 300 mg of irbesartan daily with placebo. Ten of the 194 patients in the 300 mg group (5.2%) and 19 of the 195 patients in the 150 mg group (9.7%) reached the primary end-point, as compared with 30 of the 201 patients in the placebo group (14.9%), thereby suggesting that the renoprotective effect of irbesartan is present during the incipient stages of DN. A number of abstracts in this chapter describe novel approaches to the prevention of microvascular complications that are independent of glucose control. The first of these concerns the treatment of DR. Serum or intra-occular growth factors have been implicated in the pathogenesis of proliferative retinopathy for many years. Serum IGF-1, which is a growth hormone-dependent growth factor, has been related to the risk of developing sight-threatening retinopathy although early at tempts at reducing IGF-1 levels using octreotide, which is a synthetic analogue of the growth hormone inhibitor somatostatin, in order to reduce

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the risk of developing retinopathy have been inconclusive. A pilot study reviewed in this chapter is interesting as it showed that octreotide helped to reduce the risk of pre-proliferative retinopathy advancement in a small group of patients who were at high risk of proliferative retinopathy at enrolment, although these preliminary results require confirmation in larger scale clinical trials. DN remains a major clinical problem for patients. As well as causing unpleasant symptoms for some patients neuropathy is the strongest predictor of foot ulceration. Other than optimizing glucose control, therapeutic options are limited. Pain can be helped by tricyclic antidepressant medication or the antiepileptic gabapentin, but other pharmacological approaches to preserving nerve function, including aldose reductase inhibitors, have been disappointing. A new potential therapeutic option, recombinant human nerve growth factor has been studied and the results of a randomized controlled trial are summarized in this chapter. References 1. 2.

3. 4. 5.

6. 7.

8.

9.

10.

11.

12. 13. 14.

Lindholm A, McEwen J, Riis AP. Improved postprandial glycemic control with insulin aspart. A randomized double-blind cross-over trial in type 1 diabetes. Diabetes Care 1999; 22(5):801–5. Keilson L, Mather S, Walter YH, Subramanian S, McLeod JR Synergistic effects of nateglinide and meal administration on insulin secretion in patients with type 2 diabetes mellitus. J Clin Endocrinol Metab 2000; 85: 1081–6. Avignon A, Radauceanu A, Monnier L. Nonfasting plasma glucose is a better marker of diabetic control than fasting plasma glucose in type 2 diabetes. Diabetes Care 1997; 20: 1822–6. Hanefeld M, Bouter KP, Dickinson S, Guitard C. Rapid and short-acting mealtime insulin secretion with nateglinide controls both prandial and mean glycemia. Diabetes Care 2000; 23:202–7. Brunner GA, Hirschberger S, Sendlhofer G, Wutte A, Ellmerer M, Balent B, Schaupp L, Krejs Gj, Pieber TR. Postprandial administration of the insulin analogue insulin aspart in patients with type 1 diabetes mellitus. Diabetic Med 2000; 17:371–5. Heinemann L, Weyer C, Rauhaus M, Heinrichs S, Heise T. Variability of the metabolic effect of soluble insulin and the rapid-acting insulin analog insulin aspart. Type I diabetes. Diabetes Care 2000; 11:1910–14. Heller SR, Amiel SA, Mansell P. Effect of the fast-acting insulin analog lispro on the risk of nocturnal hypoglycemia during intensified insulin therapy. U.K. Lispro Study Group. Diabetes Care 1999; 22(10): 1607–11. Stratton MI, Adler Al, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 2000; 321: 405–12. Pieber TA, Eugène-Jolchine I, Derobert E for the European Study Group of HOE 901 in Type 1 Diabetes. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. Diabetes Care 2000; 23: 157–62. Rosenstock J, Park G, Zimmerman J for the US Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care 2000; 23:1137–42. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso 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 1998; 339 (4):229–34. Bastyr EJ 3rd, Stuart CA, Brodows RG, Schwartz S, Graf CJ, Zagar A, Robertson KE. Therapy focused on lowering postprandial glucose may be superior for lowering HbA1c . Diabetes Care 2000; 23(9): 1236–41. Gale EAM. Two cheers for inhaled insulin. Lancet 2001; 357:324–5. Rosen RC, Riley A, Wagner G, Osterloh H, Kirkpatrick J, Mishra A. The International Index of Erectile Function (IIEF). Urology 1997; 49:822–30.

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15. 16.

17.

18. 19.

20.

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Freeman MS, Bodansky HJ. Effectiveness of treatment for impotence in diabetic men. Diabetic Med; 16:1048–9. Kirkegaard C, Norgaard K, Snorgaard O, Bek T, Larsen M, Lund-Andersen H. Effect of one year continuous subcutaneous infusion of a somatostatin analogue, octreotide, on early retinopathy, metabolic control and thyroid function in type I (insulin-dependent) diabetes mellitus. Acta Endocrinol (Copenh) 1990; 122(6):766–72. Mallet B, Vialettes B, Haroche S, Escoffier P, Gastaut P, Taubert JP, Vague P. Stabilization of severe proliferative diabetic retinopathy by long-term treatment with SMS 201–995. Diabetes Metab 1992; 18(6): 438–44. McCombe M, Lightman S, Eckland DJ, Hamilton AM, Lightman SL. Effect of a long-acting somatostatin analogue (BIM23014) on proliferative diabetic retinopathy: a pilot study. Eye 1991; 5(Pt 5):569–75. Mogensen CE, Neldam S, Tikkanen I, Oren S, Viskoper R, Watts RW, Cooper ME. Randomised controlled trial of dual blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the Candesartan and Lisinopril Microalbuminuria (CALM) Study. BMJ 2000; 321(7274): 1440–4. Parving HH, Lehnert H, Brochner-Mortensen J, Gomis R, Andersen S, Arner P. Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med 2001; 345(12):870–8.

Part III Advances in type 1 diabetes mellitus

Advances in type 1 diabetes mellitus

Introduction Part III of this book reviews clinical trials in a number of key areas. Chapter 5 looks at advances in the understanding of the aetiology and diagnosis of type 1 diabetes. Two variants of classical type 1 diabetes are highlighted. Japanese authors describe a novel subtype of type 1 diabetes with a rapid onset and an absence of diabetes-related autoantibodies, whilst attention is drawn to the slow-onset variant of type 1 diabetes, which is termed latent autoimmune diabetes of adults. From an aetiological perspective a novel hypothesis linking early exposure to bovine insulin in cow’s milk is reported with interesting in vitro data. Chapter 6 looks at recent work in the area of chronic complications of diabetes and associated endothelial function. The Diabetes Control and Complications Trial (DCCT) finally confirmed the benefit of tight glycaemic control in reducing the risk of complications. The DCCT cohort has been followed since the DCCT ended and interesting data are presented that suggest that the benefits of a period of improved glucose control may last for a considerable time, even though optimal control is no longer maintained. The inter-relationship of risk factors in addition to glycaemic control is highlighted in several papers. For example, the interaction between blood pressure (BP) and glycaemic control is discussed in the United Kingdom Prospective Diabetes Study (UKPDS), while other papers look at the problems associated with BP measurement in diabetes and raise the issue of white coat hypertension and the effect of autonomic dysfunction on BP profiles. Many patients with diabetes experience acute coronary syndromes and established myocardial infarction (MI). Evaluation of such patients with exercise testing and, in selected cases, coronary angiography is widely available, but the optimal revascularization procedure is still debated. The Bypass Angioplasty Revascularization Investigators (BARIs) have previously reported that patients with diabetes have a higher re-stenosis rate following angioplasty than with coronary artery grafting. The BARIs now report interesting follow-up data on survival following MI in patients with diabetes who had previously received either coronary artery grafting or coronary angioplasty. Significant survival benefit was seen in those patients who had undergone coronary artery grafting. The authors go on to discuss the possible reasons for this and speculate that coronary grafting reduces the extent of myocardial ischaemia more than angioplasty. This greater myocardiarreserve’ seems to offer long-term benefits over and above early and 1 -year survival benefit and suggests that bypass grafting should be the preferred revascularization procedure in patients with diabetes. Optimal BP control has become a central feature of the management of diabetes with a significant shift from the predominant ‘glucocentric’ emphasis of earlier decades. The evidence base underlying the importance of hypertension has been strengthened by epidemiological studies showing a consistent link

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between hypertension and the risk of stroke and MI. Intervention trials in non-diabetic subjects over the last 20 years have shown benefit in terms of reduced stroke and heart failure, but evidence in diabetic subjects has been lacking. Some authorities have also suggested that there may be a J-shaped mortality curve in treating BP, with increased mortality resulting from over-zealous BP lowering. With the publication of seminal papers from Parving et al. |1| and the Collaborative Group |2| on type 1 diabetes patients with nephropathy, optimal BP management has been an essential part of the management of patients with proteinuria and microalbuminuria. However, the significance of and the benefits of treating hypertension in type 2 diabetes have until recently been speculative. The UKPDS demonstrated clear benefit in the aggressive treatment of hypertension and this is reviewed in Chapter 6. Together with other recently published multicentre trials such as the Hypertension Optimal Management Trial, the UKPDS hypertension trial provides a firm evidence base for aggressive treatment of hypertension with no evidence of a J-shaped curve. Chapter 7 focuses on aspects of the management of diabetes. The abstracts range widely from the potential benefits of dietary fibre or dietary unsaturated fats in the management of diabetes, the description of newer portable glucose meters and a report of the application of continuous glucose monitoring in improving glycaemic control. The relationship between physical fitness and type 2 diabetes is also considered. Perhaps not surprisingly men with diabetes who were physically unfit had a mortality that was almost double that of patients who were assessed as being fit. Such data, along with the emerging research on life style intervention and the prevention of type 2 diabetes summarized in Chapter 3, place great importance on public health measures in limiting the global impact of diabetes. References 1 2

. Parving HH, Andersen AR, Smidt UM. Hommel E, Mathiesen ER, Svendsen PA. Effect of antihypertensive treatment on kidney function in diabetic nephropathy. Br Med J (ClinResEd) 1987, 294(6585):1443–7. . Lewis EJ, Hunsicker LG, Bain RR Rohde RD. The effect of angiotensin-converting—enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med 1993, 330(2): 152.

5 Current status of type 1 diabetes mellitus

A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetesrelated antibodies. Osaka IDDM Study Group. A Imagawa, T Hanafusa, J Miyagawa, Y Matsuzawa. NEngl J Med 2000; 342(5):301–7. BACKGROUND. Type 1 diabetes mellitus (DN) is now classified as autoimmune (type 1A) or idiopathic (type 1B), but little is known about the latter. The authors classified 56 consecutive Japanese adults with type 1 diabetes according to the presence or absence of glutamic acid decarboxylase (GAD) antibodies (their presence is a marker of autoimmunity) and compared their clinical, serological and pathological characteristics. They divided the patients into three groups: 36 patients with positive tests for serum GAD autoantibodies, nine patients with negative tests for serum GAD antibodies and glycosylated haemoglobin (HbA1c) values higher than 11.5% and eleven patients with negative tests for serum GAD antibodies and HbA1c values lower than 8.5%. In comparison with the first two groups, the third group had a shorter mean duration of symptoms of hyperglycaemia (4 days), a higher mean plasma glucose concentration (773 mg/dl or 43 mmol/l) in spite of lower HbA1c values, diminished urinary excretion of C-peptide, a more severe metabolic disorder (with ketoacidosis), higher serum pancreatic enzyme concentrations and an absence of islet cells, IA-2 and insulin antibodies. Immunohistological studies of pancreatic biopsy specimens from three patients with negative tests for GAD autoantibodies and low HbA1c values revealed T lymphocyte-predominant infiltrates in the exocrine pancreas, but no insulinitis and no evidence of acute or chronic pancreatitis. Some patients with idiopathic type 1 diabetes have a non-autoimmune, fulminant disorder that is characterized by the absence of insulinitis and diabetes-related antibodies, a remarkably abrupt onset and high serum pancreatic enzyme concentrations.

Comment Reference was first made to type 1B or idiopathic DM, as characterized by the absence of autoimmunity markers, in 1997 in the classification proposed by the Ameri © Clinical Publishing Services Ltd

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Table 5.1 Characteristics of 56 patients with type 1 diabetes according to whether the test for GAD antibodies was positive or negative* P value Characteristic

GAD positive (n=36)

GAD negative GAD negative Low HbA1c vs High HbA1c Low HbA1c GAD positive (n=9) (n=U)

GAD negative High HbAlc

HbA1c (%) Age (yr)

11.75±2.8

12.9±1.0

6.4±0.9

<0.001

Mean Range Male sex (no.) Body-mass indext† First-degree relative with diabetes (no.) Duration of hyperglycaemic symptoms before diagnosis (days) Abdominal pain (no.) Abnormal findings on pancreatic ultrasonography (no.) Plasma glucose (mg/dl) Urinary C peptide (jig/day) Arterial pH Serum bicarbonate (mmol/ litre) Serum amylase § Serum elastase l§ Insulin dose during first yr (U/ kg of body weight)

32 14–75 14 19.1±2.6 7

27 14–52 5 20.0±2.9

38 25–57 6 21.0±3.8 14

52.4±54.1

45.9±36.2

4.0±1.7

0 0

0 0

1 0

398±198 21.0±11.2 7.36±0.07 20.6±6.2

439±179 19.7±10.3 7.34±0.11 19.5±7.3

0.39±0.16 0.45±0.15 0.43±0.21

0.63±0.74 0.14±0.02 0.34±0.24

<0.001

0.05

0.005

0.001

773±250 3.2±1.9 7.09±0.22 9.8±6.8

<0.001 <0.001 0.001 0.004

0.004 <0.001 0.03 0.03

4.24±4.27 3.47±2.15 0.61±0.14

<0.001 0.006 0.02

0.02 0.01

*The data were obtained at the time of diagnosis. The values are means ± SDs. To convert the values for glucose to millimoles per litre multiply by 0.056. To convert the values for C-peptide to millimoles per day multiply by 0.33. †The body mass index (BMI) was calculated as weight in kilograms divided by the square of height in metres, All affected relatives had type 2 diabetes except that one relative of two patients in the antibody-positive group had type 1 diabetes. § The values for amylase and elastase I are expressed as multiples of the upper limit of the normal range. Source: Imagawa et al. (2000).

can Diabetes Association. Very little information is available about this diabetes sub-type, but it probably embraces a heterogeneous group of patients. Its prevalence is not known accurately, although it appears to affect a small proportion of type 1 DM sufferers. Some authors have found mutations to Maturity Onset Diabetes of the Young (MODY) 3 diabetes in individuals initially classified as idiopathic |1|. In other cases, fluctuating insulinopenia and the absence of a human leucocyte antigen (HLA) link have been reported |2|. Improved short-term pancreatic β cell function in individuals with positive autoimmunity markers has also been described.

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The authors of the article revealed a subpopulation with negative GAD antibodies and abrupt or fulminant onset that was reflected in practice by the absence of any symptoms before diagnosis and low HbA1c levels. Similarly, all of these patients initially presented with coronary cardiopathy and elevated exocrine pancreatic enzymes. Three of the eleven patients underwent a pancreatic biopsy that revealed an absence of insulinitis and hyperexpression of the class 1 molecule pancreatic islets in the major histocompatibility complex, while the exocrine pancre-as showed evidence of T lymphocytes. The authors postulated that the non-discovery of any infection of the endocrine pancreas plus the abrupt onset of diabetes pointed to a possibly environmental causal agency such as a viral infection that might cause the pancreatic β cells to die. The lack of autoimmunity markers in these patients and the absence of insulinitis in the pancreatic biopsy led to classification of the illness as idiopathic diabetes. Discovery of these apparently normal pancreatic islets does not exclude possible islet infection. Further morphometric studies will be needed in order to exclude or confirm a pancreatic β cell loss of up to 85% of the pancreatic β cell mass without insulinitis being present. On the other hand, HLA typing showed that eight of the eleven patients were displaying the haplotypes associated with DM in the Japanese population, whereas only three displayed protective haplotypes. In addition, four of these patients had a family history of DM. We are therefore confronted with a new, little-documented diabetes subtype. However, it would be useful to acquire more data in order to assist in the formulation of preventive and therapeutic strategies. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group M Karvonen, M Viik-Kajander, E Moltchanova, I Libman, R LaPorte, et al. Diabetes Care 2000; 23(10):1516–26. BACKGROUND. The aim of this study was to investigate and monitor patterns in the incidence of childhood type 1 diabetes worldwide. The incidence of type 1 diabetes (per 100 000 per year) from 1990 to 1994 was determined in children ≤4 years of age from 100 centres in 50 countries. The overall ageadjusted incidence of type 1 diabetes varied from 0.1 per 100 000 per year in China and

Venezuela to 36.8 per 100 000 per year in Sardinia and 36.5 per 100 000 per year in Finland. This represents a>350-fold variation in the incidence among the 100 populations worldwide. In most populations, the incidence increased with age and was the highest among children of 10–14 years of age. The range of global variation in the incidence of childhood type 1 diabetes is even larger than previously described. The earlier reported polar-equatorial gradient in the incidence does not seem to be as strong as previously assumed, but the variation seems to follow ethnic and racial distribution in the world population.

Comment The aim of this study was to investigate and monitor the incidence of childhood type 1 diabetes worldwide. The ambitious World Health Organization (WHO)-instigated |3| DiaMond Project has been in operation for 10 years (1990–2000) and this study contains the results of the first 5 years of investigation. The size of the world population sample is remarkable (75.1 million people) making it the largest standardized investigation into a disease. Apparently, the incidence of type 1 diabetes is rising worldwide, particularly in countries with a (previous) low incidence of the disease. However, the increase observed over the first 5 years may be due to environmental or life style-related changes or could simply be caused by improved vigilance and recording

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of cases. The answer is still unknown due to the short period of time for which the study has been active; sufficient data have not been accumulated for analysis. Similarly, recently published articles on investigations into the incidence of type 1 diabetes purely in Europe |4, 5| have already shown a rapid rise in the incidence that is not justifiable solely in terms of the greater frequency of susceptible genes, but most probably by changes in environmental factors. The importance of this article lies in the following. 1. The global model for type 1 diabetes incidence has not changed substantially since studies published in the 1970s and 1980s. 2. The polar-equatorial gradient that was assumed for the incidence of type 1 diabetes does not appear to be as marked as originally thought. 3. There was the expected high incidence in European countries, but relatively high incidences have also been found in tropical or subtropical countries. An inexplicably high variation is also evident between non-European races. Although this study has provided comprehensive data on the incidence of type 1 diabetes and its variation throughout the world, it has failed to supply answers about the reasons for the huge variation between populations. In conclusion, these studies and others along the same lines are clearly important as they represent one of the most powerful strategies for understanding the multifactorial aetiology of type 1 DM and, ultimately, for preventing it (population studies have generated a large number of aetiological studies). Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes A Carlsson, G Sundkvist, L Groop, T Tuomi. J Clin Endocrinol Metab 2000; 85(1):76–80. BACKGROUND. In order to characterize patients with slowly progressing autoimmune diabetes or latent autoimmune diabetes of adults (LADA) of short duration metabolically, the authors measured insulin, C-peptide and glucagon responses to glucose and arginine at three blood glucose levels (fasting and 14 and 28 mmol/l) in eleven patients with LADA, eleven patients with type 2 diabetes and 14 healthy control subjects matched for age and BMI. The acute insulin response to arginine was impaired in LADA versus type 2 diabetes patients at all glucose levels, with the greatest impairment being for the maximally stimulated insulin concentrations (P<0.04). In contrast, β cell sensitivity to glucose was unaltered in LADA and type 2 diabetes patients. The glucagon concentrations were elevated in both LADA and type 2 diabetes patients as compared with healthy control subjects (P<0.02), but did not differ between the diabetes groups. In conclusion, patients with LADA share insulin resistance with type 2 diabetes patients, but display a more severe defect in maximally stimulated β cell capacity than patients with type 2 diabetes.

Comment The new diabetes classification system proposed in 1998 by the WHO introduced the LADA-type diabetes descriptor for the first time for defming a slowly progressing form of type 1 diabetes. The patient profile was the presence of positive autoimmune markers (GAD antibodies), over 35 years of age and generally no need for insulin treatment during the first 6–12 months following diagnosis. Although insulin secretion is conserved longer in these individuals than in those affected by type 1 diabetes with rapidly progressing

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Fig. 5.1 Age-standardized incidence (per 100 000 peryear) of type 1 diabetes in children≤14 years of age in 100 populations. The data for boys and girls have been pooled. Countries are arranged in descendingorderaccordingtothe incidence. Puerto Rico and the Virgin Islands are presented separately from other populations in the USA. Source: Karvonen et al. (2000).

forms, the pancreatic reserve tends to deteriorate over a period of time and insulin administration is generally required more often than for negative GAD individuals |6, 7|.

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LADA-type diabetic patients appear to exhibit the characteristics typical of both type 1 and type 2 diabetes patients. The study found that these patients were suffering from a severe pancreatic β cell function deficiency similar to that experienced by type 1 diabetes patients. On the other hand, like type 2 diabetes patients, they apparently display insulin resistance and some high glucagon levels |6, 7|. In view of the fmdings of the study, the authors suggested that the LADA type be regarded as a subgroup within diabetes and distinct from types 1 and 2 diabetes. Genetic, autoimmune and clinical characteristics of childhood and adult onset type 1 diabetes E Sabbah, K Savola, T Ebeling, P Kulmala, P Vahsalo, et al. Diabetes Care 2000; 23:1326–32. BACKGROUND. In order to assess whether there are any differences in the genetic, autoimmune or clinical features of type 1 diabetes presenting in childhood and that diagnosed later, the authors studied 352 individuals (252 children and adolescents <20 years of age and 100 adults≥20 years of age) manifesting clinical signs of type 1 diabetes over a period of 7.5 years. The patients were analysed for susceptible and protective HLA-DQBl alleles, islet cell antibodies, insulin autoantibodies and antibodies to GAD and IA-2 protein. Their clinical symptoms and signs were recorded at diagnosis.

Comment The following article analysed the genetic, autoimmune and clinical differences between diabetic children and adults, the aim being, as in previous studies, to discover whether adult diabetes onset is characterized by a longer symptomatic lead-up to diagnosis, better-preserved pancreatic β cell function relative to the infantile population, a reduction in anti-insulin antibodies’ positivity frequency and a lower incidence of HLA class II susceptibility haplotypes. In terms of the immunological characteristics, the authors found that only 4% of the child population had autoimmunity marker negativity, whereas up to 30% of the adult population showed no marker. On the other hand, diabetic children had 70% positivity to three or more autoantibodies, whereas this percentage was 30% in adult diabetic patients. The commonest antibodies in the child population were the pancreatic anti-islet antibodies (84%) and the commonest antibodies in the adult population were the GAD antibodies (51%). Table 5.2 The frequency of HLA-DQBl genotypes in children and adults with newly diagnosed type 1 diabetes

n *02/0302 *0302/x† *02/y Other

n

Children

Adults

P

49 136 43 19

188 44 (23.4) 101(53.7) 33(17.6) 10 (5.3)

59 5 (8.5) 35 (59.3) 10 (16.9) 9 (15.3)

− 0.02 NS NS 0.03

The data are n values or n values with percentages in parentheses. X2dl=3=11.07 and P=0.01. †x other than *02. f y other than *0302. Source: Sabbah et al. (2000).

Children more often displayed HLA class II susceptibility haplotypes (in particular DQB1*02/0302), whereas a higher percentage of the adult population was found to have a greater percentage of protective haplotypes such as DQB 1*0602–03. Similarly, a higher prevalence of IA-2 antibodies was found to occur

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Fig. 5.2 Number of autoantibodies at clinical presentation of type 1 diabetes in (a) 252 children and adolescents and (b) 100 adults: no antibodies ( ), one antibody ( ), two antibodies ( ), three antibodies ( ) and four antibodies ( ). Source: Sabbah et al. (2000).

among individuals with susceptibility haplotypes while those adult diabetics carrying protective haplotypes displayed a lower autoantibody positivity percentage. On the other hand, the clinical and analytical characteristics at onset differed in both groups. Thus, the proportion of men amongst the adults was higher and the symptomatology period preceding diagnosis in adults was longer, the percentage of previous infections was lower and the weight loss was less relative to the child population. The metabolic parameters reflected lesser decompensation (a higher pH and excessive bicarbonate and base than in children) and a lower HbA1c level. The results of the study suggest that the clinical onset age of type 1 DM could be determined by how intensively pancreatic β cells are destroyed. This is probably modulated by genetic and environmental factors. Glutamic acid decarboxylase antibodies are the most important factor in the prediction of insulin therapy within 3 years in young adult diabetic patients not classified as type 1 diabetes on clinical grounds C Torn, M Landin-Olsson, J Ostman, B Schersten, H Arnqvist, et al. Diabetes Metab Res Rev2000; 16:442–7.

BACKGROUND. Differentiation between type 1 and type 2 diabetes in adults is difficult at diagnosis. In this study we tested the hypothesis that autoantibodies at diagnosis are predictive for insulin treatment within 3 years in patients initially not classified as type 1 diabetes. At diagnosis, 583 (76%) were classified as type 1, 110 (14%) as type 2 and 71 (9.3%) could not be classified. After 3 years, 93% of autoantibody-positive patients initially not classified as type 1 were on insulin. When islet cell antibodies, GAD antibodies, IA-2 antibodies, BMI and C-peptide were tested in a multiple logistic regression, only GAD antibodies were significant for insulin treatment within 3 years (odds ratio=18.8 and 95% confidence interval=1.8–191) in patients treated with diet or oral drugs at diagnosis.

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Comment Diagnosis of the type of diabetes must be correct from the onset, as patients suffering from an autoimmune diabetes have a higher risk of developing ketoacidosis as an accompaniment to a concomitant infection or other acute illness. On the other hand, most type 1 diabetic patients usually display a residual pancreatic β cell function initially and it is important to preserve this as it may lead to better subsequent prognosis. Early intensive insulin therapy from diagnosis in patients with type 1 diabetes has been suggested as a way of conserving pancreatic β cell function. In this study, patients initially classified as type 1 diabetics but with positive autoimmunity markers tended to have a lower BMI and C-peptide level than those with negative autoimmune markers. Per contra, individuals classified right from the beginning as type 1 had a higher BMI and C-peptide level although their islet cell antibodies (ICA), GAD and IA-2 antibody levels were comparable. The results of this and other earlier studies point to the advisability of performing an autoantibody determination at diabetes onset, particularly in young patients, in view of the combination of diagnostic and therapeutic implications entailed. GAD autoantibodies are positive high predictors of the need for insulin treatment. Effect of cow’s milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group J Paronen, M Knip, E Savilahti, S Virtanen, J llonen, et al. Diabetes 2000; 49:1657–65. BACKGROUND. In this study, the authors studied immunological responses to cow’s milk in infants with a first-degree relative with type 1 diabetes who were at increased genetic risk of developing type 1 diabetes. Insulin-specific

T cell responses were measured by a proliferation test, the development of insulin-binding antibodies was assessed by enzyme immunoassay and the development of insulin autoantibodies was assessed by radioimmunoassay. The infants were randomized to receive either an adapted cow’s milk-based formula or a hydrolysed casein-based formula after breast-feeding for the first 6–8 months of life. At the age of 3 months, both the cellular and humoral responses to bovine insulin (Bl) were higher in infants exposed to the cow’s milk formula than in infants fully breast-fed (P=0.015 and P=0.007). The immunoglobulin (Ig) G antibodies to Bl were higher in infants who received the cow’s milk formula than in infants who received the hydrolysed casein formula at 3 months of age (P=0.01), but no differences in T cell responses were seen between the groups. The T cell responses to Bl at 9 months of age (P=0.05) and to human insulin at 12 (P=0.014) and 24 months of age (P=0.009) as well as IgG antibodies to Bl at 24 months of age (P=0.05) were lower in children with a diabetic mother than in children with a diabetic father or a sibling, suggesting possible toleration of insulin by maternal insulin therapy. The priming of insulin-specific humoral and T cell immunity occurs in early infancy by dietary insulin and this phenomenon is influenced by maternal type 1 diabetes.

Comment Although controversial, a number of studies have linked early exposure of infants to cow’s milk (or a lack of breast-feeding) to an increased risk of developing type 1 diabetes |8, 9|. Others have not |10|. One suggested hypothesis is that the risk is related to exposure to bovine proteins that may cross the immature

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neonatal gut wall and provoke an autoimmune reaction. In early studies bovine serum albumin (BSA) was implicated by a mechanism involving molecular mimicry between epitopes on BSA and some β cell antigens |11|. The authors of this study investigated an alternative hypothesis. It has been suggested that the first insulin immunization occurs on exposure to the BI from cow’s milk that is absorbed across the immature infant gut mucosa. This hypothesis is supported by the results of this study, since, at 3 months of age, children reared on cow’s milk exhibited increased T cell reactivity to bovine insulin when compared with babies fed solely on breast milk. Later on, at 6 months, the reaction declined, whereas at 9 months no differences were recorded. On the other hand, at 9, 12 and 24 months the children of diabetic mothers displayed a lower cellular immune response to BI than those with diabetic fathers or a sibling with diabetes. The generation of insulin-reactive T cells in early infancy could indicate a pathogenic link between cow’s milk and diabetes. The fact that the children of diabetic mothers had lower specific T cell reactivity to insulin could reflect insulin tolerance through the mother’s exposure to insulin treatment. This immunological mechanism may explain why the children of diabetic mothers are less susceptible to type 1 DM than the children of diabetic fathers. In summary exposure to cow’s milk proteins results in antibody formation against BI in infants at risk of type 1 diabetes. Type 1 diabetes manifested solely by a 2-hour oral glucose tolerance test criteria C J Greenbaum, D Cuthbertson, J P Krischer, Diabetes Prevention Trial of Type 1 Diabetes Study Group. D/abetes2001; 50:470–6. BACKGROUND. The clinical presentation of type 1 diabetes usually involves symptoms such as polyuria and polydipsia. However, investigators in the Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) detected a group of subjects with type 1 diabetes who had a different phenotype. These subjects were asymptomatic and had normal fasting glucose (NFG) (<6.1 mmol/l) (group A) or impaired (6.1–7.0 mmol/l) (group B) fasting glucose (IFG), but had 2-hour glucose values>11.1 mmol/l in oral glucose tolerance tests (OGTTs). Of the 585 OGTTs performed on islet cell antibody-positive relatives with insulin autoantibodies or a low first-phase insulin response (FPIR), normal glucose tolerance (NGT) was found in 427 subjects, impaired glucose tolerance (IGT) was found in 87 subjects and diabetes by 2-hour OGTT criteria alone was found in 61 subjects. Despite marked differences in the 2-hour glucose values (NGT 5.8±1.1 mmol/l, IGT 8.9±0.9 mmol/l and group A 13.5±2.5 mmol/l), there were no significant differences in the fasting glucose values among the NGT (4.8±0.5 mmol/l), IGT (5.03±0.5 mmol/l) and group A (4.99±0.7 mmol/l) categories. The mean FPIR was higher in subjects with NGT compared with subjects with IGT and subjects diagnosed by 2-hour OGTT criteria alone. However, the correlation between the FPIR and 2-hour glucose value was low (r2=0.114). Multivariate analysis demonstrated that additional independent variables provide smaller contributions to the 2-hour glucose value. In conclusion, there are asymptomatic type 1 diabetic subjects whose diabetes is diagnosed by the 2-hour criteria in OGTTs alone. Despite the importance of β cell dysfunction in the pathogenesis of type I diabetes, factors other than impaired FPIR must also contribute to postprandial glucose tolerance in these subjects.

Comment The DPT-1 study began in 1994 with the aim of preventing or delaying the onset of type 1 DM by administration of disease-associated antigens. During the screening phase of the study, first- and seconddegree relatives of patients with type 1 diabetes (<45 years) were assessed by measurement of their islet cell

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antibodies. Those who were islet cell antibody positive and had an impaired FPIR were regarded as being at high risk of developing type 1 diabetes and were included in the trial. A group of patients with asymptomatic type 1 diabetes within the large number of people at risk were identified and characterized by abnormal (diabetic range) 2-hour glucose values in a post-75 g glucose challenge despite having NFG or IFG values. This subgroup was typically between 3 and 45 years of age and had positive islet cell autoantibodies; over half of these patients were found to present a substantial deterioration in their insulin secretion profiles, with a lower FPIR in those with IFG. However, the study suggested that insulin deficiency cannot completely account for postprandial glucose intolerance in evolving type 1 diabetes. Other factors such as tissue insulin sensitivity or the actions of gastrointestinal tract incretins may also be involved. The interrelationship between insulin deficiency and these variables needs further study in order to obtain an understanding of the pathogenesis of type 1 diabetes. Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both the thymus and peripheral lymphoid organs A Pugliese, D Brown, D Garza, D Murchinson, M Zeller, et al. J Clin Invest 2001; 107:555–64. BACKGROUND. Genes with restricted tissue expression, including those encoding the type 1 diabetes autoantigens insulin, GAD and tyrosine phosphatase-like protein IA-2, are transcribed in the thymus. This study shows that, in humans, the thymus contains a series of specialized cells that synthesize (pro) insulin, GAD and IA-2, which are mainly located in the thymic medulla, peripheral lymphoid organs, lymphatic ganglia and spleen. Phenotypical analysis of these cells showed them to be antigen-presenting cells, including both macrophage and dendritic cell types. These cells appear to be surrounded by apoptotic lymphocytes, suggesting that the function of such cells is to destroy lymphocytes reacting against its own antigens. This study supplies data about the characteristics of a class of antigenpresenting cells that express autoantigens in the lymphoid organs. The authors suggested that these cells are probably implicated in immunological tolerance regulation generally and with the proteins directly associated with type 1 DM.

Comment Autoantigen expression in thymic tissue is a vital factor in the induction of immunological tolerance to selfantigens. At the moment, the evidence suggests that autoantigen-induced loss of immunological tolerance during the first fewyears of life is responsible for autoimmune diseases, including type 1 diabetes. Susceptibility to type 1 diabetes is in part influenced by genetically determined differences in thymic insulin levels. Studies in transgenic mice have provided correlative and functional evidence that the thymic expression of peripheral proteins is crucial for immunological self-tolerance but, until now, there has been no specific data about the existence, tissue distribution, phenotype and function of those cells that express insulin and other self-antigens in the human thymus. This study shows how, at different stages of life, the pancreatic β cell-specific antigens insulin, GAD and IA2 are expressed in the thymic medulla and the peripheral lymphatic tissue. This synthesis of restricted tissue-expressing antigens occurs in the presence of antigen-presenting cells, the function of which is to destroy those lymphocytes that autoreact against their own molecules selectively. An adverse change in any of the stages of this process could precipitate autoimmune disease against pancreatic β cells. Such being the case, the promotion of immunological tolerance to autoantigens could in theory prevent the development of type 1 diabetes.

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Can clinical factors estimate insulin resistance in type 1 diabetes? K V Williams, J R Erbey, D Becker, S Arslanian, T J Orchard. D/abetes2000; 49:626–32. BACKGROUND. This study used the clinical risk factors in adults with childhood onset type 1 diabetes for devising an insulin resistance score (IRS) using data from the prospective Epidemiology of Diabetes Complications (EDC) Study, which is a prospective trial for monitoring complications of patients who have suffered from type 1 diabetes since infancy. Blood pressure (BP) measurements, waist to hip ratios, triglyceride and high-density lipoprotein cholesterol levels and glycaemic control plus the presence or absence of a family background of type 2 diabetes were graded from 1 to S.The scores were used for obtaining a general rating. The validity of the IRS clinical scores was confirmed using hyperinsulinaemiceuglycaemic clamp studies. The results confirmed a significant inverse relationship between the IRS score and measured sensitivity to insulin, i.e. higher graded patients (with more clinical data suggestive of insulin resistance) had worse sensitivity to insulin as per the clamp evaluation.

Comment Insulin resistance is a fundamental factor in the aetiopathogenesis of type 2 diabetes, which is often associated with other clinical abnormalities that are part of the plurimetabolic syndrome. However, patients with type 1 diabetes are not exempt from presenting all or some of the symptoms typifying the insulin resistance syndrome. This study is valuable in that it defines a simple insulin resistance index that is obtained from basic, clinical and laboratory data. Thus, a high waist to hip ratio, high BP and a family history of type 2 DM plus high HbA1c point to probable insulin resistance in presenting patients. Multiple regression analysis allocated around 60% of insulin resistance to the aforementioned variables for the type 1 diabetic patient sample studied. Such a clinical scoring system may be helpful in targeting treatments aimed at insulin resistance, such as the thiazolidinediones, in combination with insulin in the treatment of type 1 diabetes. The IRS score will also be applied to the entire EDC population in future studies in order to determine the effect of insulin resistance on the risk of diabetic complications. Early expression of anti-insulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes L Yu, D T Robles, N Abiru, P Kaur, M Rewers, et al. Proc Natl Acad Sci USA 2000; 15:1701–6. BACKGROUND. The authors prospectively evaluated the development of insulin autoantibody in non-obese diabetic (NOD) mice (from 4 weeks of age) and children (from 7 to 10 months of age) at genetic risk for the development of type 1 diabetes using an insulin autoantibody assay performed in 96well filtration plates. The NOD mice had heterogeneous expression of insulin autoantibody despite being inbred. Insulin autoantibody reached a peak between 8 and 16 weeks and then declined. The insulin autoantibody expression by the NOD mice at 8 weeks of age was strongly associated with the early development of diabetes, which occurred at 16–18 weeks of age (83% (five out of six) of the NOD mice that were insulin autoantibody positive at 8 weeks were diabetic by 18 weeks versus 11% (1/9) of the NOD mice that were insulin autoantibody negative at 8 weeks) (P<0.01). In human subjects, insulin autoantibody was frequently present as early as 9 months of age, the first sampling time. Four out of the five children found to have persistent insulin autoantibody before 1 year of age have progressed to diabetes (all before 3.5 years of age) and the fifth is currently less than age 2 years. Only one out of the 929 children not expressing persistent insulin autoantibody before age 1 year has progressed to diabetes

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to date (age onset 3 years) and this child expressed insulin autoantibody at his second visit (age 1.1 years). The highest levels of insulin autoantibody in new onset patients correlated with an earlier age of diabetes onset. These data suggest that the programme for developing diabetes in NOD mice and humans is relatively ‘fixed’ early in life and, for NOD mice, a high risk of early development of diabetes is often determined by 8 weeks of age. With such early determination of a high risk of progression to diabetes, immunological therapies in humans may need to be tested in children before the development of insulin autoantibody for maximal efficacy.

Comment The prevention of type 1 DM is an important, unresolved challenge. A key element of any prevention programme is the accurate identification of subjects at high risk of developing type 1 diabetes in the future. Considerable advances have been made in risk stratification using genetic markers, islet cell antibody assays and the assessment of FPIRs in first-degree relatives of index patients |12|. Earlier studies have suggested that immunological markers are more strongly predictive of type 1 diabetes when present in high titres in young children, often under 5 years of age. This report compares the evolution of insulin autoantibody in an animal model of type 1 diabetes with samples taken from high-risk infants and emphasizes that insulin autoantibody is detectable after only a few weeks or months, respectively. In view of the parallel diabetes onset in NOD mice and children who develop diabetes in the very early stages of life, the NOD mouse model will probably be able to supply more information in the future about the natural history of type 1 diabetes. This information will be of importance in evaluating potential preventive interventions for type 1 diabetes. References 1.

2. 3.

4. 5. 6.

7.

8.

Yamada S, Nishigori H, Onda H, Utsugi T, Yanagawa T, Maruyama T, Onigata K, Nagashima K, Nagai R, Morikawa A, Takeuchi T, Takeda J. Identification of mutations in the hepatocyte nuclear factor (HNF-1α) gene in Japanese subjects with IDDM. Diabetes 1997; 46:1643–7. Tan K, MacKay Y, Zimmet P, Hawkins B, Lam K. Metabolic and immunologic features of Chinese patients with atypical diabetes mellitus. Diabetes Care 2000; 23:335–8. Karvonen M, Tuomilehto J, Libman 1, LaPorte R. A review of the recent epidemiological data on the worldwide incidence of type I (insulin-dependent) diabetes mellitus. World Health Organization DIAMOND Project Group. Diabetologia 1993; 36(10):883–92. Green A, Patterson CC Trends in the incidence of childhood-onset diabetes in Europe 1989–1998. Diabetologia 2001; 44(15):83–8. EURODIAB ACE Study Group. Variation and trends in incidence of childhood diabetes in Europe. Lancet 2000; 355:873–6. Tuomi T, Carlsson A, Li H, Isomaa B, Miettinen A, Nilsson A, Nissen M, Ehrnstrom BO, Forsen B, Snickars B, Lahti K, Forsblom C, Saloranta C, Taskinen MR, Groop LC. Clinical and genetic characteristics of type 2 diabetes with and without GAD antibodies. Diabetes 1999; 48:150–7. Turner R, Stratton 1, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R. UKPDS 25: autoantibodies to islet cytoplasm and glutamic acid decarboxylase for prediction of insulin requirements in type 2 diabetes. Lancet 1997; 350:1228–93. Kimpimaki T, Erkkola M, Korhonen S, Kupila A, Virtanen SM, Ilonen J, Simell O, Knip M. Short-term exclusive breastfeeding predisposes young children with increased genetic risk of type I diabetes to progressive beta-cell autoimmunity. Diabetologia 2001; 44(1):63–9.

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9.

10.

11.

12.

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Kostraba JN, Cruickshanks KJ, Lawler-Heavner J, Jobim LF, Rewers MJ, Gay EC, Chase HP, Klingensmith G, Hamman RF. Early exposure to cow’s milk and solid foods in infancy, genetic predisposition, and risk of IDDM. Diabetes 1993; 42(2):288–95. Norris JM, Beaty B, Klingensmith G, Yu Liping, Hoffman M, Chase HP, Erlich HA, Hamman RF, Eisenbarth GS, Rewers M. Lack of association between early exposure to cow’s milk protein and beta-cell autoimmunity. Diabetes Autoimmunity Study in the Young (DAISY). JAMA 1996; 276(8):609–14. Karjalainen J, Martin JM, Knip M, llonen J, Robinson BH, Savilahti E, Akerblom HK, Dosch HM. A bovine albumin peptide as a possible trigger of insulin-dependent diabetes mellitus. N Engl J Med 1992 Jul 30; 327(5): 302–7. Bingley PJ. Interactions ofage, islet cell antibodies, insulin autoantibodies, and first-phase insulin response in predicting risk of progression to IDDM in ICA+relatives: the ICARUS data set. Islet Cell Antibody Register Users Study. Diabetes 1996; 45(12):1720–8.

6 Chronic complications of diabetes and endothelial dysfunction

Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. N Engl J Med 2000; 342(6):381–9. BACKGROUND. Intensive therapy markedly reduces the risk of microvascular complications among patients with type 1 diabetes mellitus (DM) as compared with conventional therapy. In order to assess whether these benefits persist, the authors compared the effects of former intensive or conventionai therapy on the recurrence and severity of retinopathy and nephropathy 4 years after the end of the Diabetes Control and Complications Trial (DCCT). At the end of the DCCT, the patients in the conventional therapy group were offered intensive therapy and the care of all patients was transferred to their own physicians. Retinopathy was evaluated on the basis of centrally graded fundus photographs in 1208 patients during the fourth year after the DCCT ended and nephropathy was evaluated on the basis of urine specimens obtained from 1302 patients during the third or fourth year after the DCCT ended, approximately half of whom were from each treatment group. The difference in the median glycosylated haemoglobin HbA1c values of the conventional therapy and intensive therapy groups during the 6.5 years of the DCCT (means of 9.1 and 7.2%, respectively) narrowed during follow-up (medians during 4 years of 8.2 and 7.9%, respectively) (P<0.001). Nevertheless, the proportion of patients who had worsening retinopathy, including proliferative retinopathy, macular oedema and the need for laser therapy, was lower in the mtensive therapy group than in the conventional therapy group (odds reduction of 72–87%) (P<0.001). The proportion of patients with an increase in urinary albumin excretion (UAE) was significantly lower in the intensive therapy group. The reduction in the risk of progressive retinopathy and nephropathy resulting from intensive therapy in patients with type 1 diabetes persists for at least 4 years, despite increasing hyperglycaemia.

Comment These are the results of the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. This was a long-term observational study that was © Clinical Publishing Services Ltd

begun after the end of the DCCT. This hallmark, prospective, multicentre trial (average of 6.5 years of follow-up) showed that the development and progression of early microvascular complications of diabetes was substantially lower in an intensive therapy group than in a conventional therapy group |1|. One of the

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Fig. 6.1 Cumulative incidence of the progression of retinopathy, microalbuminuria and albuminuria in the former intensive therapy group compared with the former conventional therapy group of the DCCT. Source: The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group (2000).

objectives of the EDIC trial was to compare the long-term effects of the intensive or conventional therapy provided during the DCCT on the development of more advanced retinal and renal complications of diabetes. Very interestingly, the authors found that, 4 years after the DCCT, although the two treatment groups subsequently received similar care and their HbA1c levels converged, the progression of retinopathy, microalbuminuria and albuminuria was significantly reduced in the former intensive therapy group as compared with the former conventional therapy group (Fig. 6.1). Moreover, the likelihood of progressive retinopathy in both groups was strongly associated with the mean HbA1c level during the DCCT and the EDIC studies combined. These results are in accordance with the Stockholm Diabetes Intervention Study |2|, where the prevalence of severe retinopathy after 7.5 years of follow-up was related to the mean HbA1c level during the first 5 years of follow-up. In addition, the DCCT demonstrated that intensive therapy was more effective when introduced during the first 5 years of diabetes as primary prevention than when introduced as secondary intervention after complications had begun to develop |1| and the effects of any level of hyperglycaemia increased exponentially over time |3, 4|. Altogether, these data strongly support the idea that, in patients with type 1 diabetes, the implementation of intensive therapy should be started as early as is safely possible and should be maintained for as long as possible in order to reduce the risk of complications. The effect of previous coronary artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. The Bypass Angioplasty Revascularization Investigation. K M Detre, M S Lombardero, M M Brooks, R M Hardison, R Holubkov, et al. N Engl J Med 2000; 342(14):989–97. BACKGROUND. Acute myocardial infarction (Ml) in patients with diabetes is associated with high mortality. This study addressed whether previous revascularization by coronary artery bypass grafting (CABG) as compared with percutaneous transluminal coronary angioplasty (PTCA) influences the prognosis in such patients. All patients who were eligible for the Bypass Angioplasty Revascularization

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Investigation (BARI) who underwent coronary revascularization within 3 months after entry into the study were classified according to whether they had diabetes and whether they had undergone CABG. The protective effect of CABG with regard to mortality in the presence and absence of subsequent spontaneous Q-wave Ml was estimated with the use of Cox regression models. The cumulative 5-year rates of death were 20 and 8%, respectively, among the 641 patients with diabetes and the 2962 without diabetes (P<0.001) and the 5-year rates of spontaneous Q-wave Ml were 8 and 4%, respectively (P<0.001). CABG greatly reduced the risk of death after spontaneous Q-wave Ml in the patients with diabetes (relative risk =0.09). The corresponding relative risk of death among patients with diabetes who had undergone CABG but did not have spontaneous Q-wave Mls was 0.65. No protective effect of CABG was evident among the patients without diabetes. Previous coronary bypass surgery among patients with diabetes, as compared with coronary angioplasty, has a highly favourable influence on prognosis after acute Ml and a smaller beneficial effect among patients who do not have infarction.

Comment Diabetic patients are a high-risk group for cardiovascular morbidity and mortality, with poorer long-term outcomes with or without revascularization than non-diabetic patients. The results from the BARI trial, which is the largest randomized study of coronary revascularization strategies, showed that diabetic patients with multivessel coronary disease who were undergoing an initial revascularization procedure had a significant long-term survival advantage with CABG as compared with PTCA |5, 6|. The authors investigated possible explanations for the superiority of CABG as compared with PTCA. In the present report, the authors showed that, in partici pants in the BARI trial, CABG had a strong protective effect on survival in those patients with diabetes who had a spontaneous acute MI after revascularization, although it also moderately reduced mortality in diabetic patients who did not have anMI. Interestingly, the incidence of q-wave MI was similar in the two groups (CABG and PTCA). The better outcome during an acute ischaemic episode after CABG may have been due to the greater degree of myocardial jeopardy after PTCA as compared with CABG. It has been previously shown that PTCA leaves a greater proportion of the myocardium ischaemic than CABG. Patients from the BARI trial who underwent PTCA had a more ‘at-risk’ myocardium at 1 year than those who underwentCABG|7|. The benefit of CABG among patients with diabetes is probably due to a reduction in the degree of chronic ischaemia. An important limitation of this report was the lack of information about specific factors related to diabetes, such as the duration of the disease, metabolic control or treatment. Moreover, diabetes was defined as the use of insulin or oral hypoglycaemic medication at the time of entry into the study. Further studies without these limitations are warranted. In conclusion, the benefit of CABG in diabetic patients is significantly related to a protective effect on mortality in patients who suffer an MI during follow-up after the revascularization procedure. White coat hypertension in type 1 diabetic patients without nephropathy L Flores, M Recasens, R Gomis, E Esmatjes. Am J Hypertens 2000; 13:560–3. BACKGROUND. The aim of this study was to determine the prevalence of white coat hypertension (WCH) in type 1 diabetes patients. Ambulatory blood pressure (BP) monitoring and 24-hour UAE were determined in 47 patients with type 1 DM (27 with a new diagnosis of hypertension by office BP measurement and 20 with normotension). WCH was diagnosed in 20 patients (74%). Patients with WCH presented higher values of systolic BP (SBP) and diastolic BP (DBP) and UAE than normotensive

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patients. The results indicate that WCH is very frequent in type 1 DM. Thus, WCH may represent a potential risk for the development of diabetic complications, mainly diabetic nephropathy (DN).

Comment WCH is defmed as persistently elevated clinical BP with normal ambulatory BP. Estimates of the prevalence of WCH vary according to its definition and the population studied, but its prevalence is approximately 20% among mild hypertensives and increases with age |8|. Excluding a diagnosis of WCH is an indication for outpatient BP monitoring as recommended by international hypertension authorities |9|. This study revealed a higher prevalence of WCH of 75% in patients with type 1 DM than controls and supported the recommendation that outpatient BP monitoring be carried out on all patients with type 1 diabetes with raised clinical BP in order to avoid an unnecessary diagnosis and treatment of hypertension. A higher prevalence of WCH has also been reported in type 2 diabetes |10|. Several measures of target organ damage have been compared among normotensives, white coat hypertensives and sustained hypertensives, including left ventricular mass, microalbuminuria and carotid atherosclerosis. In general, target organ damage in WCH is less than that in sustained hypertension, but in some studies it has been found to be more prevalent than in normotensives. This study reported that patients with type 1 diabetes and WCH had higher BP and UAE levels as compared with those observed in the control group and further supported the doubts raised as to the benign nature of WCH. Further longitudinal studies are needed in order to determine whether patients with type 1 diabetes and WCH should be regarded as a group with a higher risk of developing hypertension and DN. Stabilization of diabetic retinopathy following simultaneous pancreas and kidney transplants I A Pearce, B llango, R A Sells, D Wong. Br J Ophthalmol2000; 84(7):736–40. BACKGROUND. Successful simultaneous kidney and pancreas transplants are associated with longterm normoglycaemic control and improved quality of life. However, debate still continues about the benefit to patients in terms of the stabilization or amelioration of diabetic retinopathy (DR). The progression of DR in a cohort of 20 transplant patients is reported. All patients were reviewed postoperatively with corrected visual acuity, slit lamp examination and fundal biomicroscopy. Pre-operative data were collected retrospectively and DR was considered unstable if there had been a drop in Snellen acuity greater than three lines or a need for laser photocoagulation or vitrectomy in the 2 years preoperatively. Twenty patients who received transplants between March 1983 and April 1994 were reviewed (mean age 35.1 years and mean duration of insulin-dependent diabetes mellitus (IDDM)=24.6 years). Seventeen patients still had functioning grafts at a mean follow-up of 5.1 years. Nine of these patients had unstable DR before transplantation. Of these, 89% had stabilized DR following transptantation with only a single case requiring laser photocoagulation. Of the eight patients that had stable DR before transplantation all had stable DR following transplantation. Forty-one percent of cases required cataract surgery during the follow-up period. Advanced DR is present in a high proportion of cases managed with

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Table 6.1 Retinopathy status following simultaneous pancreas and kidney transplants Post-transplant retinopathy status Pre-transplant retinopathy status Successful, SPK transplants Unstable eyes Stable eyes Unsuccessful, SPK transplants Unstable eyes Stable eyes

Stabilization (%)

Progression (%)

Regression (%)

94 (16/17) 100 (16/16)

6 (1/17) 0 (0/16)

0 (0/17) 0 (0/16)

50 (2/4) 100 (2/2)

50 (2/4) 0 (0/2)

0 (0/4) 0 (0/2)

Source: Pearce et al. (2000). simultaneous kidney and pancreas transplants as a consequence of the duration of IDDM and the presence of end-stage renal disease (ESRD). More than 90% of cases have stable DR following transplantation.

Comment Hitherto, vascularized pancreas transplantation has been the only treatment capable of ensuring rigorous long-term normoglycaemic control. Its positive effect on the development of nephropathy and somatic and autonomic polyneuropathy has been demonstrated in various studies. However, its effect on retinopathy is more controversial. The DCCT and a number of other trials have consistently shown that strict blood glucose control is associated with a worsening of retinopathy during the first year of improved control. In the case of transplants, cases of deterioration and stabilization and cases in which there were no differences from a control group without pancreas transplantation have been reported. This article evaluated retinopathy development retrospectively in 17 patients (33 eyes), all with simultaneous kidney and pancreas transplants, for a mean period of 5 years. One of the main problems when evaluating the effects of pancreas transplantation on the development of retinopathy is that many patients start the transplant programme with a severe degree of retinopathy, making it particularly difficult to discern lesion regression in such patients. In this review, 76% of the eyes had received pan-retinal laser photocoagulation before the transplant, 15% had received focal photocoagulation of the macula and 12% of eyes had undergone vitrectomy. Only eight of the eyes had light background retinopathy. The results can be examined in Table 6.1 in which 17 patients with two functioning grafts are compared with three patients in whom the pancreatic transplant had stopped working. Only one of the eyes with unstable retinopathy deteriorated and needed photocoagulation in the first year after transplantation, a period during which retinal deterioration tends to be observed; the patient must therefore be monitored closely over this period. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): a prospective observational study A Adler, I Stratton, A Neil, J Yudkin, D Matthews, et al. on behalf of the UK Prospective Diabetes Study Group.

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BMJ 2000; 321:412–19. BACKGROUND. This prospective observational study was undertaken in 23 hospital-based clinics in England, Scotland and Northern Ireland with 3642 patients who were included in analyses of relative risk. The primary pre-defined aggregate clinical outcomes were any complications or deaths related to diabetes and all-cause mortality. The secondary aggregate outcomes were Ml, stroke, lower extremity amputation and microvascular disease (predominantly retinal photocoagulation). The single end-points were non-fatal heart failure and cataract extraction. The risk reduction associated with a 10 mm Hg decrease in the updated mean SBP was adjusted for specific confounders. The incidence of clinical complications was significantly associated with SBP except for cataract extraction. Each 10 mmHg decrease in the updated mean SBP was associated with risk reductions of 12% for any complication related to diabetes, 15% for deaths related to diabetes, 11% for Ml and 13% for microvascular complications. No threshold of risk was observed for any end-point. The authors concluded that, in patients with type 2 diabetes, the risk of diabetic complications was strongly associated with raised BP.

Comment The main aim of this study was to identify the relationship between SBP and the risk of macrovascular and microvascular complications in type 2 DM patients. The United Kingdom Prospective Diabetes Study (UKPDS) assessed a total of 3642 of the 5102 patients who participated in it by logging their complete BP data plus possible confounding factors. This study obtained evidence of the effectiveness of BP reduction in lowering the risk of macrovascular and microvascular illness in DM patients. The implication is that such patients, even if subjected to a BP treatment combining three or more antihypertensives in order to obtain a better BP reduction, will derive improved clinical benefit from these measures. An important result of this trial is the lack of a threshold for any of the clinical end-points. Previous literature has raised concerns about a J-shaped curve in hypertension management in which it was suggested that excessive lowering of BP (below 85 mmHg DBP) could be associated with adverse cardiovascular outcomes. The UKPDS trial provided evidence against this theory, as did the Hypertension Optimal Therapy Trial, which found a significant benefit in lowering DBP from 90 to 80 mmHg in terms of cardiovascular outcomes |11|. Captopril-induced reduction of serum levels of transforming growth factor-β1 correlates with longterm renoprotection in insulin-dependent diabetic patients K Sharma, B Eltayeb, T McGowan, S Dunn, B Alzahabi, et al. Am J Kidney Dis 1999; 34:818–23. BACKGROUND. The Collaborative Study Group Captopril Trial demonstrated the renoprotective effect of captopril on the progression of DN. Because angiotensin II is known to stimulate the prosclerotic cytokine transforming growth factor-β (TGF-β), the authors postulated that the renoprotective effect may be due to inhibition of TGF-β1 production. TGF-β1 levels were measured at baseline and 6 months in the serum of patients in the captopril trial. Analysis was performed between the percentage change in their TGF-β1 levels during the first 6 months versus the percentage change in their glomerular filtration rates (GFRs) in the subsequent 2 years. The patients’ TGF-β1 levels increased by 11% in the placebo group (n=24), whereas there was a decrease of 14% in the captopril group (n=34). There was an inverse correlation between the percentage change in the TGF-β1 levels during the first 6 months and the percentage change in the GFRs over the ensuing 2-year period in patients from both the placebo (r=0.55 and P=0. 005) and captopril groups (r=0.45 and P=0.008). There was an even stronger correlation in the percentage change in the TGF-β1 levels and the percentage change in the GFRs in both the placebo (n=9, r=0.69 and P=0.03) and captopril groups (n=21, r=0.73 and P=0.0001) in

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patients with an initial GFR below 75 ml/min. Our data suggest that captopril decreases TGF-β1 levels in DN and that changes in TGF-β1 levels may predict the course of DN.

Comment Various studies have suggested that the renoprotective effect of the angiotensin-converting enzyme (ACE) inhibitors is independent of their haemodynamic effect on BP. This study suggested that ACE inhibitors have both a hypotensive effect and a renoprotective pathogenic mechanism. It established that the reduction in TGF-β1 achieved via angiotensin II (a potent stimulator of this cytokine) blocking using an ACE inhibitor (captopril) retards the progress of DN; these results further support the fundamental role of this cytokine in DN progression. Different risk factors for micro-angiopathy in patients with type 1 diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study B Karamanos, M Porta, M Songini, Z Metelko, Z Kerenyi, et al. and the EURODIAB IDDM Complications Study Group. Diabetologia 2000; 43:348–55. BACKGROUND. In order to identify the factors associated with early development of and late protection from microvascular complications in subjects with type 1 DM, the frequency of microvascular complications and their relation to risk factors were studied in 300 type 1 diabetic subjects with a short duration of disease (≤5 years) compared with 1062 subjects with a long duration of disease (≥14 years). The prevalence of microvascular disease was 25% in the short duration group, whereas in the long duration group 18% had no evidence of microvascular complications. The factors associated with the early development of complications in the short duration group were cigarette smoking and a family history of hypertension. Subjects free of microvascular complications in spite of a long duration of diabetes had better glycaemic control, lower BP, a better lipid profile and lower Von Willebrand factor levels. Cigarette smoking and genetic susceptibility to hypertension are important risk factors for microvascular complications in the early stages of type 1 diabetes. At a later stage, the additional risk factors are poorer glycaemic control, higher BP and an unfavourable lipid profile that is possibly associated with endothelial dysfunction.

Comment EURODIAB is a large multicentre trial involving European centres that is studying the epidemiology of microvascular and macrovascular diabetic complications. The EURODIAB group has previously reported the prevalence of microalbuminuria in 733 clinic-attending IDDM patients with a diabetes duration of 1–5 years in two large multicentre studies (the EURODIABIDDM Complications Study and the World Health Organization Multinational Study |12, 13|). The prevalence of microalbu-minuria in the EURODIAB arm was 18% (95% confidence interval (CI)=13–22%) and it was also apparent in those with diabetes for 1–5 years. Repeat testing suggested that it was more likely to be transient or reversible in this group. The EURODIAB researchers have also reported a cross-sectional study of 3250 type 1 diabetic patients in Europe with a mean duration of diabetes of 14.7 (SD±9.3) years. An albumin excretion rate of 20 Jlg/min or higher was found in 30.6% (95% CI =29.0–32.2%) of all patients and 19.3% (95% CI=15.6–23.0%) of those with diabetes for 1–5 years. The prevalence of retinopathy (46% in all patients and 82% after 20 or more years) was substantially lower than in comparable studies. Of all patients 5.9% (95% CI=5.1–6.7%) had postural hypotension, 19.3% (95% CI=17.9–20.7%) had abnormal heart rate variability, 32.2% (95%

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CI=30.6–33.8%) reported one or more severe hypoglycaemic attacks during the previous 12 months and 8. 6% (95% CI=7.6–9.6%) reported a hospital admission for ketosis over the same period. The microvascular and acute complications were clearly related to the duration of diabetes and to glycaemic control. However, the relation of glycaemic control to raised albuminuria differed qualitatively from its relation to retinopathy. In this study, the EURODIAB investigators extended their observations and reported the risk factors that contribute to the development of microvascular complications in those patients with short duration and longer duration type 1 diabetes. They confirmed their earlier observations that a significant minority of patients develop microvascular complications within 5 years of diagnosis. They also found that the precipitating risk factors include a family history of high BP, which is an untreatable risk factor, and smoking, which is however a modifiable risk factor. Strategies must therefore be devised for preventing smoking and encouraging diabetics to refrain from smoking. Approximately one in five patients suffering from diabetes for more than 14 years did not have microvascular complications. Their vascular protection was related in part to more exercise, better metabolic and lipid profiles, lower BP and less smoking. Long-term prevention of renal insufficiency, excess matrix gene expression and glomerular mesangial matrix expansion by treatment with monoclonal anti-transforming growth factor-β antibody in db/db diabetic mice F Ziyadeh, B Hoffman, D Cheol, M Iglesias, S Won, et al. Proc NatlAcad Sci USA 2000; 97:8015–20. BACKGROUND. In order to establish that over-activity of the renal TGF-β system mediates the functional and structural changes of the more advanced stages of nephropathy, the authors tested whether chronic administration of alphaT prevents renal insufficiency and glomerulosclerosis in the db/ db mouse. Diabetic db/db mice and non-diabetic db/m litter mates were treated intraperitoneally with 300 jog of alphaT or control IgG, three times per week for 8 weeks. Treatment with alphaT but not with IgG significantly decreased the plasma TGF-β1 concentration without decreasing the plasma glucose concentration. The IgG-treated db/db mice developed albuminuria, renal insufficiency and glomerular mesangial matrix expansion associated with increased renal mRNAs encoding alphal(IV) collagen and fibronectin. On the other hand, treatment with alphaT completely prevented the increase in plasma creatinine concentration, the decrease in urinary creatinine ciearance and the expansion of mesangial matrix in db/db mice. The increase in renal matrix mRNAs was substantially attenuated, but the excretion of urinary albumin factored for creatinine clearance was not significantiy affected by alphaT treatment. We conclude that chronic inhibition of the biologic actions of TGF-β with a neutralizing monoclonal antibody in db/db mice prevents the glomerulosclerosis and renal insufficiency resulting from type 2 diabetes.

Comment db/db rats are a genetic model for type 2 DM. Functional and structural changes in the kidneys of these rats resemble the changes observed in human DN, making this animal the ideal DN test subject. Much current evidence suggests that the hypertrophic and sclerosing effects of hyperglycaemia on the mesangial cell matrix are indices for autocrine production and activation of TGF-β1 Thus, any agent modifying TGF-β1 production will have a positive renal action. In this study, a monoclonal antibody was used for selectively neutralizing TGF-βl and inhibition of this cytokine was shown to prevent the changes typical of the diabetic renal lesion. However, further research is required in order to confirm whether this form of additional therapy is effective in preventing the development and progression of DN in humans.

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Screening techniques for identifying people at high risk of diabetic foot ulceration: a prospective multicenter trial H Pham, D G Armstrong, C Harvey, L B Harkless, J M Giurini, et al. Diabetes Care 2000; 23:606–11. BACKGROUND. A multicentre prospective follow-up study was conducted in order to determine which risk factors in foot screening have a high association with the development of foot ulceration. A total of 248 patients from three large diabetic foot centres were enrolled in a prospective study. Foot ulcers developed in 95 feet (19%) or 73 patients (29%) during the study. Patients who developed foot ulcers were more frequently men, had diabetes for a longer duration, had non-palpable pedal pulses, had reduced joint mobility, had a high neuropathy disability score (NDS), had a high vibration perception threshold (VPT) and had an inability to feel a 5.07 Semmes-Weinstein monofilament (SWM). Clinical examination and a 5.07 SWF test are the two most sensitive tests in identifying patients at risk of foot ulceration, particularly when the tests are used in conjunction with each other. VPT measurements are also helpful and can be used as an alternative. Finally, foot pressure measurements offer a substantially higher specificity and can be used as a post-screening test in conjunction with providing appropriate footwear.

Comment Foot ulceration in patients with diabetes is a major complication that is partly caused by somatic motor, sensory and autonomic neuropathy (AN) and peripheral vasculopathy |14|. Socioeconomic factors also play an important role since ulceration is more common in older men from lower socioeconomic classes. In many instances it is an avoidable complication and is responsible for both increased morbidity and mortality and the costs generated by diabetes |15|. Highly sensitive screening techniques for detecting patients at risk and, thus, facilitating the devising of basic preventive strategies such as foot hygiene standards, toenail care, soft shoes and appropriate hosiery can lower the incidence of ulceration. This multicentre study concentrating on a large number of patients evaluated the effectiveness of techniques for investigating neuropathy and vasculopathy. It showed that physical examination plus evaluation of knee jerk and Achilles reflexes and sensitivity to vibration, pain and touch and NDS determination are considered to be the most sensitive techniques. This along with 5.07 SWM sensitivity can detect up to 99% of patients who will develop foot ulcers. This observation confirmed earlier reports of the effectiveness of monofilaments as a screening tool for identifying the ‘at-risk’ diabetic foot |16, 17|. Comparison of the progression of macrovascular diseases after kidney transplantation or pancreas and kidney transplantation in diabetic patients with end-stage renal disease G Biesenbach, R Margreiter, A Konigsrainer, C Bosmuller, 0 Janko, et al. Diabetologia 2000; 43:231–4. BACKGROUND. The progression of cerebrovascular disease (CVD), coronary heart disease (CHD) and peripheral vascular disease (PVD) in uraemic patients with type 1 (insulin-dependent) DIVI who had simultaneous pancreas-kidney transplantation (n=11) was compared with that of the recipients of a kidney transplant alone (n=10). The mean values of HbAlc (5.8 versus 7.5%) (P<0.001) and serum triglycerides (1.2 versus 2.0 mmol/l) (P<0.05) were significantly lower in the patients with pancreaskidney transplantation than in the patient group with kidney transplant alone. The serum cholesterol concentrations and BPs were similar in both cohorts. From these results the authors concluded that pancreas-kidney transplantation reduced the risk factors for the development of macro-angiopathy, but

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failed to halt the progression of similar macrovascular diseases in type 1 diabetic patients with kidney transplant alone.

Comment Simultaneous pancreas and kidney transplantation has a proven ability in achieving strict normalization of blood glucose, an improved quality of life, lower mortality and the stabilization of complications such as retinopathy, somatic neuropathy and AN and nephropathy. However, these patients continue to present a high incidence of amputations. This study shows that, although the pancreas is capable of reducing a known macro-angiopathy risk factor, the hyperglycaemia and progressive vasculopathy of these patients were no different from kidney-only transplant patients. Progression of CVD and CHD was observed in four patients (36%) and progression of PVD was observed in five subjects (45%) during 2 years of follow-up in the group with simultaneous pancreas-kidney transplantation. In the cohort with a kidney transplant alone four patients (40%) showed progression of CVD and CHD and five patients (50%) showed progression of PVD; the difference was not significant. This progression is presumed to be partially attributable to the effect of immuno-suppressive drugs. In this study, data were collected from patients administered cyclosporin and prednisone, which are drugs that are known to affect lipids and BP control adversely. In addition, transplantation was undertaken in patients who had already developed extensive vascular disease and it is possible that greater benefits may be seen if combined pancreas-kidney transplantation could be undertaken at an earlier stage of type 1 diabetes. Another suspected factor is the part played by endocrine pancreatic secretion drainage on systemic blood. Elimination of insulin hepatic extraction causes high blood insulin levels and this may engender insulin resistance and its allied adverse effects. It is probable that, as this study focuses on low-density lipoprotein cholesterol values instead of total cholesterol plus BP monitoring, it may establish whether the macro-angiopathy suffered by these patients actually continues to deteriorate despite normalization of the cardiovascular risk factors. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): a prospective observational study I M Stratton, A I Adler, H A Neil, D R Matthews, S E Manley, et al. BMJ 2000; 321(7258):405–12. BACKGROUND. The aim of this study was to determine the relation between exposure to glycaemia over time and the risk of macrovascular or microvascular complications in patients with type 2 diabetes. Each 1% reduction in the updated mean HbA1c was associated with reductions in risk of 21% for any end-point related to diabetes (P<0.0001), 21% for deaths related to diabetes (P<0.0001), 14% for Ml (P<0.0001) and 37% for microvascular complications (P<0.0001). No threshold of risk was observed for any end-point. The risk of diabetic complications was strongly associated with previous hyperglycaemia in patients with type 2 diabetes. Any reduction in HbA1c is likely to reduce the risk of complications, with the lowest risk being in those with HbA1c values in the normal range (<6.0%).

Comment This study aimed to determine the relationship between exposure to hyperglycaemia and the development of macrovascular and microvascular complications rela tive to the results of the UKPDS by involving stringent control of blood glucose in type 2 diabetes patients via a prospective study.

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It is claimed that these results can be used for determining the risk reduction associated with a 1% reduction in HbA1c subject to adjustment for possible confounding factors. It was a good study as it was randomized, it analysed a significant sample of 3642 patients, it involved a 20-year follow-up period and it took confounding factors into account. The incidence of each complication was determined for each of the different predetermined HbA1c intervals (<6%, 6–7%, 7–8%, 8–9%, 9–10% and>10%). The research showed that every 1% reduction in HbAlc is associated with a 37% reduction in the risk of developing microvascular complications and a 21% reduction in the risk of any DM-related end-point or death. The most important conclusions and new information drawn from this study are as follows. 1. A direct relationship exists between the risk of complications and hyperglycaemia. 2. There are no observable blood glucose thresholds from which a significant change in risk per clinical event or type of complication occurs. 3. The lower the blood glucose the lower the risk of complications. 4. The increased risk index for microvascular disease through hyperglycaemia is higher than for macrovascular disease. In short, although patients with worse glycaemic control are likely to benefit most from improved control with respect to the development of diabetic complications, the data suggest that any improvement in glycaemia control lowers the risk of complications. The results of the study notwithstanding, the riskbenefit in clinical practice must be evaluated for each patient (age, quality of life, etc.) before adding or starting new medication and/or insulin in order to achieve minimal improvements in blood sugar control. Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion S O’Byrne, P Forte, L J Roberts, J D Morrow, A Johnston, et al. Diabetes 2000; 49(5):857–62. BACKGROUND. The authors measured nitric oxide (NO) and isoprostane (a stable marker of in vivo lipid peroxidation) production in thirteen type 1 diabetic subjects with normal UAE and thirteen healthy volunteers. Whole body NO synthesis was quantified by measuring the urinary excretion of 15N-nitrate after the intravenous administration ofL-[15N]2-arginine. The urinary

excretion of 2,3-dinor-5,6-dihydro-F2t-lsoP was quantified as a marker of in vivo lipid peroxidation. The whole body NO synthesis was significantly higher in diabetic subjects as compared with control subjects (342 versus 216 nmol of 15N-nitrate per millimole of creatinine) (P=0.005). There was no difference in 2,3-dinor-5,6-dihydro-F2t-lsoP excretion between the diabetic subjects and control subjects (44.8 versus 41.4 ng per millimole of creatinine). However, there was an inverse correlation between NO synthesis and free radical activity in subjects with diabetes (r=−0.62 and P=0.012). They concluded that whole body NO synthesis is higher in type 1 diabetic subjects with normal UAE than in control subjects. The inverse correlation between isoprostane production and NO synthesis in diabetic subjects is consistent with the hypothesis that NO is inactivated by reactive oxygen species.

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Comment The role of NO in the development of microvascular complications in DM is still a matterofdebate. The divergent results published by some authors very probably derive from the different methods used for examining the release of NO or its vasodilating effect, as well as from differences in the characteristics of the DM patients studied. Aided by a more stable, sensitive isotope method, these authors pointed to increased longterm (>20 years) NO production in type 1 diabetic patients despite the maintenance of normal albumin excretion levels in comparison to a control group correctly matched for confounding variables. The authors did however acknowledge that this method cannot identify the origins of the NO. They theorized that, by behaving like anti-oxidants, the high levels of NO observed in these patients may protect them against the development of microalbuminuria and counter the higher free radical levels evident in DM. Asymptomatic bacteriuria may be considered a complication in women with diabetes S E Geerlings, R P Stolk, M J Camps, P M Netten, J B Hoekstra, et al. Diabetes Care 2000; 23:744–9. BACKGROUND. In order to study the prevalence of and risk factors for asymptomatic bacteriuria in women with and without diabetes, a total of 636 non-pregnant women with diabetes (type 1 and type 2) who were 18–75 years of age and had no abnormalities of the urinary tract and 153 women without diabetes who were visiting the eye and trauma out-patient clinic (control subjects) were included. The prevalence of asymptomatic bacteriuria was 26% in the diabetic women and 6% in the control subjects (P<0.001). The prevalence of asymptomatic bacteriuria is increased in women with diabetes and might be added to the list of diabetic complications in these women. Table 6.2 Risk factors for women with type 1 diabetes Risk factors

ASB-

ASB+

n Age Duration of diabetes (years) Peripherai neuropathy (n=245) Microalbuminuria (n=197) Macroalbuminuria (n=197) HbA1c (%)

205 (79) 40.3+13.5 17.9±12.9

53 (21) 43.1±13.1 22.4±12.1

44 (23)

20 (40)

2.2

0.03

30 (20)

14 (30)

1.8

0.1

8(5)

7(16)

3.6

0.02

8.5±1.3

8.8±2.9

OR

p 0.2 0.02

0.3

The data are n values with percentages. In parentheses, means±SDs or odds ratios. Risk factors for asymptomatic bacteriuria in women with type 1 DM. The number of patients (n) is given when the variable concerned is not measured in all patients. Source: Geerlings et al. (2000). Table 6.3 Risk factors for women with type 2 diabetes Risk factors

ASB-

ASB+

n

268 (71)

110(29)

OR

p

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Risk factors

ASB-

ASB+

OR

p

Age 58.0±11.7 63.0±10.0 <0.001 Duration of diabetes 9.3±7.1 11.3±9.1 0.05 (years) Microalbuminuria 78 (46) 35 (52) 1.1 0.5 (n=231) Macroalbuminuria 10 (6) 11(15) 2.9 0.03 (n=231) UTIs during the 48 (18) 30(27) 1.9 0.02 previous year 29.9±6.2 28.3±4.8 0.96 0.04 BMI (kg/m2) 8.6±1.7 8.5±1.6 0.7 HbA1c (%) The data are n values with percentages. In parentheses, means±SDs or odds ratios. Risk factors for asymptomatic bateriuria in women with type 2 diabetes. Source: Geerlings et al. (2000).

Comment The study objective was to determine the prevalence of and risks factors associated with asymptomatic bacteriuria as experienced by women with and without DM. Method adequacy was ensured by the significant sample (636 women with DM) contrasted with a control group (153 non-diabetic women) and by the fact that it was a multicentre, double-blind study Eligible women produced urine samples at 2–4-month intervals for microbiological assessment so that their bacteriuria could be evaluated. The prevalence of asymptomatic bacteriuria was 26% in women with diabetes as compared to 6% in the control group. The prevalence of asymptomatic bacteriuria in women with type 1 diabetes was 21% as against 29% in women with type 2 diabetes. The risk factors associated with the presence of asymptomatic bacteriuria in type 1 or type 2 diabetes are summarized in Tables 6.2 and 6.3, respectively. The following comments are worth noting. 1. The risk factors in women with diabetes can be considered significant if the bacteriuria is present for the duration of the diabetes and complications such as macroalbuminuria, which is indicative of an external renal lesion rendering the patient vulnerable to bacterial infection and peripheral neuropathy are present. 2. Age was the most important risk factor in women with diabetes and in control subjects. The other risk factors in women with type 2 diabetes were microalbuminuria, a low body mass index and a urinary tract infection in the previous year. The second fmding is the most striking and is hardest to explain; it may even be coincidental (as it ceases to be regarded as a risk factor in multivariant analysis). Interestingly, HbA1c levels do not affect the chance of asymptomatic bacteriuria developing in women with diabetes. In conclusion, women with diabetes are more likely to have asymptomatic bacteriuria than non-diabetic women. Asymptomatic bacteriuria should be considered as a complication of diabetes. The authors postulated that the increased prevalence results from the urine leukocyte count being lower than in nondiabetic urine (through the lower cytokine content of the urine) and not to granulocyte dysfunction in diabetes as previously suggested |18|.

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There is no consensus about whether asymptomatic bacteriuria in diabetic women should be treated. Further studies are required in order to determine the merits of intervention with antibiotics. Ambulatory blood pressure, micro-albuminuria and autonomic neuropathy in adolescents with type 1 diabetes A R Lafferty, G A Werther, C F Clarke. Diabetes Care 2000; 23(4):533–8. BACKGROUND. The aim of this study was to examine the relationship between 24-hour BP measurements, UAE rates and autonomic neuropathy (AN) in adolescents with type 1 diabetes. A total of 31 patients with microalbuminuria, 20 patients with intermittent microalbuminuria and eleven patients with persistent microalbuminuria were identified from the diabetes clinics at two major Australian tertiary care paediatric hospitals. Two control groups were used; one consisted of 19 age-, sex- and diabetes duration-matched adolescents with normoalbuminuria and the other consisted of 46 age- and sex-matched non-diabetic control subjects. A medical history and physical examination were followed by a series of non-invasive tests of cardiovascular and pupillary autonomic function and then by 24-hour

ambulatory BP (ABP) monitoring. The ABP monitoring showed an incremental increase in all BP parameters in the non-diabetic control subjects through to diabetic subjects with normoalbuminuria. A parallel incremental increase in diurnal and nocturnal ambulatory heart rates was also evident. Subjects with microalbuminuria had significantly reduced pupillary adaptation to darkness compared with nondiabetic subjects and subjects with normoalbuminuria. The above results paralleled an incremental increase in HbA1c levels in adolescents with type 1 diabetes from subjects with normoalbuminuria to subjects with persistent microalbuminuria.

Comment The aim of this study was to establish the relationship between BP, the UAE index and AN in adolescents with type 1 diabetes. Persistent microalbuminuria in type 1 diabetes is associated with raised ABP as compared with control subjects, although which is the primary abnormality remains unclear. The novel aspects of this study include the fact that the ABP registered high diurnal, nocturnal and diastolic BPs in diabetic adolescents at the stage of intermittent microalbuminuriabefore the development of persistent microalbuminuria. In addition, patients with intermittent microalbuminuria also showed early subclinical signs of AN as indicated by slower pupil accommodation to darkness as compared to those of non-diabetics and these were significant. Neither the difference in BP nor the autonomic dysfunction findings have been described previously in type 1 diabetic adolescents with intermittent micro-albuminuria. Another distinctive discovery is the direct correlation between HbA1c and the UAE index, suggesting that DN risk rises with steadily diminishing blood glucose control. The study also confirms that intermittent microalbuminuria marks a different (very early) stage in the advancement of DN. It does not result merely from acute deterioration in blood glucose control, nor is it induced by physical exercise. The authors postulated that poor blood glucose control may predispose a patient to develop microalbuminuria and AN. Interaction between these conditions may accelerate their progression with the dysregulation of 24-hour BP being an important contributory factor. Further studies are required if an

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understanding of the nature of the interaction between BP and autonomic nervous system dysfunction is to be obtained. In summary this study demonstrates that 24-hour BP values are higher and that the subclinical signs of AN are present before persistent micro-albuminuria develops. This may have important implications in timing the introduction of treatments that are designed for preventing or retarding the microvascular complications of type 1 diabetes in adolescents. This could be extremely helpful in identifying patients with incipient diabetic nephropathy and adopting countermeasures such as ACE inhibitors or another appropriate treatment. References 1.

2. 3.

4.

5.

6.

7.

8. 9. 10. 11.

12. 13.

The Diabetes Control and Complications Trial Research Group. The effects of intensive therapy of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med 1993; 329:977–86. Reichard P. Are there any glycemic thresholds for the serious microvascular complications? J Diabetes Complicat 1995; 9:25–30. The Diabetes Control and Complications Trial Research Group. The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the Diabetes Control and Complications Trial. Diabetes 1995; 44:968–83. The Diabetes Control and Complications Trial Research Group. The absence of glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes 1996; 45:1289–98. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. N Engl J Med 1996; 335:217–25. (Erratum: N Engl J Med 1997; 336:147.) The Bypass Angioplasty Revascularization Investigation. Influence of diabetes on 5-year mortality and morbidity in a randomized trial comparing CABG and PTCA in patients with multivessel disease. Circulation 1997; 96: 1761–9. Whitlow PL, Dimas AP, Bashore TM, Califf RM, Bourassa MG, Chaitman BR, Rosen AD, Kip KE, Stadius ML, Alderman EL. Relationship of extent of revascularization with angina at one year in the Bypass Angioplasty Revascularization Investigation (BARI). J Am Coll Cardiol 1999; 34:1750–9. Pickering TG, Coats A, Mallion JM, Mancia G, Verdecchia P. Blood Pressure Monitoring. Task force V: whitecoat hypertension. Blood Pressure Monit 1999; 4(6): 333–41. Ramsay LE, Williams B, Johnston GD, MacGregor GA, Poston L, Potter JF, Poulter N, Russel G. British Hypertension Society guidelines for hypertension management 1999: summary. BMJ 1999; 319:630–5. Nielsen FS, Gaede P, Vedel P, Pedersen O, Parving HH. White coat hypertension in NIDDM patients with and without incipient and overt diabetic nephropathy. Diabetes Care 1997; 20(5): 859–63. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998; 351(9118):1755–62. EURODIAB IDDM Complications Study. Microvascular and acute complications in IDDM patients. Diabetologia 1994; 37(3):278–85. Stephenson JM, Fuller JH. Microalbuminuria is not rare before 5 years of IDDM. EURODIAB IDDM Complications Study Group and the WHO Multinational Study of Vascular Disease in Diabetes Study Group. J Diabetes Complicat 1994; 8(3):166–73.

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15. 16.

17. 18.

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McNeely MJ, Boyko EJ, Ahroni JH, Stensel VL, Reiber GE, Smith DG, Pecoraro RK The independent contributions of diabetic neuropathy and vasculopathy in foot ulceration: how great are the risks? Diabetes Care 1995; 18:216–19. Ramsey SD, Newton K, Blough D, McCulloch DK, Sandhu N, Reiber GE, Wagner EH. Incidence, outcomes and costs of foot ulcers in patients with diabetes. Diabetes Care 1999; 22:383–6. Kumar S, Fernando DJ, Veves A, Knowles EA, Young MJ, Boulton AJ. Semmes-Weinstein monofilaments: a simple, effective and inexpensive screening device for identifying diabetic patients at risk of foot ulceration. Diabetes Res Clin Pract 1991; 13(1–2):63–7. Mueller MJ. Identifying patients with diabetes mellitus who are at risk for lower-extremity complications: use of Semmes-Weinstein monofilaments. Phys Ther 1996; 76(1):68– 71. Proceedings from the 39th Interscience Conference of Antimicrobial Agents and Chemotherapy. San Francisco, CA, 1999, p. 388.

7 Management of diabetes mellitus

Intervention study for smoking cessation in diabetic patients N Canga, J De Irala, E Vara, M Duaso, A Ferrer, et al. Diabetes Care 2000; 23:1455–60. BACKGROUND. In order to evaluate the effectiveness of a nurse-managed smoking cessation intervention in diabetic patients, this controlled clinical trial involved 280 diabetic smokers who were randomized into either control (n=133) or intervention (n=147) groups. The intervention consisted of a 40-minute nurse visit that included counselling, education and contracting information (a negotiated cessation date). The control group received the usual care for diabetic smokers. At the 6-month followup, the smoking cessation incidence was 17.0% in the intervention group as compared with 2.3% in the usual care group, which was a 14.7% difference (95% confidence interval (Cl)=8.2–21.3%).

Comment Much clinical and epidemiological evidence is available for showing the link between tobacco consumption and the early development of macro- and microvascular complications of diabetes mellitus (DM). Smoking cessation has considerable health benefits. Health care professionals frequently advise patients to improve their health by ceasing to smoke. Such advice may be brief or part of more intensive interventions. A recent systematic review of the Cochrane Database of controlled trials evaluated randomized trials of smoking cessation advice from a medical practitioner in which abstinence was assessed at least 6 months after advice was first provided |1|. Thirty-four trials, which were conducted between 1972 and 1999, including over 27 000 smokers were included. In some trials, subjects were at risk of specified diseases (chest disease, diabetes and ischaemic heart disease), but most were from unselected populations. The most common setting for the delivery of advice was primary care. Other settings included hospital wards, outpatient clinics and industrial clinics. Pooled data from 16 trials of brief advice versus no advice (or usual care) revealed a small but significant increase in the odds of ceasing (odds ratio (OR)=1.69 and © Clinical Publishing Services Ltd

95% CI=1.45–1.98) equating to an absolute difference in the cessation rate of approximately 2.5%. Direct comparison of intensive versus minimal advice showed a small advantage of intensive advice (OR=1.44 and 95% CI=1.23–1.68). The review concluded that simple advice had only a small effect on cessation rates.

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Additional manoeuvres appeared to have only a small effect, though more intensive interventions were more effective than minimal interventions. Various authors have published widely varying percentage success rates for anti-smoking treatment, depending on the measures adopted. However, the results obtained improved when the patient was included in a treatment programme that included psychological support, drug treatment for nicotine dependency and monitoring the patient whilst they were trying to give up the habit |2|. These authors showed the results obtained for 280 diabetic smokers on an anti-smoking programme comparing an intervention programme using a nurse-led coun-selling service with appropriate support and follow-up with standard management. This study included follow-up visits, telephone and mail contact and checking that the reported tobacco consumption (nicotine) abandonment had in fact taken place by verification with urinary cotinine measurements. During the 6-month monitoring, the success rate was 17% in the intervention group and 2.3% in the other group, confirming the efficacy of a structured intervention programme on tobacco cessation by diabetic patients. It will be important to verify that this benefit is maintained during longer-term follow-up and that the approach can be implemented in other clinics with similar success. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus M Chandalia, A Garg, D Lutjohann, K Von Bergmann, S M Grundy, et al. N Engl J Med 2000; 342(19):1392–8. BACKGROUND. The effect of increasing the intake of dietary fibre on glycaemic control in patients with type 2 DM is controversial. In a randomized, cross-over study, thirteen patients with type 2 diabetes were assigned to follow two diets for 6 weeks each: a diet containing moderate amounts of fibre (total 24 g with 8 g of soluble fibre and 16 g of insoluble fibre), as recommended by the American Diabetes Association (ADA) and a high-fibre diet (total 50 g with 25 g of soluble fibre and 25 g of insoluble fibre) containing foods not fortified with fibre. Both diets, which were prepared in a research kitchen, had the same macronutrient and energy contents. The effects of the two diets on glycaemic control and plasma lipid concentrations were studied. Compliance with the diets was excellent. During the sixth week, the high-fibre diets’ mean daily pre-prandial plasma glucose concentrations were 13 mg/dl (0.7 mmol/l) lower (P=0.04) and mean daily urinary glucose excretion was 1.3 g lower (P=0.008) as compared with the sixth week of the ADA diet. The high-fibre diet also lowered the area under the curve (AUC) for 24-hour

plasma glucose and insulin concentrations by 10% (P=0.02) and 12% (P=0.05), respectively. The highfibre diet reduced the patients’ plasma total cholesterol by 6.7% (P=0.02), triglyceride (TG) concentrations by 10.2% (P= 0.02) and very low-density lipoprotein (VLDL) cholesterol by 12.5% (P=0. 01). A high intake of dietary fibre, particularly of the soluble type, above the level recommended by the ADA, improves glycaemic control, decreases hyperinsulinaemia and lowers plasma lipid concentrations in patients with type 2 diabetes.

Comment This excellently designed study was aimed at determining the effects of increasing dietary fibre intake through the consumption of foods not fortified with fibre on glycaemic control and plasma lipids. The crossover design, the 6-week treatment period, the identical macronutrient composition of the two diets and the

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isocaloric content ensured an adequate comparison between the two interventions used: the ADA diet (with 24 g of total fibre per day), following ADA guidelines and a highfibre diet (50 g fibre with 50% soluble fibre and 50% insoluble fibre). Despite the low number of participants (n=13), the investigators showed that a high-fibre diet improves glycaemic control and plasma lipid levels. It also demonstrated the feasibility of increasing dietary fibre intake through the consumption of unfortified foods. The authors concluded that dietary guidelines for patients with diabetes should emphasize an overall increase in dietary fibre though the consumption of unfortified foods. Low cardiorespiratory fitness and physical inactivity as predictors of mortality in men with type 2 diabetes M Wei, LWGibbons, J B Kampert, M Z Nichaman, SN Blair. Ann Intern Med 2000; 132:605–11. BACKGROUND. In order to evaluate the association of low cardiorespiratory fitness and physical inactivity with mortality in men with type 2 diabetes the authors studied 1263 men (50±10 years of age) with type 2 diabetes who received a thorough medical examination between 1970 and 1993 and were followed for mortality up to 31 December 1994. Cardiorespiratory fitness was measured by a maximal exercise test, self-reported physical inactivity at baseline and subsequent death as determined by using the National Death Index. One hundred and eighty patients died during an average follow-up of 12 years. After adjustment for age, baseline cardiovascular disease (CVD), their fasting plasma glucose (FPG) level, their high cholesterol level, being overweight, current smoking, high BP and parental history of CVD, the men in the low-fitness group had an adjusted risk for all-cause mortality of 2.1 as compared with fit men. Men who reported being physically inactive had an adjusted risk for mortality that was 1.7-fold higher than that in men who reported being physically active. Low cardiorespiratory fitness and physical

inactivity are independent predictors of all-cause mortality in men with type 2 diabetes.

Comment A number of studies have highlighted the benefits of moderate exercise in terms of the primary prevention of type 2 diabetes. In a population-based sample of 897 middle-aged Finnish men, after adjustment for age, baseline glucose values, body mass index (BMI), serum TG levels, parental history of diabetes and alcohol consumption, moderately intense physical activities (≥5.5 metabolic units) undertaken for at least 40 min per week were associated with a reduced risk of type 2 diabetes (OR=0.44 and 95% CI=0.22–0.88) |3|. Similar evidence has been reported from the Nurses Health Study in America showing that regular moderate exercise was associated with a reduced risk of type 2 diabetes |4|. This well-conducted epidemiological study extended the observations regarding the effect of a lack of exercise and poor physicial fitness and showed that, after correction for multiple confounding factors, low fitness remains an independent risk factor for CVD in type 2 diabetes. Similar data have been reported previously in different populations. Data from a prospective study of 8715 men (average age 42 years) followed for an average of 8.2 years (range 1–15 years) were reported in 1992 |5|. Their age-adjusted death rates increased with higher levels of fasting blood glucose (FBG). Regardless of glycaemic status, fit men had lower age-adjusted, all-cause death rates than their less fit counterparts. For men with FBG ≥7.8 mM or physician-diagnosed type 2 diabetes, the age-adjusted death rates per 10 000 person years of follow-up in unfit and fit subjects were 82.5 and 45.9, respectively. The age-adjusted relative risk (RR) of death due to

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all causes was significantly elevated in the lower fitness group within each of three glycaemic status levels: FBG<6.4 mM (RR=1.93 and 95% CI=1.15–3.26), FBG 6.4–7.8 mM (RR=3.42 and 95% CI= 2.27–5.15) and FBG≥7.8 mM or with NIDDM (RR=1.80 and 95% CI=1.25– 2.58). Multivariate analyses controlling for the risk factors of mortality (age, resting systolic BP, serum cholesterol, BMI, family history of heart disease, follow-up interval and smoking habit) showed a higher risk of death due to all causes for unfit men compared with fit men. In summary, low cardiorespiratory fitness and physical inactivity are independent predictors of all-cause mortality in men with type 2 diabetes. Such patients should be encouraged to take regular moderate exercise for 40 min or more per week in order to obtain significant health benefit. Newer portable glucose meters: analytical improvement compared with previous generation devices? R Weitgasser, B Gappamyer, M Pichler. Clin Chem 1999; 45(10):1821–5. BACKGROUND. Newer glucose meters are easier to use, but direct comparisons with older instruments are lacking. The authors compared the analytical performances of four new and four previous generation meters. On average, 248 glucose measurements were performed with two instruments of each brand of meter on capillary blood samples from diabetic patients attending out-patient clinics. Two to three different lots of strips were used. All measurements were performed by one experienced technician using blood from the same sample for the meters and the comparison method (Beckman Analyser 2). The results were evaluated by analysis of clinical relevance using the percentage of values within a maximum deviation of 5% from the reference value by the methods of residuals, error grid analysis and the coefficients of variance for measurements in series. Altogether, 1987 blood glucose values were obtained with the meters as compared with the reference values. The newer devices gave more accurate results without significant differences within the group by error grid analysis (zone A, 98– 98. 5%). Except for the One Touch II (zone A, 98.5%), the other older devices were less exact (zone A, 87– 92.5%), which was also true for all other evaluation procedures. New generation blood glucose meters are not only smaller and more aesthetically appealing, but are more accurate compared with previous generation devices except the One Touch II. The performance of the newer meters improved but did not meet the goals of the latest ADA recommendations in the hands of an experienced operator.

Comment Patient self-monitoring is fundamental to the intensive treatment of type 1 and type 2 DM. The ability for making appropriate changes to food, exercise and insulin dosage regimes depends largely on a patient’s ability for interpreting their capillary blood sugars. This can only be done properly if the blood sugar readings analysed are reliable. It is pleasing to see the results of this comparative study, which focuses attention not only on the ease of handling but also the greater accuracy of new generation capillary blood sugar meters (Glucocard, Glucometer Esprit, Glucotouch and Glucotrend) by comparing them with those of the previous generation (Accutrend, Companion 2, Glucometer 3 and One Touch II). The reliability of One Touch II and the reliabilities of the new generation were found to be much the same. The results are based on the percentages of blood sugars differing from reference values by less than 5% and the values range between 49 and 57% for new generation meters as opposed to 32.5-50% for older generation meters. Hopefully, within the next few years technical advances will ensure greater reliability that, in turn, will mean achievement of improved control.

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Continuous glucose monitoring used for adjusting diabetes therapy improves glycosylated haemoglobin: a pilot study B W Bode, T M Gross, K R Thornton, J J Mastrotaro. Diabetes Res Clin Pract 1999; 46:183–90. BACKGROUND. A 5-week pilot study was conducted in order to determine whether continuous glucose monitoring could be used for improving glycaemic control. A total of nine subjects with type 1 diabetes and glycosylated haemoglobin (HbA1c) values greater than 8.5% completed the study. The subjects wore a continuous glucose monitor for two 1-week periods during the study. After each sensor use, changes were made to the subjects’ diet, insulin dosage and self-monitoring of blood glucose schedule. The subjects’ HbA1c decreased from 9.9% at baseline to 8.8% at 5 weeks after baseline (P=0. 0006), but their daily insulin usage was unchanged over the same period of time (P=0.428). The glucose sensors performed accurately, with a median correlation of 0.92 and a mean absolute difference of 19. 1%. The continuous glucose profiles allowed identification of glucose patterns and excursions that helped direct changes in therapy. These treatment changes would not have been made on the basis of meter data alone and were effective in improving glucose control. Additional studies are needed in order to validate these findings. This pilot study highlights the potential for continuous glucose monitoring in providing the valuable information necessary for making therapy adjustments that can dramatically improve patients’ glycaemic control and reduce the risk of long-term complications.

Comment Practical medical results can allow nobody to doubt the importance to diabetic patients of good metabolic control. New techniques, including amperometric implantable glucose-sensing electrodes, interstitial fluid microdialysis and intophoresis, are providing clincians with new information about glycaemic control that should allow more accurate adjustment of treatment regimens in patients with diabetes. By introducing a new ‘adaptability’ element into the treatment for diabetic patients, this pilot study has achieved positive results in the degree of metabolic control exercised by using continuous glucose monitoring technology in establishing the precise nature of blood sugar excursions throughout the day. These meters allow the patient to check their blood sugar readings every 5 min (this blood glucose value is the average of readings taken at 10-second intervals) during the period in question. The study points out that the treatment was modified, not in terms of the overall doses of insulin administered, but in order to ensure more effective insulin distribution throughout the day and better matching of insulin to diet and exercise, thanks to the (greater) glucose profile awareness achieved by this new technology. Limitations of glycosylated haemoglobin as an index of glucose intolerance C Snehalatha, A Ramachandran, K Satyavani, V Vijay. Diabetes Res Clin Pract 2000; 47(2):129–33. BACKGROUND. This study was conducted in order to establish a normal cut-off value for glycosylated haemoglobin measured as HbA1c in South Indian subjects and in order to evaluate its usefulness in demarcating different categories of glucose intolerance. HbA1c measurement was carried out in 1261 cases with no known history of diabetes while being tested by an oral glucose toterance test (OGTT) (male:female ratio 850:411 and mean age 40±12 years). Only a small percentage of the variance in HbA1c in the normal glucose tolerance (NGT) group was explained by FPG with more than 35% of the variance in HbA1c being unexplained by plasma glucose. HbA1c values of≥6.0% gave a reasonably high sensitivity and specificity for diagnosis using the World Health Organization (WHO) or ADA

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criteria. Wide interindividual variations even in the normoglycaemic range make the test unsuitable for diagnostic purposes.

Comment The aim of this study was to establish the normal cut-off value for glycosylated haemoglobin measured as HbA1c and to evaluate its usefulness as a marker for different glucose intolerance categories. The method involved performing the OGTT on a sample of 1261 patients with no known history of diabetes (non-DM) over a 6-month period. One problem was that the sample selected had a certain bias, given that all had a marked family history of DM or other DM-important risk factors resulting in a high DM prevalence. Based on the results obtained, the cases studied were classified as NGT, impaired glucose tolerance (IGT) and DM in line with WHO criteria. The results indicate a gradual significant increase in HbA1c for the three glucose tolerance categories (Fig. 7.1). Only a small percentage of the HbA1c variations in the NGT group is explicable in terms of basal blood glucose values. The authors concluded that an HbA1c≥6% provides reasonable sensitivity and specificity for DM diagnosis as per the WHO or ADA criteria. However, similarly, approximately 35% of the variations in HbA1c cannot be explained in terms of plasma blood glucose. Furthermore, these variations were significantly high in the NGT group. The authors emphasized that HbA1c values vary markedly amongst patients with a given plasma blood glucose level. Earlier studies have shown that HbA1c variations between individuals are low, but these authors and other authors have reported large variations between individuals. Owing to this substantial variation in HbA1c even for NGT subjects, this parameter cannot be considered viable for diabetes screening programmes. From these results, the authors postulated that factors unconnected with glucose metabolism determine the HbA1c indices in healthy individuals and diabetics alike. Other studies |6| in which HbA1c determination has been proposed as an alternative have supported these fmdings. However, considerable overlap between NGT and IGT, as defined by WHO criteria, has been noted. Consequently, an OGTT is required for diagnosis. Yet, despite all this, the authors (still) asserted that measurement of HbA1c is considered to be the most suitable test for long-term blood glucose evaluation for both type 1 and type 2 diabetes. Potential short-term economic benefits of improved glycaemic control: a managed care perspective J Menzin, C Langley-Hawthorne, M Friedman, L Boulanger, R Cavanaugh. Diabetes Care 2001; 24:51–5. BACKGROUND. There are limited data relating glycaemic control to medical costs among patients with diabetes. This study examined the potential impact of improved glycaemic control on selected shortterm complications of diabetes and their associated costs in a managed care setting. In-patient (hospital or skilled nursing facility) admissions for selected acute (short-term) complications, as represented by selected infections, hyperglycaemia, hypoglycaemia and electrolyte disturbances and their associated medical charges were evaluated across three HbA1c groups representing good, fair and poor glycaemic control. Multivariate analyses were used for controlling for differences in several potential confounding factors among the study groups. All findings were expressed on a 3-year basis. Of 2394 patients with diabetes, approximately 10% (251) had at least one in-patient stay for a short-term complication, accounting for 447 admissions. Over 3 years, the adjusted rate of in-patient treatment ranged from 13

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Fig. 7.1 Upper panel: percentage distribution of HbA1c in different categories of glucose tolerance. The categorization of glucose tolerance was performed based on the 1998 WHO criteria. Lower panel: percentage distribution of HbA1c categories in non-diabetic and diabetic ranges of FPG. The 1997 ADA criteria were used. Source: Snehalatha et al. (2000). per 100 patients with good glycaemic control to 16 per 100 patients with fair glycaemic control and 31 per 100 patients with poor glycaemic control (P<0.05). The corresponding mean adjusted charges were approximately $970, $1380 and $3040, respectively. Among the 30% of the study population with longterm diabetic complications, the results were more marked. The adjusted admissions per 100 patients (mean charges) were estimated to be 30 ($2610), 38 ($3810) and 74 ($8320) over 3 years for patients with HbA1c values of<8, 8–10 and>10%, respectively. In typical practice, better glycaemic control is associated with a reduced rate of admission for selected short-term complications and, therefore, reduced medical charges for these complications over a 3-year period. The potential short-term economic benefits are important to consider when making decisions regarding the adoption and use of new interventions for the management of diabetes.

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Comment This study aimed to determine the potential impact of improved glycaemic control on a series of short-term and long-term diabetes complications and their associated costs. A total of 2394 patients were allocated to three cohorts according to their HbA1c values over a period of 3 years as follows: good control (<8%), regular control (8-10%) andpoor control (>10%). The authors drew attention to a series of limitations. 1. Although the analysis indicated a significant HbA1c /acute DM complications correlation, it did not succeed in proving that these events were avoidable. 2. Specific diagnoses varying with the degree of short-term blood glucose control appeared to be questionable. Further studies are needed in order to identify whether diagnoses correlate better with shortterm blood glucose control. 3. Errors that were inherent in reliance on the (primary or secondary) diagnosis at discharge from the clinical coding data for the study of these shortterm diabetic complications may have led to certain events being underreported. These may not have been the sole reason for admission or may have been incidental discoveries or findings secondary to the main medical problem for which the patient was admitted. It is better not to use methods incurring the cost of multiple diagnoses. 4. Admissions are likely to be related to diabetes disease duration and severity. The fmdings of this study may have been partly conditioned by these two confounding factors despite the use of multivariate analysis. 5. The financial results of this study are not generally applicable since they depend on local management protocols, the health plan recommendations of each country, geographical regions, etc. 6. Finally, it was not clear to what extent the excess health care costs were directly related to poor glycaemic control, since patients who have poor self-management skills are more likely to be noncompliant with other aspects of treatment such as diet, obesity and smoking, which may all contribute to increased health care costs. In conclusion, these limitations notwithstanding, the results suggested that, in clinical practice, patients who achieve better, sustained glycaemic control over 3 years have fewer hospital admissions and reduced health care expenses. These data are important for new interventions in diabetes management and also tally with the results of other studies of a similar nature. Owing to the fact that most economic research performed hitherto has related to chronic complications and the limitations cited, more information should be gathered on this subject. Education and the metabolic syndrome in women S P Wamala, J Lynch, M Horsten, M A Mittleman, K Schenck-Gustafsson, et al. Diabetes Care 1999; 22:1999–2003. BACKGROUND. The main objective of this study was to examine the association between metabolic syndrome and socioeconomic position (as indicated by education) among women. The study sample comprised healthy women (aged 30-65 years) in Sweden who were representative of the general population in a metropolitan area. Their socioeconomic position was measured by educational level (mandatory, high school or college/university). Metabolic syndrome was defined as the presence of two or more of the

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following components: an FPG level of≥7.0 mmol/l, arterial BP≥160/90 mmHg, fasting plasma TGs≥1. 7 mmol/l and/or high-density lipoprotein (HDL) cholesterol <1.0 mmol/l and central obesity (waist to hip ratio>0.85 and/or BMI>30 kg/ m2). After adjustment for age, the risk ratio for the presence of metabolic syndrome comparing the lowest with the highest education levels was 2.7. These findings show that, not only are women with low socioeconomic position at increased risk of individual risk factors that are associated with CVD and type 2 diabetes, they are also at increased risk for the metabolic clustering of risk factors

Comment Various studies have reported a relationship between mortality/morbidity risk and low socioeconomic status. In addition, recent studies have also associated diabetes-related mortality with low socioeconomic status. This study took account of the components of metabolic syndrome (Table 7.1) and an association was observed between the features of metabolic syndrome and the education-indexed socioeconomic position of healthy women aged 30-60 years in Sweden. Metabolic syndrome has been encountered in lower academic achievers (≤9 years of education) relative to higher academic achievers (college and university education) (Tables 7.2 and 7.3). Similar correlations between socioeconomic class and the metabolic syndrome have been reported in other studies from the Table 7.1 Definition of metabolic syndrome according to the WHO Component

Factor

Cutoff point

n (%) for each component

Fasting plasma glucose level ≥7.0 mmol/l 2(1) sBP and/or ≥160 mmHg 6(2) dBP ≥90 mmHg 37 (12) Dyslipidaemia Fasting plasma triglycerides and/or ≥1.7 mmol/l 36 (12) HDL cholesterol <1.0 mmol/l 11(4) Central obesity Waist-to-hip ratio and/or >0.85 62 (21) BMI >30 kg/m2 39 (13) Subjects are defined as having metabolic syndrome if two or more of the components listed are present (n=37). Source: Wamala et al. (1999).

Hyperglycaemia Elevated arterial blood pressure

Table 7.2 Distributions of the components of metabolic syndrome in relation to educational attainment (after adjusting for age) Educational attainment

n BMI (kg/m2) Waist-to-hip ratio sBP dBP HDL cholesterol (mmol/l) Tryglicerydes (mmol/l) Fasting glucose (mmol/l)

Mandatory

High school

University/college

P value

158 25.8±0.4 0.82±0.01 124±1.3 80±0.8 1.64±0.03 1.01±0.04 5.01±0.01

61 24.5±0.5 0.79±0.01 119±2.0 75±1.3 1.69±0.04 0.96±0.04 4.48±0.04

81 23.2± 0.4 0.76±0.01 115±1.8 73±1.0 1.82±0.03 0.84±0.04 4.68±0.02

— 0.01 0.01 0.005 0.001 0.004 0.03 0.47

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Educational attainment Mandatory

High school

University/college

P value

The data are least-squares means±SEMs. Source: Wamala et al. (1999).

Whitehall II Epidemiological Trial |7|. This association may be partly explained by life style differences, since individuals with a low socioeconomic status are more likely to be overweight |8|, smoke and take less exercise than subjects with higher social status. Table 7.3 Metabolic syndrome in relation to educational attainment and other risk factors Risk ratios (95% Cl) Risk factor

n

Educational attainment Mandatory 158 High school 61 College/university 81 (reference category) Lack of physical exercise 55 Low alcohol consumption (no 67 alcohol or ≤1.9 g/day) Family history of diabetes 32 Older age (>60 years) 106 Postmenopausal women not on HRT 154 Marital status (not cohabiting) 95 89 Cigarette smoking (current)

Unadjusted

Age-adjusted

Multivariableadjusted

2.73(1.09–6.83) 1.31(0.40–4.39) 1

2.63(1.04–6.62) 1.33(0.40–4.39) 1

2.34(0.98–5.84) 1.27(0.39–4.14) 1

3.32(1.81–6.03) 2.00 (1.02–3–95)

3.29(1.80–5.98) 1.96 (1.00–3.87)

2.82(1.46–5.44) 1.64 (0.73–3.64)

1.95(0.94–4.08) 1.39(0.76–2.56) 1.26(0.53–2.99) 1.19 (0.63–2.26) 1.18(0.57–1.85)

1.97(0.95–4.11)

1.80(0.87–3.71) 1.19(0.65–2.16) 1.10(0.47–2.61) 0.99 (0.53–1.86) 0.77(0.39–1.54)

1.24(0.53–2.93) 1.16 (0.61–2.21) 1.13(0.47–1.85)

All risk factors were simultaneously included in the model for the multivariable-adjusted risk ratios. The risk ratios of metabolic syndrome in relation to a lack of physical exercise, no/low alcohol consumption, a family history of diabetes, older age, post-menopausal status, marital status and cigarette smoking are relative to the protective category of each risk factor. Source: Wamala et al. (1999). Dietary unsaturated fatty acids in type 2 diabetes: higher levels of postprandial lipoprotein on a linoleic acid-rich sunflower oil diet compared with an oleic acid-rich olive oil diet C Madigan, M Ryan, D Owens, P Collins, G H Tomkin. Diabetes Care 2000; 23(10):1472–7. BACKGROUND. The present study was undertaken in order to examine the effect of a polyunsaturated fat diet as compared with an isocaloric Mediterranean-style monounsaturated fat diet. This was a randomized, 2-week, cross-over study on either a high-polyunsaturated or a highmonounsaturated fat diet in eleven well-controlled diabetic men. Blood was taken after fasting and for up to 8 h after a high-fat meal. Lipoproteins were isolated by sequential ultracentrifugation. Apolipoprotein (apo) B48 and apo BIOO were separated by polyacrylamide gel electrophoresis. Fatty acids were analysed by gas-liquid chromatography. The subjects’ FBG and insulin levels were

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significantly higher on the linoleic acid diet as compared with the oleic acid diet. Their plasma cholesterol and LDL cholesterol levels were also significantly higher on the linoleic acid diet. Likewise, their fasting chylomicron apo B48 and apo BIOO and postprandial chylomicron and VLDL apo B48 and apo BIOO were also higher on the linoleic acid diet. This study suggested that, in type 2 diabetes, an oleic acid-rich Mediterranean-type diet versus a linoleic acid-enriched diet may reduce the risk of atherosclerosis.

Comment Dyslipidaemia is an important cause of atheroma in diabetes. Lipoproteins are considered to be atherogenic and their impairment is common in diabetes. Postprandial lipoproteins are regarded as atherogenic particles. The main lipoprotein is chylomicron, such as apo B48. The benefits of a Mediterranean-type monounsaturated diet are well known, but the postprandial effects of polyunsaturated and monunsaturated diets on lipoproteins are not so well documented. This project compares the effects of a diet rich in polyunsaturated fat with an isocalorific monounsaturated diet. Type 2 diabetes males with well-controlled DM were included in the randomized, cross-over study; they were divided into two groups. Each group was given a diet rich in monounsaturated fatty acids or a diet rich in polyunsaturated fatty acids for 2 weeks. Lipoproteins, VLDL, LDL and HDL cholesterol and TGs plus HbA1c, glucose and insulin were measured. Chylomicron apolipoproteins apo B48 and apo BIOO were measured after fasting and 8 h after a meal rich in fatty acids; fatty acids were also measured. The results revealed no differences in BMI between the two diet groups, but the subjects’ fasting glucose was significantly greater in the group treated with a diet rich in linoleic fatty acid than in the oleic acid group (P<0.01). Fasting insulin was significantly higher in the group with the linoleic acid diet (P<0.002). The subjects’ plasma cholesterol and LDL cholesterol levels were significantly higher in the linoleic acid group (P<0.001), although their TG plasma levels and HDL cholesterol levels were similar in both diet groups. The subjects’ fasting and postprandial chylomicron apo B48 and apo BIOO responses were significant amongst the linoleic and oleic acid diets, but found to be much higher in the group with the linoleic acid rich diet (P<0.05) (Fig. 7.2). It was discovered that there was a significant difference between the diets in the postprandial responses of VLDL apo B48 and apo BIOO (P<0.01 and P<0.05 respectively) (Fig. 7.3). This study suggested that a diet rich in oleic acid would be eminently suitable for patients with type 2 DM. Conclusion Type 1 diabetes is a chronic, autoimmune disease in which the insulin-producing β cells are progressively destroyed by the patient's own immune system. The peak incidence occurs between 10 and 15 years of age and 70% of cases present in patients under 30 years of age. In Northern European countries, however, the incidence by decade then remains constant with some reports of typical type 1 diabetes being diagnosed in nonogenarians! A number of epidemiological studies that have been undertaken have shown a marked regional variation in incidence. Northern European countries and North America have the highest incidence with a low incidence in Japan. In addition, European studies have suggested a rising incidence of type 1 diabetes over the last few decades for reasons that remain unclear. The Diamond project reported in Chapter 5 has extended these epidemiological observations by including over 100 population groups worldwide. The dramatic finding of a 350-fold difference in disease incidence between the lowest (China)

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Fig. 7.2 Postprandial response to a high-fat meal of chylomicron (a) apo B100 and (b) apo B48 in type 2 diabetic subjects after 2 weeks on a linoleic acid-rich diet (open circles) or an oleic acid-rich diet (filled circles). The apo B48 and apo BIOO AUCs were significantly different between the linoleic and oleic acid diets (P<0.05 by Student’s paired t-test). Source: Madigan et al. (2000).

and highest (Sardinia and Finland) incidences is interesting in itself, but it is to be hoped that gathering such incidence data in the longer term may provide information for providing some clues as to why these large between-population differences occur. Environmental factors are likely to be important in this respect. Both genetic and environmental factors have been implicated in the aetiology of type 1 diabetes. It was appreciated as long ago as 1965 that the onset of type 1 diabetes was associated with an infiltration of immunologically active cells around the islets of Langerhans. Over the last 25 years evidence has accumulated of associations between type 1 diabetes and certain histocompatability antigens (human leucocyte antigen (HLA)), in particular class II antigens. An individual with HLA DR3 and DR4 class II antigens carries a 15-fold increased risk of developing type 1 diabetes, whereas other class II antigens confer a degree of protection. Under normal circumstances β cells do not express such antigens on their cell

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Fig. 7.3 Postprandial response to a high-fat meal of VLDL (a) apo BIOO and (b) apo B48 in type 2 diabetic subjects after 2 weeks on a linoleic acid-rich diet (open circles) or an oleic acid-rich diet (filled circles). The VLDL apo B48 and apo BIOO AUCs were significantly different between diets (P<0.01 and P<0.05, respectively, by Student’s paired ttest). Source: Madigan et al. (2000).

surface, but aberrant expression is a feature of type 1 diabetes and may be one of the earliest immunological abnormalities. These HLA associations explain some of the genetic predisposition to the disease. Islet cell antibodies were first described in 1974 and have been the focus of intense research interest ever since. A range of antibodies has been described, including anti-insulin, islet cell surface, cytotoxic and antigen-specific antibodies, which have different antigenic targets within the β cell. Islet cell antibodies have been identified in up to 90% of patients at presentation of type 1 diabetes and can usually be detected for several years before the clinical onset of the disease. A range of β cell antigens has been identified, but one that has attracted particular interest is the glutamic acid decarboxylase (GAD) enzyme. Anti-GAD

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antibodies can be detected in up to 90% of recent-onset patients. The predictive power of islet autoantibodies is significantly increased if several are measured in any individual patient. Higher titres are also associated with an increased predictive power. The paper by Sabbah et al (p. 135) presents interesting data suggesting that the immunological ‘assaulf on the B cells occurs with greater intensity in young patients than in those presenting in adult years. Three or more islet autoantibodies were detected in 70% of childhood onset cases as compared with 30% of those with adult onset disease. The clinical presentation also tended to be more rapid with a greater severity of metabolic disturbance in the childhood onset group. The study does not provide any explanations for the differences, which are likely to be due to complex interactions between genetic predisposition and the environmental trigger(s). The islet cell antibody profiles of childhood and adult onset disease also differed. The commonest antibodies in childhood onset disease were islet cell antibodies, whereas anti-GAD antibodies were most prevalent in adults. In an important study from Scandinavia these GAD antibodies were found to be the best predictors of insulin therapy in young adults who had not been classified as type 1 diabetes on clinical grounds. Latent autoimmune diabetes of adults (LADA) describes a slowly progressive form of type 1 diabetes in which patients over 35 years of age had measurable autoimmune markers, but did not rapidly progress to insulin therapy within 1 year of diagnosis. LADA has also been termed type 1 and a 1/2, since it may have features of both type 1 and type 2 diabetes. It is reported to account for up to 15% of patients with diabetes that behaves clinically like type 2 diabetes. Whether it represents a ‘slow-burn’ type 1 diabetes with a less intense immunological attack on β cells or whether it is a separate disease entity from childhood onset type 1 diabetes is unknown. Carlsson et al (p. 134) found that patients with LADA had characteristics of insulin resistance that were typical of type 2 diabetes, but had a more severe insulin secretory defect. The insulin resistance associated with LADA is likely to stress the β cell and such patients are more likely to need insulin therapy than antibody-negative patients. The environmental factors that are thought to trigger type 1 diabetes are incompletely understood. Various viruses have been implicated, including cocksackie B viruses, rubella and mumps. Dietary factors have also received attention, including cow's milk exposure in infancy. One suggested mechanism related to molecular mimicry between epitopes on the bovine serum albumin molecule and some β cell antigens. An alternative hypothesis is that insulin immunization occurs with exposure to bovine insulin (BI), which is able to cross the immature infant’s gut mucosa. Supportive data from in vitro work is presented which suggests that exposure to cow’s milk protein results in the development of antibodies against BI in infants at risk of type 1 diabetes. Studies on the effective treatment of the illness and its complications were conducted in the 1990s. Prominent amongst these was the Diabetes Control and Complications Trial (DCCT), which fmally provided defmitive proof in support of several European studies conducted in the 1980s that optimal glucose control reduced the risk of microvascular complications. Interesting follow-up data are presented in the Epidemiology of Diabetes Intervention and Complications (EDIC) studies, which demonstrate continued benefit from the initial period of intensive therapy as com pared with conventional therapy even though glycaemic control in the two groups was similar during 6 years of post-DCCT follow-up. It is interesting that this fmding is consistent with the clinical studies in dogs by Engerman and Kern |9| almost 15 years ago. In order to assess the extent to which the progression of diabetic retinopathy could be arrested by improved glycaemic control, they allocated 35 normal dogs into a non-diabetic and three alloxan-induced diabetic groups. Their diabetes was then treated prospectively as follows: poor control for 5 years, good control for 5 years and poor control for 2.5 years followed by good control for 2.5 years. The development of retinopathy occurred in the dogs with poor control whilst those with 5 years of good control were protected. In the dogs

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with good followed by poor control, retinopathy was absent or equivocal at 2.5 years of poor control and, surprisingly, was found to develop subsequently despite good glycaemic control. These data and that of the EDIC trial emphasize the importance of striving for good glycaemic control from the outset in patients with type 1 diabetes in order to minimize the long-term risk of microvascular complications. The EURODIAB Insulin-dependent Diabetes Mellitus Complications Study Group is an international collaboration from many countries in Europe investigating, amongst other things, the epidemiology of diabetic complications. An important paper that is reviewed in Chapter 6 reinforces the importance of good glycaemic control in reducing the risk of early onset microvascular complications, but also highlights smoking and a family history of hypertension as additional significant risk factors. Smoking is clearly a modifiable risk factor, but persuading patients to stop can be a challenge. A more intensive approach with a nurse-led counselling session plus longer term support, as reported on p. 165, may suggest a way forward since this approach caused almost one in five smokers to stop as compared with only one in 50 who received 'usual' medical advice. The message from this and the trials on life style intervention that are summarized in Chapter 3 seems to be that interventions need to be more intensive and sustained over time with appropriate support services in order to achieve success in changing behaviour. Such interventions need to be subject to financial assessment in order to assess their cost-effectiveness before widespread implementation can be advocated. Two papers that evaluate the benefits of simultaneous pancreas and kidney transplant are reviewed. Over 7000 such procedures have been undertaken worldwide with the 1-year graft survival exceeding 80% in most series. It has proved effective in restoring normoglycaemia, but reports on the impact on diabetic complications have been mixed. Most patients requiring such transplantation will already have microvascular and macrovascular complications that are at an advanced stage, thereby involving irreversible tissue damage. It is perhaps optimistic to expect restoration of normoglycaemia at this stage of disease to be associated with benefit, but the report on the impact on retinopathy progression by Pearce et al. (p. 149) is encouraging in terms of the stabilization of retinopathy post-transplantation. Concerns that abrupt restoration of glucose levels to normal would cause transient deterioration of retinopathy, as has been seen in studies in Europe and the DCCT in intensively treated patients, did not materialize, although it must be accepted that the sample size, at only 20 patients, was small. The impact on macrovascular disease progression following transplantation was less encouraging in that certain known risk factors such as glycaemic control and serum lipid profiles were improved, but similar numbers of patients progressed to cerebrovascular and cardiovascular events and to peripheral vascular disease following renal transplantation whether or not they had received a simultaneous pancreas graft. Diabetes management remains a challenge to patients and physicians alike. Dietary recommendations abound, but it is often difficult to persuade patients to make the necessary changes to their diet in order to achieve weight loss (or stabilization) and optimal glucose control. The benefits of fibre in glucose control have been known for many years and the report from Chandalia et al. (p. 166) confirms substantial benefits in terms of glucose and lipid profiles from a high fibre intake. Similar findings have been reported from the UK and Europe over many years. The real problem in making significant changes to dietary recommendations is patient patients only followed the diet for 6 weeks in the context of a clinical trial. Whether compliance. This was said to be ‘excellent’ in the report by Chandalia et al., but the such compliance would have persisted in patients after 6 months is debatable. Technological developments undoubtedly advance clinical management and the prospect of non-invasive glucose monitoring has nowbeen realized with the introduction of the Glucowatch non-invasive glucose monitor in America and Europe in 2001. The potential of such technology is being investigated at present and an interesting preliminary report is summarized in this chapter. In a study using a Minimed continuous

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glucose sensor in nine patients with type 1 diabetes, it was possible for patients to alter their diet/insulin regimen and improve their glycaemic control by over 1%. Whilst this pilot study is encouraging larger studies are needed in order to confirm this preliminary data. It is likely that such glucose monitoring technology will become a useful 'diagnostic' tool in some patients with suboptimal glycaemic control, thereby allowing the identification of abnormal patterns of hyperglycaemia that may respond to an altered regimen. It may also give patients insight into their diabetes and the effect that various life style choices (food, exercise, etc.) have on glycaemic control and may motivate some to change. References 1. 2. 3.

4.

5. 6. 7.

8. 9.

Silagy C, Stead LF. Physician advice for smoking cessation (Cochrane Review). Cochrane Database Syst Rev 2001; 2: CD000165. Haire-Joshu D, Glasgow RE, Tibbs TL. Smoking and diabetes. Diabetes Care 1999; 22(11):1887–98. Lynch J, Helmrich SP, Lakka TA, Kaplan GA, Cohen RD, Salonen R, Salonen JT. Moderately intense physical activities and high levels of cardiorespiratory fitness reduce the risk of non-insulin-dependent diabetes mellitus in middle-aged men. Arch Intern Med 1996; 156(12):1307–14. Hu FB, Sigal RJ, Rich-Edwards JW, Colditz GA, Solomon CG, Willett WC, Speizer FE, Manson JE. Walking compared with vigorous physical activity and risk of type 2 diabetes in women: a prospective study. JAMA 1999; 282(15):1433–9. Kohl HW, Gordon NF, Villegas JA, Blair SN. Cardiorespiratory fitness, glycemic status, and mortality risk in men. Diabetes Care 1992; 15(2):184–92. Larsen ML. The clinical usefulness of glycated haemoglobin in diabetes care evaluated by use of a medical technology assessment strategy. Dan Med Bull 1997; 44:303–15. Brunner EJ, Marmot MG, Nanchahal K, Shipley MJ, Stansfeld SA, Juneja M, Alberti KG. Social inequality in coronary risk: central obesity and the metabolic syndrome. Evidence from the Whitehall II Study. Diabetologia 1997; 40(11):1341–9. Martikainen PT, Marmot MG. Socioeconomic differences in weight gain and determinants and consequences of coronary risk factors. Am J Clin Nutr 1999; 69(4):719–26. Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycaemic control. Diabetes 1987; 36:808–12.

Part IV Insulin resistance: type 2 diabetes mellitus and obesity

Insulin resistance: type 2 diabetes mellitus and obesity

Introduction Type 2 diabetes mellitus accounts for between 80 and 90% of all cases of diabetes in most Western countries. There are several subtypes under the broad classification of type 2 diabetes, which have a different and in some instances a better-defined aetiology. 1. Maturity onset diabetes of the young. This genetic form of type 2 diabetes is thought to affect approximately 1-2% of the type 2 diabetic population. 2. Latent autoimmune diabetes of the adult. This is also termed slow onset type 1 diabetes and accounts for between 5 and 15% of the type 2 diabetic population. 3. Rare genetic syndromes associated with diabetes. This group of approximately 50 genetic syndromes accounts for between 1 and 2% of the type 2 diabetic population. The remaining population of ‘garden-type’ type 2 diabetes form the majority of cases (approximately 80-90%) and this group continues to presents challenges in terms of underlying aetiology, clinical management and long-term prognosis. Nevertheless, most authors are in agreement about the following series of general points that characterize the pathogenic factors of this common variety of type 2 diabetes. 1. Type 2 diabetes is a condition that presents heterogeneous clinical symptoms and has a heterogeneous aetiology. 2. The clinical phenotype results from a complex interaction between genetic and environmental factors. 3. Its origins are clearly polygenic, signifying that various genetic abnormalities need to be present before it can develop. It is possible, as the genetics of type 2 diabetes are increasingly understood, that further subtypes of the condition will be identified with different patterns of genetic abnormalities. 4. In the natural history of type 2 diabetes there should be no confusion about the diabetogenic genetic determinants (essential and specific to diabetes but insufficient alone) and the genetic determinants associated with diabetes. 5. Insulin resistance and impaired insulin secretion usually coexist and both are important phenomena in the aetiology of the illness. Both these phenomena are influenced by genetic factors and are modulated by acquired (environmental) factors. 6. Two-thirds of patients with type 2 diabetes are overweight or obese.

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7. Type 2 diabetes is a clear independent risk factor in the development of cardiovascular disease (CVD), the latter being the main source of the high morbidity and mortality resulting from the illness. The importance and relevance of type 2 diabetes in health economics terms stems from the complexity of its clinical management, including its wide range of complications and from its association with other vascular risk factors as part of the insulin resistance syndrome. Arteriosclerosis is responsible for 80% of the deaths amongst patients with type 2 diabetes, with 75% of these being attributable to coronary atheroma and the remainder to strokes or peripheral vascular events. Type 2 diabetes has been characterized as a disease of accelerated arteriosclerosis leading to increased cardiovascular risk. These factors include the following. 1. Chronic hyperinsulinaemia. 2. Dyslipidaemia accompanied by quantitative and qualitative changes in the serum lipoprotein profile. 3. Hyperglycaemia. 4. Heightened oxidative stress. 5. A haemostatic imbalance favouring coagulation and preventing fibrinolysis. Abnormal function of the endothelial cells, which form the inner lining of all blood vessels, has become a central feature in current ideas about the development and progression of atheromatous disease. Termed endothelial dysfunction, this abnormality is thought to be one of the first steps in the development of atheroma. All of the metabolic abnormalities seen in type 2 diabetes may contribute to endothelial dysfunction, with the result that oxidative stress in the vasculature may be prolonged, vasoconstriction may occur and the balance of haemostasis and fibrinolysis may alter in favour of an increased thrombotic tendency. Part IV reviews recent papers in the field of type 2 diabetes. Chapter 8 focuses on the strong association of type 2 diabetes with cardiovascular risk. Conventional risk factors, such as smoking, hyperlipidaemia and hypertension, account for approximately two-thirds of cardiovascular risk in epidemiological studies. Other factors, such as serum homocysteine concentrations and inflammatory markers, are being associated with the development of vascular disease and are the focus of new studies. Abstracts from the prospective Hoorn Study in The Netherlands, which relate plasma homocysteine and C-reactive protein levels to the mortality risk from CVD, are summarized. Attention is also focused on the coagulation system in diabetes in several abstracts that investigate the relationship between hyperinsulinaemia and haemostatic factors. The clinical diagnosis of type 2 diabetes is usually preceded by a long pre-clinical phase during which patients move from a state of normal to impaired glucose tolerance (IGT) and then to a progressively rising fasting glucose. Vascular risk is clearly associated with IGT (or pre-diabetes) in epidemiological studies. Pa tients with IGT are insulin resistant and may have associated vascular risk factors for partly explaining their increased vascular risk. Haffner et al report on a 7-year follow-up of the San Antonio Heart Study investigating the vascular risk profile of pre-diabetic patients with measures of insulin resistance and insulin secretion in which it is clearly shown that vascular risk factors are related to insulin resistance, an important consideration when developing prevention strategies for type 2 diabetes and cardiovascular disease (p. 201). Chapter 9 looks at recent clinical trials aimed at managing the associated problems of obesity and type 2 diabetes. This is an area receiving considerable interest at present because of the availability of pharmacological agents for the treatment of obesity. Orlistat is a pancreatic lipase inhibitor that induces a state of fat malabsorption and, hence, weight loss. Sibutramine is a centrally acting appetite suppressant that enables patients to reduce their daily calorie intake. Both products are now available for use in patients with body mass index levels in excess of 28 kg/m2 provided there is co-morbidity such as type 2 diabetes. Several

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papers evaluating clinical responses when these agents are used in patients with diabetes are reviewed in this chapter. In addition, Chapter 9 summarizes some important papers that address the underlying pathophysiology of obesity. Much as with type 2 diabetes, the development of obesity is the result of a complex interaction between genetic and environmental factors. Recent seminal observations have fuelled a whole new area of research involving the endocrinology of the adipocyte (fat cell). Previously thought of as an inert ‘storage’ cell for triglycerides, the discovery that adipoyctes secrete leptin, which is a satiety hormone acting in the hypothalamus, suggested a more important regulatory role in regulating body weight. This has been strengthened by reports of rare families with severe leptin deficiency associated with morbid obesity who achieve significant weight loss associated with markedly reduced hyperphagia when treated with recombinant leptin. Resistin is a second protein that has recently been identified as an adipocyte-derived hormone. Resistin is thought to influence insulin action in peripheral tissues in rodents and, if confirmed in humans, may provide a plausible link between the well-known link between obesity and increasing insulin resistance. 7

8 Type 2 diabetes mellitus and cardiovascular risk

Hyperhomocysteinemia increases the risk of death, especialiy in type 2 diabetes: 5-year follow-up of the Hoorn Study E K Hoogeveen, P J Kostense, C Jakobs, J M Dekker, G Nijpels, et al. Circulation 2000; 101(13):1506–11. BACKGROUND. A high serum total homocysteine (tHcy) concentration is a risk factor for death, but the strength of the relation in patients with type 2 diabetes mellitus (DM) is not known. The authors investigated the combined effect of hyperhomocysteinaemia and type 2 diabetes on mortality. Serum was saved between 1 October 1989 and 31 December 1991 from 2484 men and women of 50–75 years of age who were randomly selected from the town of Hoorn. Fasting serum tHcy was measured in 171 subjects who died (case subjects) (76 died of cardiovascular disease (CVD)) and in a stratified random sample of 640 survivors (control subjects). Mortality risks were calculated over 5 years of follow-up by means of logistic regression. After adjustment for major cardiovascular risk factors, serum albumin and glycosylated haemoglobin (HbA1c), the odds ratio (OR) for the 5-year mortality was 1.56 for hyperhomocysteinaemia and 1.26 per 5 jomol/l increment of tHcy. The OR for the 5-year mortality for hyperhomocysteinaemia (tHcy>14 jomol/l) was 1.34 in non-diabetic subjects and 2.51 in diabetic subjects (P=0.08 for interaction). Hyperhomocysteinaemia was related to the 5-year mortality independent of other major risk factors and appeared to be a stronger (1.9-fold) risk factor for mortality in type 2 diabetic patients than in non-diabetic subjects.

Comment The traditional risk factors for coronary artery disease can only explain approximately two-thirds of the observed clinical events. Other factors are likely to be implicated and two such factors are dietary antioxidants and plasma homocysteine. Established risk factors such as hypertension, smoking and DM are associated with increased oxidative stresses due to excess free radical activity in the vascular wall. Increased oxidative stress is associated with the oxidation of low-density lipoprotein (LDL) particles, which are more readily taken up by macrophages in the vascular wall. Oxidant stress also leads to the inactivation of endothelium-derived nitric oxide and is directly cytotoxic to endothelial cells. © Clinical Publishing Services Ltd

Homocysteine is a sulphydryl-containing amino acid that is derived from the demethylation of dietary methionine. Many epidemiological studies |1, 2| over 30 years have linked hyperhomocystinaemia with

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premature vascular disease. This link is independent of other risk factors, is consistent across many studies and is strongly dose related. Recent evidence has suggested a biologically plausible mechanism for vascular injury because homocysteine promotes oxidant injury to the vascular endothelium, impairs endotheliumdependent vasomotor regulation and may also alter the coagulant properties of the blood. This prospective, population-based study with a 5-year follow-up is the first to relate hyperhomocystinaemia to mortality in type 2 diabetes. The authors have clearly shown that hyperhomocysteinaemia is a risk factor for overall mortality in type 2 diabetic patients, independent of major cardiovascular risk factors and serum albumin. Interestingly, the association of hyperhomocystenaemia with death was much stronger in diabetic than in non-diabetic subjects. The risk of 5-year mortality rose by 17% in the non-diabetic subjects for each 5 µmol/l increase in tHcy and by 60% in the diabetic subjects. The study was not powered for assessing the relationship between hyperhomocysteinaemia and cardiovascular death in particular. Plasma homocysteine levels can be reduced by dietary supplements of folic acid and B vitamins. Studies are currently being undertaken in order to examine the impact of these vitamins in high-risk patients and thereby establish a causative role for homocysteine in promoting vascular events. Hyperinsulinemia, hyperglycemia and impaired hemostasis. The Framingham Offspring Study J B Meigs, M A Mitleman, D M Nathan, G H Tofler, D E Singer, et al. JAMA 2000; 283(2):221–8. BACKGROUND. The authors evaluated the associations between fasting insulin levels and haemostatic factors in subjects with normal and impaired glucose homeostasis. A cross-sectional analysis was conducted between January 1991 and June 1995 in the population-based Framingham Offspring Study (FOS) in which 1331 men and 1631 women (26-82 years) without diagnosed diabetes or CVD were classified as having normal glucose tolerance (NGT) (80.2%) or glucose intolerance (impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) combined (15.2%) or previously undiagnosed diabetes (4.7%)) using an oral glucose tolerance test (OGTT). Trends across quintiles of fasting insulin in the levels of plasminogen activator inhibitor 1 (PAI-1) antigen, tissue-type plasminogen activator (TTPA) antigen, Von Willebrand factor antigen, factor VII antigen, fibrinogen and plasma viscosity were evaluated. The data were stratified by sex and glucose tolerance status and haemostatic factor levels were adjusted for obesity, lipid levels and traditional CVD risk factors. The mean levels of all haemostatic factors (except for fibrinogen in men) increased across the fasting insulin quintiles among subjects with NGT (P<0.001 for trend). The levels

of PAI-1 antigen and TTPA antigen but not other haemostatic factors were higher when comparing subjects with glucose intolerance with those with NGT (P<0.001). The levels of PAI-1 antigen and TTPA antigen in men and women (P<0.01 for trend) and Von Willebrand factor antigen in men (P<0.05 for trend) increased significantly across the insulin quintiles among subjects with glucose intolerance, but their levels of factor VII antigen, fibrinogen and plasma viscosity did not increase. Elevated levels of fasting insulin were associated with impaired fibrinolysis and hypercoagulability in subjects with NGT. Hyperinsulinaemia was associated primarily with impaired fibrinolysis in the subjects with glucose intolerance. Excess risk for CVD associated with hyperinsulinaemia and glucose intolerance may be mediated in part by an enhanced potential for acute thrombosis.

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Comment Patients with diabetes and IGT have an increased cardiovascular risk that is not fully explained by the higher prevalence of traditional cardiovascular risk factors such as hypertension and low high-density lipoprotein (HDL) cholesterol. In this cross-sectional analysis of the FOS, the authors found an association between fasting insulin levels and markers of impaired fibrinolysis in both normal subjects and in patients with glucose intolerance. Fasting insulin was only also associated with the parameters of hypercoagulability among subjects with NGT. Patients with glucose intolerance had higher levels of PAI-1 antigen and TTPA antigen, but not other haemostatic factors, thereby suggesting that glucose intolerance thrombotic risk may be mediated more by impaired fibrinolysis than by hypercoagulability. The elevated levels of PAI-1 antigen and TTPA antigen associated with hyperinsulinaemia, glucose intolerance and hypertriglyceridaemia support the inclusion of impaired fibrinolysis as an additional feature of the insulin resistance syndrome. Impaired fibrinolysis may be an important mechanism that links hyperinsulinaemia, insulin resistance and increased cardiovascular risk in glucose intolerance. Prospective studies should define whether the levels of haemostatic factors enhance risk prediction among patients with diabetes and IGT. Interleukin 6 gene polymorphism and lipid abnormalities in healthy subjects J M Fernandez-Real, M Broch, J Vendrell, C Richart, W Ricart. J Clin Endocrinol Metab 2000; 85:1334–9. BACKGROUND. A polymorphism in the interleukin 6 (IL-6) gene that is associated with differences in the IL-6 transcription rate has recently been described. The authors aimed to study whether this IL-6 gene polymorphism leads to differences in fasting and post-glucose load plasma lipids in healthy subjects. Serum IL-6 levels correlated positively with fasting triglycerides (TGs), very low-density lipoprotein (VLDL) TGs and post-load free fatty acids

and negatively with HDL cholesterol. A tendency towards higher serum IL-6 levels was observed among G carriers. The results of the present study suggest that subjects with the G allele, which is associated with higher IL-6 secretion, are prone to lipid abnormalities. Whether this polymorphism contributes to lipid alterations that are associated with other metabolic disorders awaits additional studies.

Comment Recent reports have shown that the cytokines, including tumour necrosis factor (TNF) and IL-6, are important in classic inflammatory reactions, but also in energy metabolism regulation. In turn, a complex cytokines-hormones-metabolism network with various phenotype profiles is formed, probably due to various polymorphisms that produce variable cytokine transcription responses. However, little information is available about the characteristics of the phenotypes of these polymorphisms and about how these are distributed. The authors produced interesting data about IL-6 G/C polymorphism in relation to plasma lipid levels. They not only confirmed greater hyperlipidaemia in the C/G and G/G genotype relative to the C/C genotype, but that patients displaying a G allele also exhibited distinctly higher basal insulinaemia levels, a result favouring the theory that IL-6 may be responsible for the lipid changes associated with insulin resistance syndrome. This fact is particularly important in view of the fact that, in this study, there were no discernible differences between the two genotypes at an anthropometric level. A possible association

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between the lipid changes through IL-6 polymorphism and other metabolic changes, as these authors suggested, merits further study. Body mass index, diabetes and C-reactive protein among US adults E S Ford. Diabetes Care 1999; 22(12):1971–7. BACKGROUND. The author examined the relationship between C-reactive protein (CRP), body mass index (BMI) and diabetes status among 16 573 participants aged≥20 years of the Third National Health and Nutrition Examination Survey (NHANES III) (1988–1994) in a cross-sectional design. The geometric mean concentrations of CRP were lowest among individuals with a BMI<18.5 kg/m2 and increased with increasing BMI categories. Restricting the analysis to participants without various medical conditions did not change the relation. After adjusting for age, sex, race or ethnicity and education, the ORs for an elevated CRP concentration among participants with a BMI of 25 to<30, 30 to<35, 35 to<40, and≥40 kg/m2 were 1.51, 3.19, 6.11 and 9.30, respectively, as compared with participants with a BMI<25 kg/m2. The CRP concentrations were lowest among individuals without diabetes or with IFG and highest among those with newly or previously diagnosed diabetes. Compared with participants with a normal fasting

glucose (NFG)T participants with IFG, newly diagnosed diabetes and previously diagnosed diabetes had 0.99, 1.84 and 1.59 odds of having an elevated CRP concentration after adjustment for age, sex, race or ethnicity, education and BMI. These results confirm cross-sectional findings from previous studies that have shown elevated CRP concentrations among individuals who are obese or have diabetes. However, the implications of these findings remain unclear.

Comment The author analysed the results from the NHANES III. The levels of CRP, which is a marker of subclinical inflammation, in this group of 16 573 participants were found to be positively associated with BMI. Patients with known diabetes or with newly diagnosed diabetes had higher CRP levels than patients with NFG or IFG. Thirtyfour to thirty-nine percent of individuals with diabetes had elevated CRP and this was not completely explained by their BMIs. CRP was also positively associated with insulin concentrations, HbA1c concentrations and glucose levels. The interest in these exhaustive analyses relies on the fact that CRP has been correlated with evidence of micro-angiopathy in type 2 diabetic subjects. In addition, CRP has been identified as a risk marker of CVD in different large-scale prospective studies such as the Physician’s Health Study |3|. Pickup et al. |4| postulated that syndrome X and diabetes may be manifestations of an ongoing acute-phase response that may represent a chronic adaptation of the immune system. Among the potential mechanisms that may link obesity, syndrome X, diabetes and vascular disease, TNF-α production and IL-6 production by the adipose tissue, which are stimulators of CRP production, are good candidates. The relationship of CRP and morbidity-mortality in obese and diabetic individuals should be assessed in longitudinal studies. The author pointed out that research on the ability of CRP to predict future risk of diabetes may also prove fruitful. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the USA S H Mehta, F L Brancati, M S Sulkowski, S A Strathdee, M Szklo, et al. Ann Intern Med2000; 133:592–9.

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BACKGROUND. Hepatitis C virus (HCV) infection may contribute to the development of DM, but its biological mechanism remains unknown. In order to examine the prevalence of type 2 diabetes among persons with HCV infection in a representative sample of the general adult population of the USA, the authors carried out a cross-sectional national survey on 9841 persons older than 20 years of age for whom data on HCV infection and diabetes were complete. In the USA, type 2 diabetes occurs more often in persons with HCV infection who are older than 40 years of age.

Comment Many studies have linked HCV infection with changes in glucose tolerance |5|. Although this association is probably partly explained in terms of infection of the liver, the prime function of which is to metabolize carbohydrate, the prevalence of diabetes in patients infected with HCV without hepatic dysfunction tends to be higher than that of the population as a whole. Similarly, patients with HCV plus cirrhosis more often than not also present with type 2 diabetes (30% in HCV positive as opposed to 6% with cirrhosis and hepatitis B virus positive). This implies that some factor other than hepatic dysfunction is increasing the risk of developing type 2 diabetes. This population study evaluated over 9000 patients with or without HCV infection for the prevalence of type 2 diabetes, taking account of factors such as age, BMI, socioeconomic grading and other factors associated with the presence of diabetes. The highest incidence of type 2 diabetes occurred among patients infected with HCV, the extent of this difference being greater among the 40–49 year age group. Curiously, type 2 diabetes was no more prevalent among patients infected with HCV who were under 40 years of age. It could be speculated that certain agerelated biological changes are necessary or hepatic dysfunction needs to have deteriorated sufficiently or some extra-hepatic phenomenon is required before the risk of type 2 diabetes becomes manifest. The higher prevalence of DM in HCV-positive patients can be related to the degree of hepatic infection only if levels of liver disease are rated histologically, a task outside the scope of this study. However, a study aiming not at this objective specifically but at assessing the effect of treatment with interferon discovered that an inverse relationship existed between the degree of fibrosis, the first phase of insulin secretion and insulin sensitivity, indicating that the degree of liver infection was a determinant |6|. Von Willebrand factor, C-reactive protein and 5-year mortality in diabetic and non-diabetic subjects: the Hoorn Study A Jager, V W Van Hinsbergh, P J Kostense, J J Emeis, J S Yudkin, et al. Arterioscler Thromb Vasc Biol 1999; 19(12):3071–8. BACKGROUND. Increased levels of Von Willebrand factor and CRP predict cardiovascular mortality in selected populations. This study investigated the association of Von Willebrand factor and CRP with cardiovascular and all-cause mortality among diabetic and non-diabetic subjects. An age-, sex- and glucose tolerance-stratified sample (n=631) of a population-based cohort aged 50–75 years was followed prospectively for 5 years. After 5 years of follow-up, 58 subjects had died (24 from cardiovascular causes). The Von Willebrand factor (> 1.56 lU/ml) and CRP (>2.84 mg/l) levels in the upper tertile were associated with

three- and twofold increases, respectively, in cardiovascular mortality after adjustment for age, sex and glucose tolerance status. Analyses in non-diabetic and diabetic subjects separately gave similar results. Increased levels of Von Willebrand factor are independently associated with cardiovascular and

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all-cause mortality in both diabetic and non-diabetic subjects. The association between increased levels of CRP and cardiovascular mortality was partly explained by other risk factors. Mutual adjustment of Von Willebrand factor and CRP did not markedly change the results, favouring the hypothesis that Von Willebrand factor and CRP predict mortality through different pathways.

Comment This longitudinal study analysed whether Von Willebrand factor and CRP predict cardiovascular and allcause mortality in diabetic and non-diabetic individuals. Several prospective studies have shown that CRP levels predict the risk of cardiovascular events and mortality in the general population |3|. However, this is the first study to show that this association also applies to the diabetic population. The authors concluded that Von Willebrand factor and CRP predict cardiovascular mortality in diabetic individuals by acting on different pathways: thrombosis and in-flammation. These observations are important in cardiovascular risk assessment and in designing drug prevention strategies in the diabetic population, which has indeed a high cardiovascular risk. Hypertension and anti-hypertensive therapy as risk factors for type 2 diabetes mellitus T Gress, J Nieto, E Shahar, M Wofford, F Brancati, forthe Atherosclerosis Risk in Communities Study. N Engl J Med 2000; 342:905–12. BACKGROUND. Previous research has suggested that thiazide diuretics and beta blockers may promote the development of type 2 DM. The authors conducted a prospective study of 12 550 adults of 45–64 years old who did not have diabetes. The incidence of new cases of diabetes was assessed after 3 and 6 years by measurement of fasting serum glucose concentrations. After simultaneous adjustment for age, sex, race, education, adiposity, family history with respect to diabetes, physical activity level, other health-related behaviour and coexisting illnesses, subjects with hypertension who were taking thiazide diuretics were not at greater risk for the subsequent development of diabetes than subjects with hypertension who were not receiving any anti-hypertensive therapy (relative hazard=0.91). Likewise, subjects who were taking angiotensin-converting enzyme (ACE) inhibitors and calcium channel antagonists were not at greater risk than those not taking any medication. In contrast, subjects with hypertension who were taking beta blockers had a 28% increased risk of subsequent diabetes (relative hazard=1.28). The use of beta blockers appears to increase the risk

of diabetes, but this adverse effect must be weighed against the proven benefits of beta blockers in reducing the risk of cardiovascular events.

Comment This was a prospective study involving an open anti-hypertensive treatment regimen aimed at clarifying the possible relationship between different anti-hypertensive agents and the risk of developing DM. The DM incidence was higher among the group of patients receiving beta blockers and this relationship persisted after adjustment for confounding variables. The underlying mechanism for explaining the increased risk of diabetes with beta blocker therapy remains unclear since treatment was not associated with weight gain or hyperinsulinaemia. On the other hand, the authors pointed out that the proven benefits of beta blockers for lessening the risk of cardiovascular events are incontrovertible and, hence, their use must be considered despite the risk of DM development by patients with cardiovascular risk factors. Another

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important outcome of this study is that it proved that other anti-hypertensives (thiazide diuretics, ACE inhibitors and calcium antagonists) do not have adverse metabolic effects and, consequently, do not carry the risk of developing DM. Cardiovascular risk factors clustering with endogenous hyperinsulinaemia predict death from coronary heart disease in patients with type 2 diabetes S Lehto, T Ronnemaa, K Pyorala, M Laakso. Diabetologia 2000; 43:148–55. BACKGROUND. Information on the association of hyperinsulinaemia with coronary heart disease (CHD) in patients with type 2 (non-insulin-dependent) diabetes is limited and controversial. Therefore, the authors carried out a prospective study in order to examine the predictive value of fasting plasma insulin and ‘hyperinsulinaemia cluster’ with regard to the risk of CHD mortality. The results support the notion that cardiovascular risk factors clustering with endogenous hyperinsulinaemia increase the risk of death from CHD in type 2 diabetes patients who are not treated with insulin.

Comment The risk factors for CHD were studied in 902 type 2 diabetes patients aged 45–64 years who were not treated with insulin. The participants were followed prospectively for up to 7 years for cardiovascular mortality. The authors found that CHD mortality (16.2% in men and 9.2% in women) increased significantly with increasing plasma insulin tertiles (P=0.006 for men and P=0.09 for women). The predictive value of hyperinsulinaemia with regard to CHD death was independent of conventional cardiovascular risk factors, including total cholesterol, smoking and hypertension, but not from risk factors clustering with hyperinsulinemia. By applying factor analysis, they showed that hyperinsulinemia cluster (a factor with positive loadings for BMI, TGs and insulin and negative loadings for HDL cholesterol components of the insulin resistance syndrome) was predictive of death from CHD in patients with type 2 diabetes (hazard ratio=1.43 and with 95% confidence interval (CI)=1.18– 1.73) (P<0. 001). These results are in accordance with the Paris Prospective Study, which showed that, during an 11year follow-up, high fasting plasma insulin predicted the risk of CHD death in both subjects with type 2 diabetes and in non-diabetic individuals. Moreover, the present study found that clustering of cardiovascular risk factors with hyperinsulinemia is a strong predictor of CHD death in patients with type 2 diabetes even after adjustment for a previous history of myocardial infarction. Interventions aimed at reducing hyperinsulinemia cluster (weight loss, exercise and insulin-sensitizing agents) may prove beneficial in the prevention of CHD death in patients with type 2 diabetes. Insulin-resistant pre-diabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the pre-diabetic state S M Haffner, L Mykkanen, A Festa, J P Burke, M P Stern. Circulation 2000; 101:975–80. BACKGROUND. Subjects who convert to type 2 DM have increased cardiovascular risk factors. However, it is not known whether these atherogenic changes result from insulin resistance, decreased insulin secretion or both. Atherogenic changes in the pre-diabetic state are mainly seen in insulinresistant subjects and strategies to prevent type 2 diabetes might focus on insulin-sensitizing interventions rather than interventions that increase insulin secretion because of potential effects on cardiovascular risk.

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Comment The authors examined whether insulin resistance or decreased insulin secretion is responsible for the atherogenic pre-diabetic state in a 7-year follow up of the San Antonio Heart Study. In this prospective population-based study of diabetes and cardiovascular risk in Mexican-Americans and non-Hispanic Whites, 195 out of 1734 subjects converted to type 2 diabetes. Insulin resistance was assessed by the homeostasis model assessment (HOMA) and insulin secretion was assessed by the ratio of early insulin increment to early glucose increment (∆I30–0/∆G30–0) during an OGTT. Fifty-four percent of converters had both an insulin secretory defect and were insulin resistant as compared with 1.5% of converters who were insulin sensitive with good secretion at baseline. Twenty-eight percent of converters had insulin resistance with good insulin secretion and 15.9% had low insulin secretion but were insulin sensitive. At baseline, converters had significantly higher BMIs, waist circumferences, TG concentrations and blood pressures (BP) and lower HDL cholesterol levels than non-converters. Adjusting for HOMA insulin resistance, the differences between converters and non-converters were no longer significant, whereas when adjusting for insulin secretion (∆I30–0/∆G30–0) the differences persisted. Comparison of predominant insulin-resistant converters (n=56) with those with a predominant decrease in insulin secretion (n=31) and with non-converters (n= 1539) revealed that only converters who were insulin resistant had higher BP and TG levels and lower HDL cholesterol levels than non-converters. These important data provide information to support the use of insulin-sensitizing strategies rather than interventions that promote insulin secretion in preventing type 2 diabetes, because of the potential beneficial effects on cardiovascular risk. Response of pancreatic β cells to improved insulin sensitivity in women at high risk of type 2 diabetes T A Buchanan, A H Xiang, R K Peters, S L Kjos, K Berkowitz, et al. Diabetes 2000; 49:782–8. BACKGROUND. The purpose of this study was to examine the response of pancreatic β cells to changes in insulin sensitivity in women at high risk of type 2 diabetes. OGTTs and frequently sampled intravenous glucose tolerance tests (FSIGTs) were conducted on Latino women with IGT and a history of gestational diabetes before and after 12 weeks of treatment with 400 mg/day troglitazone (n= 13) or placebo (n=12). Insulin sensitivity was assessed by minimal model analysis and β cell insulin release was assessed as acute insulin responses (AIRs) to glucose (AIRg) and tolbutamide (AIRt) during FSIGTs and as the 30-minute incremental insulin response during OGTTs. β cell compensation for insulin resistance was assessed as the product of minimal model insulin sensitivity and each of the three measures of β cell insulin release. There was no significant change in insulin sensitivity or in any measure of insulin release, β cell compensation for insulin resistance or glucose tolerance in the placebo group. Troglitazone treatment resulted in a significant increase in insulin sensitivity, as reported previously. The predominant response of β cells to improved insulin sensitivity in women at high risk of type 2 diabetes was a reduction in insulin release in order to maintain nearly constant glucose tolerance.

Comment Women who develop gestational diabetes have a high risk of developing established type 2 DM over the subsequent 15–20 years. In this study, women with a history of gestational diabetes were treated with the thiazolidinedione troglitazone and compared with placebo for 12 weeks in order to

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Table 8.1 Parameters from FSIGTs at baseline and after 12 weeks of study Troglitazone group

Placebo group Intergroup

Variable Insulin sensitivity S1 (min1 µU/ ml×104) β-Cell function Fasting insulin (pmol/l) AIRg (pmol/ l×min) AIRt (pmol/ l×min) Glucose and glucose tolerance Fasting glucose (mmol/l) Average glucose, 19–40 min (mmo1/1) Kg10–19 (min1×100) Kg19–40 (min1×100) Sg (min1×100) β-Cell compensation for insulin resistance S1×AIRg S1×AIRt

Baseline

12 weeks

P

Baseline

12 weeks

P

P

2.29±1.91

3.80±0.64

0.002

2.41±1.53

2.04±0.79

0.24

0.0007

109±72

67±82

0.001

98±41

86±16

0.29

0.08

3504 ±3228

3540 ±3198

0.90

3078 ±3168

3306 ±2334

0.58

0.70

8604 ±4788

5904 ±4626

0.0001

6816 ±4224

7350 ±4314

0.42

0.0004

5.4±0.5

5.1±0.4

0.002

5.4±0.3

5.3±0.3

0.21

0.06

11.1±1.1

10.4±1.0

0.001

11.1±0.8

11.0±0.6

0.54

0.06

1.32±0.44

1.50±0.41

0.10

1.42±0.30

1.45±0.33

0.77

0.31

1.47±0.58

1.58±0.56

0.40

1.45±0.48

1.50±0.52

0.76

0.77

1.41±0.34

1.49±0.39

0.94

1.44±0.20

1.51±0.36

0.56

0.90

5784 ±3954 14 266 ±7446

8880 ±3780 16 014 ±7356

0.004

5478 ±3618 13 200 ±7590

5718 ±2466 12 996 ±5910

0.76

0.02

0.90

0.35

0.22

AIRg, the incremental area under the plasma insulin curve during the first 10 min after glucose injection; AIRt, the incremental insulin area during 20 min after tolbutamide injection calculated relative to the 19-minute plasma insulin concentration; Kg10–19 the fractional glucose disappearance rate (×100) between 10 and 19 min after glucose injection; Kgl9–40, the fractional glucose disappearance rate (×100) between 19 and 40 min after glucose injection; S,, the minimal model insulin sensitivity index; S , the minimal model glucose effectiveness (fractional glucose disappearance at basal insulin) (Sg). The data are means±SDs. The troglitazone and placebo group P-values were by a paired t-test within a group and the intergroup P-values were by between-group comparison of the change from baseline using a non-paired t-test.

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Troglitazone group

165

Placebo group Intergroup

Variable Baseline 12 weeks P Baseline 12 weeks *The means of 19-, 22-, 24-, 25-, 27-, 30- and 40-minute plasma glucose concentrations. Source: Buchanan et al. (2000).

P

P

assess the effect of improved insulin sensitivity on the function of the pancreatic β cell. The results were encouraging (Table 8.1). Although troglitazone has been withdrawn from world markets due to hepatotoxic side-effects, two second-generation thiazolidinediones are now available, namely rosiglitazone and pioglitazone. The former agent has also been shown to improve β cell function in established type 2 diabetes patients when used in combination with metformin |7|. It is also of interest that, in a rodent model of type 2 diabetes, pancreatic islet hyperplasia, ultrastructural evidence of β cell work hypertrophy and derangement of a cell distribution within the islet were prominent features of Zucker fatty control rats, but that these adaptive changes were ameliorated (intervention group) or prevented (prevention group) by rosiglitazone treatment |8|. More research is needed into the potential long-term effects of this new class of drug on the natural history of β cell dysfunction in the evolution of type 2 diabetes. Polymorphism of the tumor necrosis factor-α receptor 2 gene is associated with obesity, leptin levels and insulin resistance in young subjects and diet-treated type 2 diabetic patients J M Fernandez-Real, J Vendrell, W Ricart, M Broch, C Gutierrez, et al. Diabetes Care 2000; 23:831–7. BACKGROUND. The purpose of this study was to evaluate a polymorphism in the 3’-untranslated region of the TNF-α receptor 2 gene on chromosome 1 in relation to BMI, leptin levels and insulin resistance. Using single-strand conformation polymorphism, the polymorphism was analysed in 107 nondiabetic subjects (60 women and 47 men) and in 110 consecutive patients with type 2 diabetes (79 women and 31 men). Insulin sensitivity (minimal model analysis) was also evaluated in a subset of 33 healthy subjects. The presence of the A2 allele in the TNF-α receptor 2 gene may predispose subjects to obesity and higher leptin levels, which may in turn predispose them to insulin resistance or vice versa. The TNFα receptor 2 gene may be involved in weight control mechanisms.

Comment The authors identified a polymorphism in the TNF-α receptor 2 gene that may be associated with body weight regulation and insulin resistance. The authors analysed a polymorphism in the 3'-untranslated region of the TNF-α receptor 2 gene on chromosome 1 using single-strand conformation polymorphism. Four alleles of the TNF-α receptor 2 gene were identified (Al, A2, A3 and A4). BMI and serum leptin were increased in young (<54 years old) carriers of the A2 allele. In contrast, the polymorphism was not associated with BMI in diabetic patients treated with oral agents or insulin. No differences in soluble TNF-α receptor 2 levels were detected among the different TNF-α receptor 2 variants. Carriers of the A2 allele showed higher BMIs, fat masses, waist to hip ratios, serum total and VLDL TG levels and leptin levels and had a lower insulin sensitivity index than non-carriers of the A2 variant. The frequency of different alleles was similar in diabetic versus non-diabetic patients. However, diet-treated diabetic subjects who were carriers of the A2 allele exhibited higher BMIs and leptin levels than diet-treated non-carriers of the A2 allele.

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There has been increasing evidence that TNF-α plays a key role in mediating insulin resistance as a result of obesity. TNF-a signals through at least two cell surface receptors: TNF-a receptor 1 and TNF-α receptor 2. Mice lacking TNF-α receptors display alterations in their leptin levels and insulin sensitivity. TNF-α in humans is over-expressed in the adipose and muscle tissues of obese subjects in proportion to their degree of insulin resistance. This study links genetic variants in the TNF-α receptor gene with body weight and insulin resistance. In a prior study the authors showed that soluble TNF-α receptor 2 levels were associated with BMI, the waist to hip ratio and insulin resistance, whereas none of these variables was correlated with soluble TNF-α receptor 1 levels. Although in the present study, no differences in soluble TNF-α receptor 2 levels were found among the different allele variants, the authors proposed that hyperglycaemia and its treatment could have masked differences between patients. Another potential explanation that arises from the study is that polymorphism in the TNF-α receptor 2 gene may represent markers for another susceptibility gene in this region. In this regard, a linkage was found between several microsatellite markers near the TNF-α receptor 2 gene and BMI and fat mass as well as fasting insulin in the Quebec Family Study |9|. In conclusion the authors proposed that TNF-α receptor 2 gene variants can be associated with body weight regulation, leptin levels and insulin resistance. Further studies will be needed in order to determine the molecular mechanism by which this association occurs. Insulin sensitivity and secretion influence the relationship between growth hormone-binding protein and leptin J M Fernandez-Real, M L Granada, A Ruzafa, R Casamitjana, W Ricart. Clin Endocrinol 2000; 52:159–64. BACKGROUND. A direct relationship between BMI, visceral adipose tissue, insulin levels and growth hormone-binding protein (GHBP) activity has consistently been reported. It was recently described that GHBP depends directly on serum leptin levels. Since leptin covaries with insulin secretion and/or sensitivity, the authors aimed to study the influence of these variables on plasma GHBP activity. In order to isolate the effects of obesity per se from those of insulin secretion, three groups of subjects were prospectively studied: 14 lean subjects, ten obese subjects and nine obese subjects with glucose intolerance. The subjects’ percentage of body fat was measured through bioelectric impedance, their insulin

sensitivity and secretion was determined through an FSIGT with minimal model analysis, their serum leptin was measured by radioimmunoassay and their GHBP activity was determined by the highperformance liquid chromatography-gel filtration method. The subjects' plasma GHBP activity was found to correlate circumference (r=0.64 and P<0.001), waist to hip ratio (r=0.42 and P=0.01), with their BMI (r=0. 65 and P<0.0001), fat mass (r=0.51 and P=0.003), waist insulin sensitivity (r=0.61 and P=0. 0001), insulin secretion (r=0.48 and P= Table 8.2 Anthropometrical and biochemical variables of the study subjects Variable

Lean

Obese

Ob-lntol

ANOVA(P)

n Men/women Age (years)

14 8/6 33.2±5.3

10 5/5 37.2±6.5

9 5/4 38.7±3.8

NS NS

TYPE 2 DIABETES MELLITUS AND CARDIOVASCULAR RISK

Fig. 8.1 Association between plasma GHBP levels and (a) insulin sensitivity and (b) leptin levels. Solid triangles, control subjects; open circles, obese subjects; solid circles, obese subjects with glucose intolerance. (a) r=−0.61 and P<0.0001. (b) r=−0.49 and P=0.004. Source: Fernandez-Real et al. (2000). Variable

Lean

Obese

Ob-lntol

ANOVA(P)

Body mass index (kg/ m2) Fat mass (kg) Waist-to-hip ratio Fasting glucose (mmol/l) Fasting insulin (mU/l) AUC glucose during OGTT (mmol/l)

22.7±2.9*

32.2±2.3

32.6±2.5

<0.00001

12.3±6.3* 0.94±0.06* 5±0.59

32.4±8 1.00±0.05 4.98±0.47

30.3±10.7 1.01±0.06 6.2±1.05

<0.00001 0.036 0.0005

7.5±2.4† 6.9±1.4

9.6±3.1 7.5±1.3

15.1±8.4† 12.1±2.4

0.0058 <0.00001

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Variable

Lean

Obese

Ob-lntol

ANOVA(P)

AUC insulin during OGTT (mmol/l) AIRg (mU/l) Insulin sensitivity (min−1mU/l) SD score-leptin GHBP (%) 95% Cl

55.2±32.2§

86.9±34.3

114.7±87.4

0.045

367.2±195.8† 3.89±1.6*

755.1±414.3 2.2±0.55

250.2±217.7† 0.99±0.98

0.0011 <0.00001

0.144±0.026* 23.5±6.03* 20.1−27.07

0.247±0.018 37.4±10.1 29.7−45.2

0.246±0.04 36.3±11.7 27.9−44.7

<0.00001 0.0012

Ob-lntol, obese subjects with glucose intolerance; AUC, glucose and insulin integrated area under the curve of the serum glucose and insulin concentrations measured in response to a 75 g oral glucose challenge; AIRg, acute insulin response to intravenous glucose; 95% Cl, 95% Cl for the mean. *Significantly different from the obese and obese-intolerant groups (P<0.05). †Significantly different from the obese group (P<0.05). Significantly different from the obese and lean groups (P<0.05). §Significantly different from the obese-intolerant group (P<0.05). Source: Fernandez-Real et al. (2000). 0.006) and leptin concentration (r=0.49 and P=0.004). Since insulin secretion and insulin sensitivity usually covary in glucose-tolerant subjects, the authors constructed a multiple linear regression for predicting GHBP activity. In this model, the insulin sensitivity, insulin secretion and leptin SD scores independently contributed to 34, 10 and 8% of the variability in serum GHBP activity, respectively. The results suggest that plasma GHBP activity is simultaneously influenced by insulin secretion and sensitivity and leptin. Perhaps leptin, through increased insulin secretion, might induce GHBP/GH secretion, thereby explaining the normal to high insulin-like growth factor 1 (IGF-1) levels found in overnutrition.

Comment Obesity is often accompanied by reduced growth hormone (GH) secretion and by increased specific activity of growth hormone-transporting protein (GHTP), which has high GH affinity. Strong evidence suggests that a direct relationship exists between BMI and the activityofGHTP|10|. The essential linking mechanism between GH secretion, GHTP and nutritional state is unknown. This study suggested that insulin and leptin secretion influences the plasma activity of GHTP and that insulin sensitivity may affect the plasma activity of GHTR The role of leptin in raising insulin secretion and GHTP/GH secretion provides a possible explanation of the normal to high levels of IGF-1 encountered in over-nutrition. Abnormal glucose tolerance and increased risk of cardiovascular disease in Japanese-Americans with normal fasting glucose D Liao, J B Shofer, E J Boyko, M J McNeely, D L Leonetti, et al. Diabetes Care 2001; 24:39–44. BACKGROUND. This study compared the American Diabetes Association (ADA) fasting glucose criteria and the World Health Organization (WHO) OGTT criteria for diagnosing diabetes and detecting people at increased risk of CVD. Of 503 patients with NFG, 176 had IGT and 20 had DM These patients had worse CVD risk factors than those with NGT. Patients with NFG who had IGT or

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DM had more intra-abdominal fat and total adiposity, higher insulin, C-peptide and TG levels, lower HDL cholesterol levels and higher BP than those with NGT. The authors concluded that classification by fasting glucose misses many Japanese-Americans with abnormal glucose tolerance and less favourable cardiovascular risk profiles.

Comment In 1997, the ADA recommended changes in the criteria for diagnosing diabetes. The oral glucose tolerance test (OGTT) was to be reserved solely for epidemiological and clinical studies and patients were to be categorized in terms of their fasting plasma glucose (FPG). The categories are normal fasting glucose (NFG) <6.1 mmol/1, impaired fasting glucose (IFG) 6.1−7.0 mmol/1 and diabetes mellitus (DM)≤7.0 mmol/L However, the WHO is still recommending the 75 g OGTT for DM screening. Many recent studies have questioned the use of FPG for diagnosing diabetes owing to the extremely variable sensitivity displayed by different glucose tolerance categories based on fasting glycaemia. Similarly, the IFG is a heterogeneous group that includes patients with impaired glucose tolerance (IGT) and type 2 diabetes (based on the 75 g OGTT) and, hence, these patients have a greater chance of developing diabetic complications. The authors of this study therefore aimed to compare the ADA diagnostic criteria with those of the WHO for classifying patients into different glucose tolerance categories. They studied 596 Japanese-Americans, classified as NFG, IFG and DM Table 8.3 Distribution of 596 study subjects by fasting glucose and glucose tolerance categories Fasting glucose category (ADA criteria) Giucose tolerance category (WHO criteria)

Normal (n=503)

Impaired (n=59)

Diabetic (n=34)

Normal (n=307) Impaired (n=212) Diabetic (n=77)

306 176 20

0 36 23

0 0 34

The data are n values. Source: Liao et al. (2001).

in line with the ADA recommendations by means of fasting glucose. Glucose tolerance was defined as normal (NGT), impaired (IGT) and DM by subjecting each to an OGTT in line with the WHO diagnostic criteria. They likewise tested all participants in order to determine their fasting glucose, lipid profiles, Cpeptide levels, systolic and diastolic BPs and total and intra-abdominal fat using scanning techniques. The results revealed that all subjects graded NGT according to the WHO were graded NFG according to the ADA (Table 8.3). Of the 77 patients graded DM according to the WHO criteria, half were NFG or IFG and only 34 were DM according to the ADA criteria. Hence, compared to the WHO criteria, the ADA standards offer a 44% diabetes detection sensitivity. One major problem was that subjects with IGT exhibited a greater progression towards diabetes plus a series of intermediate metabolic alterations (higher plasma insulin, C-peptide and TG levels, lipoprotein alteration, lower HDL cholesterol and greater deposition of abdominal fat) between NGT and DMGT. The ADA’s IFG criteria failed to detect most individuals with IGT, as 83% of these had NFG and would slip

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through the net under the ADA criteria. They would therefore have a greater risk of cardiovascular complications but would remain undetected using ADA criteria alone. In conclusion, the ADA criteria based on fasting glucose have been introduced because they are much easier to perform than an OGTT, so there may be a rise in their use in screening and, consequently, diabetes detection. However, according to the results of this study, the ADA criteria are markedly less sensitive than those of the WHO for diagnosing diabetes and for detecting changes in glucose homeostasis (the WHO criteria detect twice as many diabetics as the ADA criteria). A number of diabetes diagnoses are missed when using the ADA criteria and this is an important group because it carries a high risk of developing DM plus a greater risk of cardiovascular complications than the general population. These data are supported by other earlier studies |11|. The authors nevertheless asserted that, regardless of this evidence, fasting glucose must be used for diagnosing diabetes owing to its simplicity and specificity in clinical practice, but that, for type 2 diabetes aetiology and pathogenesis, an OGTT must continue to be used. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus C Weyer, C Bogardus, D M Mott, R E Pratley. J CIin Invest 1999; 104:787–94. BACKGROUND. The aetiopathogenesis of type 2 DM is linked with three types of metabolic abnormalities: resistance to the effect of insulin, abnormal hormone secretion and anomalies in endogenous glucose production (EGP). However, the sequence with which these abnormaiities develop and their relative contributions to the deterioration in glucose tolerance remain unclear in the absence of a detailed longitudinal study. In this study, the authors monitored a group of 17 Pima Indians whose oral glucose tolerance declined progressively over a period of 5 years. The transition from NGT to IGT was associated with an increase in body weight, a decline in insulin-stimulated glucose disposal and a decline in the acute insulin secretory response to intravenous glucose, but no change in EGP. Progression from IGT to diabetes was accompanied by a further increase in body weight, further decreases in insulin-stimulated glucose disposal and the acute insulin secretory response and an increase in basal EGP. Thirty-one control subjects who retained NGT over a similar period also gained weight, but their acute insulin secretory response increased with decreasing insulin-stimulated glucose disposal. Thus, defects in insulin secretion and insulin action occur early in the pathogenesis of diabetes. Intervention to prevent diabetes should target both abnormalities.

Comment In recent years various prospective studies identifying a variety of factors giving a predisposition to and predicting the onset of type 2 DM have been published. In most of these, obesity, adverse changes in sensitivity to insulin and poor insulin secretion were the commonest symptoms. A previous prospective study of Pima Indians |12| assessed the predictive effect of insulin resistance and insulin secretory dysfunction separately for the progression from NGT to IGT and from IGT to diabetes. During each stage of the development of type 2 diabetes, insulin resistance and insulin secretory dysfunction were found to be independent predictors of worsening glucose tolerance. However, this paper was able to investigate the natural course of the illness in more detail in a group of people at risk of developing diabetes but presenting with NGT in terms of the changes in insulin sensitivity, insulin secretion and EGP.

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The fact that EGP does not decline during the initial stages of the natural history of diabetes should be stressed. Only after IGT has developed does the postprandial level of EGP increase demonstrably. Establishment of the relationship between EGP, post-prandial hyperglycaemia and the macrovascular pathology of type 2 DM is currently the subject of controversy. This study also confirms that the main difference between subjects who develop type 2 DM and those who do not reflects the inability of the former to compensate for the progressive decline in sensitivity to insulin by increasing endogenous insulin secretion. References 1.

2. 3. 4. 5. 6.

7. 8.

9.

10. 11.

12.

Kark JD, Selhub J, Adler B, Gofm J, Abramson JH, Friedman G, Rosenberg IH. Non-fasting plasma total homocysteine level and mortality in middle-aged and elderly men and women in Jemsalem. Ann Intern Med 1999; 131(5):321–30. Maxwell SR. Coronary artery disease—free radical damage, antioxidant protection and the role of homocysteine. Basic Res Cardiol 2000; 95 (Suppl 1): 165–71. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997; 336:976–9. Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute-phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 1997;40: 1286–92. Alexander GJ. An association between hepatitis C virus infection and type 2 diabetes mellitus: What is the connection? Ann Intern Med 2000; 133:650–1. Konrad T, Zeuzem S, Vicini P, Toffolo G, Briem D, Lormann J, Herrmann G, Berger A, Kusterer K, Teuber G, Cobelli C, Usadel KH. Evaluation of factors controlling glucose tolerance in patients with HCV infection before and after 4 months therapy with interferon-a. Eur J Clin Invest 2000; 30:111–21. Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000; 283(13):1695–702. Buckingham RE, Al-Barazanji KA, Toseland CD, Slaughter M, Connor SC, West A, Bond B, Turner NC, Clapham JC. Peroxisome proliferator-activated receptor-gamma agonist, rosiglitazone, protects against nephropathy and pancreatic islet abnormalities in Zucker fatty rats. Diabetes 1998; 47(8):1326–34. Chagnon YC, Perusse L, Lamothe M, Chagnon M, Nadeau A, Dionne FT, Gagnon J, Chung WK, Leibel RL, Bouchard C. Suggestive linkages between markers on human Ip32-p22 and body fat and insulin levels in the Quebec Family Study. Obesity Res 1997; 5:115–21. Holl RW, Snehotta R, Siegler B, Scherbaum W, Heinze E. Binding protein for human growth hormone: effects of age and weight. Hormone Res 1991; 35(5):190–7. Gimeno SG, Ferreira SR, Franco LJ, lunes M. Comparison of glucose tolerance categories according to World Health Organization and American Diabetes Association diagnostic criteria in a population-based study in Brazil. The Japanese-Brazilian Diabetes Study Group. Diabetes Care 1998; 21:1889–92. Weyer C, Tataranni PA, Bogardus C, Pratley RE. Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Diabetes Care 2001; 24(1):89–94.

9 Diabetes and obesity

Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults S B Heymsfield, K R Segal, J Hauptman, C P Lucas, M N Boldrin, et al. Arch Intern Mec/2000; 160(9):13 321-6. BACKGROUND. Orlistat is a gastrointestinal lipase inhibitor that reduces dietary fat absorption and promotes weight loss. In order to test the hypothesis that orlistat combined with dietary intervention improves glucose tolerance and prevents the worsening of diabetes more effectively than placebo, the authors pooled the data from 675 obese adults in three randomized, double-blind, placebo-controlled, multicentre clinical trials. After a 4-week run-in period during which patients received a low-calorie diet plus placebo they were randomized to receive continued placebo or orlistat 120 mg three times daily for a treatment period of 104 weeks. The primary end-points of the study were the categorical assessment of glucose tolerance (normal, impaired or diabetic) and changes in status from randomization to the end of treatment. The secondary measures were fasting and post-challenge glucose and insulin levels. The mean length of follow-up was 582 days. Subjects who were treated with orlistat lost more weight (mean±-SEM 6.72±0.41 kg from their initial weight) than subjects who received placebo (mean±-SEM 3.79±0.38 kg) (P<0.001). A smaller percentage of subjects with impaired glucose tolerance (IGT) at baseline progressed to diabetic status in the orlistat (3.0%) versus placebo (7.6%) group. Conversely, among subjects with IGT tolerance at baseline, the glucose levels normalized in more subjects after orlistat treatment (71. 6%) versus placebo (49.1%) (P=0.04). The addition of orlistat to a conventional weight loss regimen significantly improved oral glucose tolerance and diminished the rate of progression to the development of IGT and type 2 diabetes.

Comment This study contributes to existing knowledge about the benefits of weight reduction on deteriorating diabetes status. It provides information on patients who received 2 years of orlistat therapy in combination with a low-calorie diet. The mean length of follow up was 582 days. Despite a relatively small difference in body weight, amounting to 3 kg, between the two treatment groups, there was a signifi © Clinical Publishing Services Ltd

cant reduction in progression from IGT to diabetes and an increase in patients whose glucose tolerance improved. Interest in the use of anti-obesity drugs in the management of overweight type 2 diabetes patients has been growing due to the potential improvements in cardiovascular risk factors associated with successful

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weight loss. In a previous multicentre trial in 391 patients with type 2 diabetes orlistat therapy in combination with a calorie-restricted diet resulted in significantly greater improvements than placebo in several lipid parameters, namely greater reductions in total and low-density lipoprotein (LDL) cholesterol triglycerides (TGs), apolipoprotein B and the LDL to HDL (high-densitylipoprotein) cholesterol ratio |1|. Overall, this study provides interesting results on the benefits of orlistat in combination with a calorierestricted diet in preventing deterioration in glucose tolerance. Current prescribing guidelines for orlistat advise a treatment limit of 2 years, but it is not clear whether weight loss will be sustained in the long term. In a multicentre trial looking at this issue |2|, non-diabetic obese adults (body mass index (BMI)=30–43 kg/ m2) received a calorie-controlled diet and either placebo three times a day or 120 mg orlistat three times a day for 1 year. After 1 year, the subjects began a weight maintenance diet. One group (n=133) continued to receive placebo whilst orlistat-treated subjects were re-randomized to receive either placebo three times a day (n–138) or 60 mg (n=152) or 120 mg (n=153) orlistat three times a day for an additional year. During the first year orlistat-treated subjects lost significantly more weight (mean 8.76 kg) than placebotreated subjects (5.81 kg), but all groups regained some weight during the second year. Subjects treated with 120 mg orlistat three times a day during years 1 and 2 regained less weight during year 2 (3.2 kg, a 35.2% regain) than those who received 60 mg orlistat (4.26 kg, a 51.3% regain) or placebo (5.63 kg, a 63.4% regain) in year 2 (P<0.001). Benefits in terms of improvements in their fasting LDL cholesterol and insulin levels were seen in the group treated with 120 mg orlistat three times a day. It is clear from these data that longer term studies over several years are needed in order to establish whether the benefits on glucose tolerance and other vascular risk factors suggested by these reports can be sustained. The effect of orlistat on body weight and coronary heart disease risk profile in obese patients: the Swedish Multimorbidity Study F Lindgarde. J Intern Med 2000; 248:245–54. BACKGROUND. The aim of this study was to assess the effect of orlistat on body weight and cardiovascular risk amongst obese patients at high coronary risk. A total of 382 obese adults (BMI=28 −38 kg/m2) with type 2 diabetes, hypercholesterolaemia and/or hypertension were recruited, 376 of whom

were randomized to orlistat or placebo. After 1 year the mean weight loss was significantly greater with orlistat as compared with placebo (5.9 versus 4.6%) (P<0.05). Orlistat was also associated with significantly greater improvements than placebo in LDL cholesterol (−7.0 versus−1.1%) (P<0.05), total serum cholesterol (−3.3 versus -0.5%) (P<0.05), fasting glucose (5.1 versus −0.1%) (P<0.01) and glycosylated haemoglobin (HbA1c) (−2.7 versus − 0.5%) (P<0.05). Treatment with orlistat in conjunction with diet promoted significantly greater weight loss and cardiovascular risk factor reduction than diet alone amongst obese patients at high risk of future coronary events.

Comment This study assessed the effect of orlistat on cardiovascular risk factors in a cohort of people at risk of coronary disease. As expected, the observed weight loss was greater in the orlistat group than in the placebo group, although the difference was small in terms of the overall percentage body weight. The additional weight loss in the orlistat-treated group was associated with clinically significant improvements in their fasting

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glucose and HbA1c, but much smaller differences in their lipid profiles. For example, there was a 3.3% improvement in total cholesterol compared with the commonly achieved reductions of 25% using statin medication. There were no reported differences in blood pressure (BP). It is uncertain whether the use of orlistat alone will therefore achieve sufficient improvements in certain cardiovascular risk factors to avoid using conventional drugs. A recent economic health assessment of 14 published, randomized, controlled trials |3| has attempted to systematically assess the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. Most of these trials showed greater weight loss and better weight maintenance with orlistat as compared to placebo for all end-points (statistically significant differences for both outcomes). A regime of 120 mg orlistat three times daily was the optimum in terms of weight loss. Most trials showed significant improvement in at least some lipid concentration parameters and in three of the trials orlistat produced statistically significant reductions in BP relative to placebo. Orlistat resulted in a significantly greater weight loss at 1 year compared with placebo in obese patients with type 2 diabetes and some parameters of glycaemic control and lipid concentration also showed significantly greater improvements compared with placebo. The incidence of adverse gastrointestinal events was consistently higher in the orlistat groups compared with placebo and orlistat use was associated with lower serum levels of fat-soluble vitamins. The cost per quality-adjusted life year for orlistat was £ 45 881, which is a relatively expensive intervention. The authors concluded that, although many trials have demonstrated statistically significant differences between groups in terms of weight loss in favour of orlistat versus placebo, the differences may not always be of clinical significance. Further studies are needed in order to evaluate the clinical significance of using orlistat in the treatment of obesity, type 2 diabetes and associated cardiovascular risk factors before it can be widely recommended. Effect of long-term treatment with metformin added to a hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese women with and without polycystic ovary syndrome R Pasquali, A Gambineri, D Biscotti, V Vicennati, L Gagliardi, et al. J Clin Endocrinol Metab 2000; 85:2767–74. BACKGROUND. This study assessed whether the use of metformin in women with polycystic ovary syndrome (PCOS) enhances the effect of a low-calorie diet by improving their sensitivity to insulin and the resulting hyperandrogenism and also investigated whether changes in weight and fat distribution might be associated with the use of metformin. The authors conducted a 6-month, randomized, placebocontrolled, intervention study in 20 obese (BMI>28 kg/m2) women with PCOS and age-, weight- and body fat distribution-matched controls. Baseline measurement of their sex hormone, sex hormone-binding globulin (SHBG) and serum leptin concentrations were performed and the subjects underwent an oral glucose tolerance test (OGTT) and computerized tomography (CT) at the L4–L5 level in order to measure their subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) areas. These measures were repeated after a 1-month low-calorie diet (1200– 1400 kcal/day) alone. While continuing the dietary treatment the women were randomized to receive metformin (850 mg twice daily) with a double-blind design for the following 6 months. All assessments were repeated at the end of the study period. Three women from the control group (all treated with placebo) were excluded because of noncompliance and two PCOS women, both treated with metformin, were excluded because they became pregnant. Metformin therapy improved hirsutism and menstrual cycles significantly more than placebo in the PCOS group. Hypocaloric dieting for 1 month reduced the BMI values and waist circumferences in both the PCOS and control groups, without any significant effect on the CT scan parameters. However, metformin treatment reduced the women’s body weight and BMI significantly more than placebo in both the PCOS and control women. Metformin significantly decreased the SAT values in both

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groups, although the SAT changes were significantly greater than with placebo treatment in the control group only. The VAT values decreased significantly during metformin treatment in both the PCOS and control groups, but the effect was significantly higher than with placebo only in the PCOS women. Fasting insulin significantly decreased in both the PCOS women and controls, regardless of treatment, whereas glucose-stimulated insulin decreased significantly only in the PCOS women and controls treated with metformin. The levels of luteinizing hormone (LH), follicle-stimulating hormone, dehydroepiandrosterone sulphate and progesterone were unchanged in both groups, whereas the testosterone concentrations decreased in the PCOS women treated with metformin. The SHBG concentrations remained unchanged in all PCOS women, whereas in the control group they increased significantly after

both metformin and placebo. The leptin levels only decreased during metformin treatment in both the PCOS and control groups.

Comment Abdominal obesity and hyperinsulinaemia play a key role in the development of PCOS. Dietary-induced weight loss and the administration of insulin-lowering drugs such as metformin are usually followed by improved hyperandrogenism and related clinical abnormalities. A 12-week trial in women with PCOS treated with metformin resulted in a decline in insulin as well as their total and bioavailable testosterone, leading to significant improvement in clinical manifestations of hyperandrogenism |4|. Other reported clinical benefits of metformin include a greater success rate with ovulation induction therapy using clomiphene in women with PCOS who take metformin |5|. This was a well-conducted, detailed study of a small cohort of women with PCOS compared with controls. The beneficial effects of metformin on the clinical features of PCOS were confirmed in a longer duration trial. In addition, important effects of metformin on the women's VAT and SAT areas were studied and showed significant reductions in the VAT areas with metformin therapy in PCOS women. Since VAT is associated with insulin resistance the trial provides one possible mechanism by which metformin exerts its beneficial effects. Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus K Fujioka, T B Seaton, E Rowe, C A Jelinek, P Raskin, et al. and the Sibutramine/Diabetes Clinical Study Group. Diabetes Obesity Metab 2000; 2:175–87. BACKGROUND. The aim of this study was to determine the efficacy and tolerability of sibutramine hydrochloride in obese patients whose type 2 diabetes was poorly controlled on diet alone or with an oral anti-diabetic agent. This study was a 24-week, double-blind, multicentre trial following a 5-week placebo run-in period. One hundred and seventy-five obese (BMI≥27 kg/m2) patients with poorly controlled type 2 diabetes mellitus (DM) were randomized to either sibutramine or placebo at 16 participating centres. In order to achieve moderate calorie restriction, sibutramine was titrated up by 5 mg biweekly through to week 6 and maintained at 20 mg through to week 24. The parameters measured included changes in weight, BMI, waist and hip circumference, glycaemic control, lipid profile, quality of life and adverse events. When comparing those who completed the course at week 24, sibutramine compared with placebo patients showed significantly greater (P<0.001) absolute (−4.3 versus −0.4 kg) and percentage (−4.5 versus −0,5%) weight losses. Weight losses of >5% or 10% were achieved by 33 and 8% of sibutramine patients, respectively, but no placebo

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Fig. 9.1 Disposition of randomized patients. Source: Fujioka et al. (2000). patients (P<0.03 or better). The improvement in glycaemic control was correlated with weight loss (P<0.001). Sibutramine patients also showed improvements in their fasting insulin, TGs, HDL cholesterol

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Fig. 9.2 (a) Mean change from baseline in HbA1c relative to placebo (LOCF). *P<0.05 versus all of the placebo group (n=82) and HbA1c expressed in typical (%) units. (b) Mean change from baseline fasting plasma glucose (FPG) (LOCF). *P<0.05 versus all of the placebo group (n=84). Source: Fujioka et al. (2000). and quality of life. Sibutramine was well tolerated compared with placebo. Sibutramine produced significant weight loss when used in combination with recommendations for moderate caloric restriction. This weight loss was associated with improvements in metabolic control and quality of life.

Comment Obesity is a chronic metabolic illness that is widespread at the present time, in particular in the Western world. Type 2 DM is twice as prevalent in the obese as in the population at large. Sibutramine works by inhibiting noradrenaline and 5-hy Table 9.1 Baseline demographic and clinical characteristics (last observation carried forward [LOCF] analysis) Parameter

Sibutramine

Placebo

No. (%) of patients Sex: No. (%) M : F Race: Caucasian/black/other

89 (51) 51 (57):38 (43)

86 (49) 42 (49):44 (51)

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Parameter

Sibutramine

Placebo

No. of patients % of patients Age (years) Diet therapy only, no. (%) Diet therapy+sulphonylurea, no. (%) Diet therapy+metformin, no. (%) Weight (kg) Body mass index (kg/m2) Waist circumference (cm) Hip circumference (cm) Supine systolic BP (mmHg) Supine diastolic BP (mmHg) Supine PR (b.p.m.) FPG (mmol/l) HbA1c (%) Insulin (pmol/l) Triglycelide (mmol/l) Total cholesterol (mmol/l) HDL cholesterol (mmol/l) LDL cholesterol (mmol/l)

65/14/10 73/16/11 53.5±10.0 18 (20) 58 (65) 13 (15) 99.3±16.5 34.1±3.7 108.6±10.2 114.7±9.3 128±14 79±8 71±8 10.2±1.9 8.4±1.0 122±62 2.42±1.51 5.43±0.93 1.11±0.32 3.34±0.80

63/16/7 73/19/8 55.0±10.2 12 (14) 60 (70) 14 (16) 98.2±14.6 33.8±3.5 110.0±12.4 115.5±11.2 128±15 79±7 72±9 9.9±2.3 8.3±1.2 116±64 2.21±1.29 5.38±1.03 1.08±0.24 3.36±0.80

Continuous variables are presented as means±SDs. Source: Fujioka et al. (2000).

droxytryptamine reuptake, dulling appetite and increasing thermogenesis. Addition of a drug such as sibutramine as an obesity treatment accompanied by recommendations about good eating habits and physical activity could be a useful alternative. Long-term changes in insulin action and insulin secretion associated with gain, loss, regain and maintenance of body weight C Weyer, K Hanson, C Bogardus, R E Pratley. Diabetologia 2000; 43:36–46. BACKGROUND. The authors quantified the changes in insulin action and insulin secretion that are associated with long-term gain, loss, regain and

maintenance of body weight in subjects with normal glucose tolerance (NGT) or IGT. Insulin action (hyperinsulinaemic clamp) and insulin secretion (intravenous glucose challenge) were measured longitudinally in 209 obese Pima Indians (mean±SD body weight of 120 men 94.4±22.8 kg, with 151 NGT and 58 IGT) who either lost (n=110) or gained (n=99) weight (−23% to+29%) over 2.6±2.0 years. Assessments were repeated on a third occasion in 33 subjects who lost at least 5% body weight over 1.5 ±0.8 years and then either regained or maintained their weight over the subsequent 1.8±1.1 years. There was a linear negative relation between the changes in body weight and changes in insulin-stimulated glucose disposal in subjects with NGT (r=−0.51 and P<0.0001) and IGT (r=−0.54 and P<0.0001). In

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contrast, the changes in the acute insulin response were positively related to weight changes in subjects with NGT (r=0.26 and P<0.005), but negatively in those with IGT (r=−0.51 and P<0.0001). Improvements in insulin action after an average of 10% weight loss were lost with weight regain, but were largely preserved with weight maintenance.

Comment Obesity is a known risk factor in the development of type 2 DM. Weight changes have been associated with changes in glucose tolerance, so weight loss is generally recommended to the overweight with or without IGT. However, weight reduction as a therapeutic tool poses many questions with regard to its effect on insulin action and secretion mechanisms in the short, medium and long term. Many projects have suggested that improved glucose tolerance relative to weight loss is attributable to recovered insulin action. Little is known about its effect on insulin secretion. This project provided information on the long-term effects of weight fluctuations on insulin action and secretion, not only in normal people but also in those presenting insulin resistance syndrome. It is apparent from this study that insulin secretion, instead of increasing, decreases when people with glucose intolerance put on weight. An inability to compensate for increased insulin resistance was demonstrated in subjects susceptible to developing type 2 diabetes. However, it would be important to reproduce these results in a population with a lower risk of developing diabetes than the Pima Indians. In conclusion, improvements in insulin action are proportional to the amount of weight loss, which is similar in magnitude to the impairment in insulin action with weight gain, preserved with long-term weight maintenance and similar between subjects with NGT and with IGT. However, weight gain could have more detrimental effects in people with IGT, in whom insulin secretion decreases rather than increases in order to compensate for the decreased insulin action. The hormone resistin links obesity to diabetes C M Steppan, S T Bailey, S Bhat, E J Brown, R R Banerlee, et al. Nature 2001; 409:307–12. BACKGROUND. Adipocytes secrete a unique signalling molecule called resistin. Circulating resistin levels are decreased by the diabetic drug rosiglitazone and increased in diet-induced and genetic forms of obesity. Administration of an anti-resistin antibody improves blood sugar and insulin action in mice with diet-induced obesity. Moreover, the treatment of normal mice with recombinant resistin impairs glucose tolerance testing and insulin action. Insulin-stimulated glucose uptake by adipocytes is enhanced by neutralization of resistin and is reduced by resistin treatment.

Comment Insulin is less able to promote glucose use by the muscles and adipose tissue and to inhibit glucose production in the liver in patients suffering from type 2 diabetes. Obesity-linked insulin resistance has been attributed to various factors such as fatty acids, leptin and tumour necrosis factor-α (TNF-α), although the precise mechanism involved is unknown. There is a new category of oral anti-diabetic drugs, the thiazolidinediones, which reduce insulin resistance by acting via certain protein nuclear receptors that are present in the adipocytes in great numbers. This receptor is an adipogenic differentiation factor.

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By treating an adipocyte line with thiazolidinediones, the authors identified a new gene that is expressed as adipose tissue and eliminated by the action of thiazolidinediones. This gene encodes a protein called resistin that increases the levels circulating in different models of obese rats, whereas administration of antiresistin antibodies improves glucose blood levels and insulin action. Although these findings are at the experimental stage and limited, they suggest that this protein may be one of the links between diabetes and obesity as it would be antagonistic to insulin and inhibit glucose use by the adipocytes. Its effect on the muscles or liver is still unknown. Future studies, targeting a complete definition of the part played by this new hormone will be required. Visceral adiposity and the risk of type 2 diabetes: a prospective study among Japanese-Americans E J Boyko, W Y Fujimoto, D L Leonetti, L Newell-Morris. Diabetes Care 2000; 23:465–71. BACKGROUND. The authors conducted a prospective study of diabetes incidence among JapaneseAmericans in relation to visceral and regional

adiposity, fasting insulin and C-peptide and a measure of insulin secretion. The baseline variables included plasma glucose, C-peptide and insulin measured after an overnight fast and 30 and 120 min after a 75 g OGTT, abdominal, thoracic and thigh fat areas by CT, BMI (kg/m2) and insulin secretion (incremental insulin response). The study subjects included 290 second-generation (nisei) and 230 thirdgeneration (sansei) Japanese-Americans without diabetes, 65 and 13 of whom developed diabetes, respectively. Significant predictors of diabetes risk for a 1 SD increase in continuous variables among the nisei included their intra-abdominal fat area (odds ratio (OR)=1.6 and 95% confidence interval (Cl) =1.1–2.3), fasting plasma C-peptide (OR=1.4 and 95% Cl=1.1–1.8) and incremental insulin response (OR =0.5 and 95% Cl=0.3–0.9) after adjusting for age, sex, IGT, family history of diabetes and CT-measured fat areas other than intra-abdominal fat areas. Greater visceral adiposity preceded the development of type 2 diabetes in Japanese-Americans and demonstrated an effect independent of fasting insulin, insulin secretion, glycaemia, total and regional adiposity and family history of diabetes.

Comment The connection between visceral fat and type 2 DM is well known and is reflected in the many epidemiological studies that have shown a relationship between the waist to hip ratio and the risk of type 2 diabetes |6|. This report confirmed that intra-abdominal fat is a factor in predicting the development of type 2 DM in Japanese-Americans and has an effect independent of fasting insulin, insulin secretion, blood glucose, regional and overall fat and family history of diabetes. Abdominal obesity, particularly excess intraperitoneal fat, is considered to play a major role in causing insulin resistance and type 2 diabetes. In a study of 21 men with type 2 diabetes areas of abdominal fat were calculated from axial magnetic resonance images obtained at the level of the umbilicus and insulin sensitivity was evaluated by an insulin tolerance test. The blood glucose disappearance rate was negatively correlated to deep abdominal fat (r=0.72 and P=0.0025). In contrast, areas of subcutaneous abdominal fat, total body fat, BMI and the waist to hip ratio were not related to the blood glucose disappearance rate. Carey et al. |7| found a strong negative relationship using euglycaemic hyperinsulinaemic clamp techniques in 22 women between central abdominal (intra-abdominal plus abdominal subcutaneous) fat and whole-body insulin sensitivity (r=−0.89 and P<0.0001) and non-oxidative glucose disposal (r=−0.77 and

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P<0.001), independent of total adiposity, family history of non-insulin-dependent DM and past gestational diabetes. There was a large variation in insulin sensitivity, with a similar variation in central fat, even in those whose BMI was<25 kg/m2. Abdominal fat had a significantly stronger relationship with insulin sensitivity than peripheral non-abdominal fat (r2=0.79 versus 0.44) and higher levels were associated with increased fasting non-esterified fatty acids, lipid oxidation and hepatic glucose output. Reversing adipocyte differentiation: implications for the treatment of obesity Y T Zhou, Z W Wang, M Higa, C B Newgard, R H Unger. Proc Natl Acad Sci USA 1999; 96:2391–5. BACKGROUND. Adenovirus-induced hyperleptinaemia in normal rats resulted in a rapid nonketotic fat loss that persisted after hyperleptinaemia had disappeared, whereas pair-fed controls regained their weight in 2 weeks. The authors reported that the hyperleptinaemia depletes adipocyte fat while profoundly down-regulating lipogenic enzymes and their transcription factor peroxisome proliferator-activated receptor (PPAR)-γ in epididymal fat. At the same time, enzymes of fatty acid oxidation and their transcription factor PPAR-α, which are normally low in adipocytes, are upregulated, as are uncoupling proteins 1 and 2. This transforms adipocytes that store TGs to fatty acidoxidizing cells and is accompanied by loss of the adipocyte markers, adipocyte fatty acid-binding protein 2, TNF-α and leptin and by the appearance of the pre-adipocyte marker Pref-1. These findings suggest a strategy for the treatment of obesity by alteration of the adipocyte phenotype.

Comment Conventional weight reduction treatments are capable of reducing the fat stored in mature adipocytes, but the latter retain their lipogenic enzymatic mechanisms and quickly resume fat synthesis. This factor is reckoned to be the partial cause of treatment failure. A previous report from this laboratory has shown that adenovirus-induced hyperleptinaemia in normal rats results in rapid non-ketotic fat loss that persists after hyperleptinaemia disappears, whereas pair-fed controls regain their weight in 2 weeks |8|. In this work sustained hyperleptinaemia of 8 ng/ml was induced for 28 days in normal Wistar rats by infusing a recombinant adenovirus containing the rat leptin cDNA. Hyperleptinaemic rats exhibited a 30–50% reduction in food intake and gained one-sixth of the weight of control animals. Body fat was absent in hyperleptinaemic rats, whereas control rats pair-fed to the hyperleptinaemic rats retained approximately 50% body fat. This project investigated the mechanism of weight reduction accompanying hyperleptinaemia caused by leptin adenovirus c transfection and found increased expression of the enzymes associated with fatty acid oxidation and thermogenesis. These adipocytes in turn expressed proteins solely as immature adipocytes. The results disclosed in this paper open up interesting prospects for treating obesity using the concept of hyperleptinaemia induction, although it has to be borne in mind that leptin actions are likely to be determined by species and the dramatic results seen in animal models may not reflect responses in humans. Role of the brain insulin receptor in the control of body weight and reproduction J C Brüning, D Gautam, D J Burks, J Gillette, M Schubert, et al. Science 2000; 289:2122–8. BACKGROUND. Insulin receptors and insulin signalling proteins are widely distributed throughout the central nervous system (CNS). In order to study the physiological role of insulin signalling in the brain, the authors created mice with a neuron-specific disruption of the insulin receptor gene (Neuronspecific insulin receptor knockout [NIRKO] mice). Inactivation of the insulin receptor had no impact on

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brain development or neuronal survival. However, female NIRKO mice showed an increased food intake and both male and female mice developed diet-sensitive obesity with increases in their body fat and plasma leptin levels, mild insulin resistance, elevated plasma insulin levels and hypertriglyceridaemia. NIRKO mice also exhibited impaired spermatogenesis and ovarian follicle maturation because of hypothalamic dysregulation of LH. Thus, insulin receptor signalling in the CNS plays an important role in the regulation of energy disposal, fuel metabolism and reproduction.

Comment The physiological mechanisms regulating food intake and body weight appear to involve two types of signals. One is associated with the quantity and quality of the ingested food and appears to implicate peptide signals released by the gastrointestinal tract. The second is modulated by the existing mass of adipose tissue and appears to involve hormones such as leptin, resistin and insulin. Earlier studies have suggested that insulin signalling may play a part in regulating food intake. Thus, insulin, in addition to being a lipogenic hormone, may regulate body weight via actions on the brain in a manner similar to that of leptin. In order to investigate the specific contribution made by insulin signalling in the brain to body fat control, Brüning et al. |9| created mice (NIRKO mice) in which the cerebral insulin receptors had been disrupted. These mice displayed changes in food intake, higher adipose weight and were more inclined to obesity when fed a fat-rich diet, confirming the regulatory role of insulin with regard to body weight and adipose mass. They also exhibited reproductive changes, suggesting that lower neuronal signalling with insulin could also be involved in the fasting adaptation mechanism. Although leptin appears to be a more important agent than insulin in energy homeostasis control by the CNS, the NIRKO mouse phenotype, with a neuronal insulin receptor deficit, proves that insulin signalling in the brain is also involved in regulating food intake and body weight. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice B Li, L A Nolte, J-S Ju, D H Han, T Coleman et al. Nat Med 2000; 6(10):1115–20. BACKGROUND. In order to determine whether uncoupling respiration from oxidative phosphorylation in skeletal muscle is a suitable treatment for obesity and type 2 diabetes, the authors generated transgenic mice expressing the mitochondrial uncoupling protein (UCP) in skeletal muscle. The skeletal muscle oxygen consumption was 98% higher in UCP-L mice (with low expression) and 246% higher in UCP-H mice (with high expression) than in wild-type mice. UCP mice fed a chow diet had the same food intake as wild-type mice, but weighed less and had lower levels of glucose and TGs and better glucose tolerance than did control mice. UCP-L mice were resistant to obesity induced by two different high-fat diets. UCP-L mice fed a high-fat diet had less adiposity, lower levels of glucose, insulin and cholesterol and an increased metabolic rate at rest and with exercise. They were also more responsive to insulin and had enhanced glucose transport in skeletal muscle in the setting of an increased muscle TG content. These data suggest that manipulating respiratory uncoupling in muscle is a viable treatment for obesity and its metabolic sequelae.

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Comment Research into the aetiology of obesity has been increasingly focused on elucidating the cellular and molecular mechanisms regulating mammalian energy intake and expenditure. One area of considerable research interest is the UCPs. Mitochondrial UCPs, which are mitochondrial transporters, function as proton channels and increase thermogenesis. UCP-1 is expressed in brown adipose tissues, UCP-2 is widely expressed in multiple tissues and UCP-3 is expressed in skeletal muscle. Thus, UCPs, in particular UCP-3 in skeletal muscles, are good candidates for the prevention of obesity and diabetes. However, the role of UCP-3 in skeletal muscle in energy expenditure and obesity has been controversial. There is some evidence that UCP-3 is possibly regulated by energy substrates, such as lipid and glucose. These observations suggested that increased energy substrate entry into muscle results in an increase in UCP-3 expression, which leads to an increase in energy expenditure. Activation of the uncoupling capability of UCPs is a logical strategy for counteracting the metabolic effects produced by excessive energy storage in the form of fat, leading to the development of obesity and, consequently, diabetes, hyperlipidaemia and cardiovascular diseases (CVDs). The results obtained by Li et al. |10| showed that stimulation of UCP activity in muscle tissue in a transgenic mouse model can be effective in obesity treatment. Paradoxical and conflicting observations about the possible function and regulation of UCP-1, UCP-2 and UCP-3 in rodents and humans confirmed the complexity of this system and means that extrapolation of data from animal models to human obesity should be done with extreme caution. The results obtained in this study confirmed that intervention aimed at treating obesity and its complications via the expression of specific UCP proteins is a possibility. This is undoubtedly a field offering new and promising prospects. The challenge of diet, exercise and life style modification in the management of the obese diabetic patient J P Foreyt, WS Poston. Int J Obesity Relat Metab Disord 1999; 23(Suppl 7): 55–11. BACKGROUND. Type 2 diabetes is associated with many comorbid medical conditions, including obesity, neuropathy, microvascular pathology and atherosclerotic arterial disease. Patients must learn how to adopt lifelong, low-fat eating habits and regular activity patterns, with formal treatments focusing on weight loss, increased physical activity and low-fat, low-saturated fat diets. In this article the authors reviewed the efficacy of life style modification programmes for obese diabetic patients. They discussed barriers to life style changes and methods for improving long-term adherence. Finally, they presented information on how this approach has been adapted to a group of Mexican-Americans in the USA, a population at high risk of type 2 diabetes, obesity and a sedentary life style.

Comment Approximately 85% of diabetic patients are classified as type 2 diabetes patients and 50–60% of these patients are overweight (BMI 25–30 kg/m2) or obese (BMI>30 kg/m2). Type 2 DM is associated with cardiovascular risk factors. Life style modification recommendations for these obese diabetic patients are (therefore) based mainly on diet and physical activity. The authors of a recent publication |11| drew attention to the concept of obesity as an environmental issue. Societies that are transitioning to Westernized life styles are experiencing substantial increases in its

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Fig. 9.3 Prevalence of obesity (BMI≥30 kg/m2) and little or no leisure time physical activity (LTPA) in MexicanAmericans. Results from the Third National Health and Nutrition Examination Survey. Adapted from NIH (National Institutes of Health) and NHLBI (National Heart, Lung and Blood Institute), US, and Crespo et al. Source: Foreyt and Poston (1999).

prevalence. The primary environmental determinants of obesity are a high calorie intake and low levels of activity. Socioeconomic status and place of residence are important contributors. These factors together comprise an obesogenic or ‘toxic’ environment where the development of obesity is the expected course for humans leading life styles incompatible with their evolutionary development. Only by addressing and modifying the toxic environment will we be able to stem the obesity epidemic. Zimmet |12| coined the term diabesity in succinctly summarizing the inter-relationship between the global rising tide of obesity and the epidemic of type 2 diabetes. The authors emphasized that modification of life style behaviours that contribute to obesity (e.g. an inappropriate diet and inactivity) is the cornerstone of treatment. Behaviour modification involves using such techniques as self-monitoring, stimulus control, cognitive restructuring, stress management and social support for systematically altering obesity-related behaviours. In addition, adjunctive pharma-cotherapy can play an important role in the routine medical management of obesity |13|. Wing |14| reviewed the improvements made in the behavioural treatment of obesity from the 1970s to the early 1990s. Wing |14| presented evidence to show that structured exercise, very low-calorie diets and intensification of treatment programmes may be useful in improving the long-term outcomes of behavioural weight loss interventions. In other reports Wing et al. |15| found that type 2 DM patients who had experienced a 16-week intervention in the form of a food habits adaptation programme achieved a 5–10% reduction in their body weight. The development of behavioural strategies for modifying life style behaviours has been recently reviewed |15|. Four key topics related to obesity and physical activity that should be given high priority in future research efforts were highlight

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Table 9.2 Strategies for promoting changes in dietary and activity behaviours Strategy

Example(s)

Self-monitoring Stimulus control CBT techniques -Cognitive restructuring

Food or exercise diary Reminder notes to exercise; no snack foods in the house

-Stress management/ inoculation -Relapse prevention Social support friend community

Addressing discrepancies between desired weight loss and realistic weight loss; challenging patients’ beliefs that self-worth is based on weight Progressive muscle relaxation, diaphragmatic breathing, mediation Normalizing slips and lapses; practice high-stress coping skills; visualization Participation in support group; exercising with or family member; taking classes at college

CBT, cognitive behavioural therapy. Source: Foreyt and Poston (1999).

ed in that review: environmental factors related to obesity, eating and physical activity, the adoption and maintenance of healthy eating, physical activity and weight, the aetiology of eating and physical activity and multiple behaviour changes. Wing et al. |15| also conducted a random two-diet programme (400 or 1000 kcal/ day) for 32 weeks during which the observed weight loss was approximately 11% of the initial weights. Although the 400 kcal/day diet represented a very low calorie intake, it had a beneficial effect on metabolic control. The authors concluded that very low-calorie diets are not very effective in maintaining weight loss in the long term, but a recent innovative approach using intermittent very low-calorie diet therapy as part of a behaviour modification programme has reported encouraging results|16|. This review also supplied information about the follow-up of a population of Mexican-American women in the USA with high-risk obesity and type 2 DM who had derived benefit from intervention via 6-months follow-up and 6-months maintenance after their weight loss. Resources such as bilingual professionals, social identification and support, cultural and behavioural barriers associated with diet and inactivity and the skills for overcoming such obstacles were taken into account Life style change programmes were limited to the weight loss maintenance phase as far as the habits of obese diabetic patients were concerned. More cost-benefit studies and longer follow-up programmes are required. Effect of energy restriction, weight loss and diet composition on plasma lipids and glucose in patients with type 2 diabetes L K Heilbronn, M Noakes, P M Clifton. Diabetes Care 1999; 22:889–95. BACKGROUND. The aim of this study was to determine the optimal diet for improving the glucose and lipid profiles of obese patients with type 2 diabetes during moderate energy restriction. A total of 35 free-living obese patients with type 2 diabetes were assigned to one of three 1600 kcal/day diets for 12 weeks. The diets were a high carbohydrate diet (10% fat and 4% saturated fat), a high monounsaturated fatty acids (MUFA) diet (32% fat and 7% saturated fat) or a high saturated fatty acids (SFA) diet (32% fat and 17% saturated fat). The composition of the diets did not affect the magnitude of the subjects’ weight loss, with the subjects losing an average of 6.6 kg. Energy restriction and weight loss resulted in reductions in the subjects’ glucose response area (−17%), systolic (−7%) and diastolic (−10%) BP levels, FPG (−14%), insulin (−27%) and glycosylated haemoglobin (GHb) (−14%), independent of diet composition. The composition of the diets did affect the subjects’ lipoprotein profiles. The subjects’ LDL

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cholesterol was 10 and 17% lower with the high-carbohydrate and high-monounsaturated fatty acids diets, respectively, whereas no change was observed with the high-saturated fatty acids diet (P<0.001 for effect of diet). The subjects’ HDL cholesterol was transiently reduced on the high-carbohydrate diet at weeks 1, 4 and 8. Energy Table 9.3 Dietary composition of the study diets derived from the subjects’ 3-day food records

n Energy (kcal/day) Carbohydrate (% of energy) Total fat (% of energy) SFA (% of energy) MUFA (% of energy) Polyunsaturated fat (% of energy) Protein (% of energy) Fibre (g/day) Cholesterol (milligrams/megajoule)

High-carbohydrate diet

High-MUFA diet

High-SFA diet

12 1541±41* 72.6±0.7* 9.9±0.4* 3.5±0.2* 3.0±0.1* 2.1±0.1*

13 1596±34* 49.5±0.4† 32.3±0.4† 6.8±0.1† 14.8±0.2† 9.0±0.1†

10 1613±61* 52.2±0.6† 31.4±0.6† 16.6±0.4† 9.9±0.2† 2.1±0.1*

16.8±0.5* 38.6±0.9* 11.5±0.9*

18.2±0.3* 37.7±1.1* 11.1±0.5*

16.6±0.4* 39.4±1.2* 21.5±0.7†

The data are means±SEMs. The subjects were required to maintain 3-day dietary food records on six occasions during the study. No significant differences were found between the records so the data for the recordings were averaged. Different superscripts between diets indicate thatthe diets were significantly different (P<0.01). Source: Heilbronn et al. (1999).

restriction, independent of diet composition, improved glycaemic control. However, reducing their saturated fatty acids intake by replacing saturated fatty acids with carbohydrate or monounsaturated fatty acids reduced the subjects’ LDL cholesterol maximally during weight loss and to a greater degree than has been shown in weight-stable studies.

Comment The criteria justifying medical intervention in obesity is based on the knowledge that a moderate loss in body weight (of 5–10%) can result in a distinct improvement in the comorbidity associated with obesity and in the quality of life of grade II and III obese patients |17|. Glucose tolerance is amongst the parameters that can improve weight reduction. This project studied 35 obese patients with type 2 DM in three groups assigned a 1600 kcal/day diet for 12 weeks. These diets were high in carbohydrate, high in monounsaturated fatty acids or high in saturated fatty acids and their repercussions on the patients’ metabolic parameters were recorded. Energy restriction, regardless of diet composition, was found to improve blood glucose control, but a reduced intake of saturated fatty acids and the substitution of carbohydrates or monounsaturated fatty acids lowered the patients’ LDL cholesterol (Table 9.3). Intentional weight loss and mortality among overweight individuals with diabetes

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Fig. 9.4 Change in weight (kg) from baseline during 12 weeks of energy restriction. The values are means±SEMs. Obese patients with type 2 diabetes were treated with an energy-restricted, high-carbohydrate diet (n=12), highmonounsaturated fatty acids diet (n=13) or high-saturated fatty acids diet (n=10). The subjects’ body weights were recorded at baseline and at weeks 1, 4, 8 and 12 of dietary intervention. The asterisks indicate significant decreases in weight from baseline (P<0.001). CHO, carbohydrate. Source: Heilbronn et al. (1999). D F Williamson, T J Thompson, M Thun, D Flanders, E Pamuk, et al. Diabetes Care 2000; 23:1499–504. BACKGROUND. In order to estimate the effect of intentional weight loss on mortality in overweight individuals with diabetes, the authors performed a prospective analysis with a 12-year mortality followup (1959–1972) of 4970 Table 9.4 Mortality rate ratios (RR) for weight change categories: prospective data from 4970 diabetic individuals of 40–64 years of age in the CPS-l (1959–1972) All causes

CVD+diabetes

Weight-change category

Deaths

RR (95%Cl)

Deaths

RR (95%Cl)

No change (referent)* Unintentional loss Adjusted for

980 280

100

774 218

100

Crude

1.18 (1.03–1. 35) 1.06 (0.93–1. 22) 0.98 (0.85–1. 13)

Age, sex, initial BMI Full† Unintentional gain

58

1.16 (1.00–1. 35) 1.04 (0.90–1. 22) 0.98 (0.83–1. 15) 40

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Fig. 9.5 Glucose concentrations (mmol/l) during an OGTT at weeks 0, 1 and 12 of energy restriction. The values are means±SEMs. Glucose response was assessed by finger-prick glucose measured every 30 min for 3 h after ingestion of 75 g glucose. No differences were observed in the glucose responses between dietary interventions (n=35). The asterisks indicate significant differences between weeks 0 and 12 (P<0.01) and the daggers indicate significant differences between weeks 0 and 1 (P<0.01). Source: Heilbronn et al. (1999). All causes Weight-change category

Deaths

CVD+diabetes RR (95%Cl)

Deaths

RR (95%Cl)

Adjusted for Crude

1.11 (0.85–1. 44) 1.26 (0.96–1. 64) 1.04 (0.79–1. 36)

Age, sex, initial BMI Full† Intentional loss Adjusted for

561 Crude Age, sex, initial BMI +Exercise

+Disease history/sings/symptoms

0.97 (0.71–1. 33) 1.11 (0.80–1. 52) 0.90 (0.65–1. 25) 434

0.83 (0.75–0. 93) 0.78 (0.70–0. 87) 0.77 (0.69–0. 86) 0.75 (0.67–0. 84)

0.82 (0.73–0. 92) 0.76 (0.67–0. 86) 0.75 (0.66–0. 85) 0.73 (0.64–0. 83)

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All causes Weight-change category

Deaths Full†

189

CVD+diabetes RR (95%Cl) 0.75 (0.67–0. 84)

Deaths

RR (95%Cl) 0.72 (0.63–0. 82)

The data for 19 people (seven deaths) who reported intentional weight gain are not shown. *The referent group includes those who did not answer the weight change questions. †Adjusted for age, sex, race, smoking, initial BMI, education, alcohol, physical activity, disease history and current signs and symptoms. Source: Williamson et al. (2000). overweight individuals with diabetes of 40–64 years of age. Rate ratios comparing the overall death rates and death from CVD or diabetes in individuals with and without reported intentional weight loss were calculated. Intentional weight loss was reported by 34% of the cohort. After adjustment for the subjects’ initial BMI, sociodemographic factors, health status and physical activity, intentional weight loss was associated with a 25% reduction in total mortality (rate ratio=0.75) and a 28% reduction in CVD and diabetes mortality (rate ratio=0.72). Intentional weight loss of 20–29 Ib (approximately 9–13 kg) was associated with the largest reductions in mortality (approximately 33%). A weight loss of>70 lb (approximately 32 kg) was associated with small increases in mortality. Intentional weight loss was associated with substantial reductions in mortality in this observational study of overweight individuals with diabetes.

Comment Weight loss is a central part of the management of overweight patients with type 2 diabetes and this study set out to assess the effect of intentional weight loss on the mortality of overweight diabetics. It targeted a population of more than 1 000 000 men and women over 30 years of age enrolled by the American Cancer Society for the basal survey entitled the Cancer Prevention Study 1 (CPS-1). The analysis was prospective and involved 12-year monitoring of 34% of the population cohort who reported intentional weight loss. The subjects’ initial BMI was adjusted for sociodemographic factors, state of health and physical activity. Overweight subjects with type 2 DM who signalled an intention to lose weight displayed a mortality level 25% lower than the overall mortality of those who did not express an intention to lose weight. They also had a 28% lower incidence of CVD (subject to adjustment for covariables) (Table 9.4) and mortality through diabetes. This study provided important confirmation of the significant benefits open to patients who can make life style changes in order to lose weight. It was also discovered that a lower intentional weight loss of 20–29 lbs (approximately 9–13 kg) (10–15% of initial weight) was linked with a greater reduction in mortality (33%). In contrast, weight losses of>70 lbs (approximately 32 kg) (≥30% of the initial weight) correlated with a lower rise in mortality reduction (Fig. 9.6), thereby raising the possibility of comorbidity contributing to the excessive weight loss. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle J K Kim, M D Michael, S F Previs, O D Peroni, F Mauvis-Jarvis, et al. J Clin Invest 2000; 105:1791–7.

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Fig. 9.6 Amount of intentional weight loss and overall mortality rate ratios. The bar graph shows the rate ratios for the weight loss categories as indicator variables. The continuous line represents the continuous relationshipfrom a linear spline proportional hazards model with knots at 20–29 lb (approximately 9–13 kg) and 60–69 lb (approximately 27–31 kg). The rate ratios are represented by solid squares with 95% confidence limits. Prospective data from 4970 overweight diabetic individuals aged 40–64 years. CPS-l values (1959–1972) are shown. The asterisk indicates the number of deaths. Source: Williamson et al. (2000). BACKGROUND. The authors of this study aimed to evaluate the role of a selective defect in the insulin receptor muscle in the pathogenesis of type 2 DM. The study was performed on a sample of muscle insulin receptor knockout (MIRKO) mice, a rodent strain in which the muscle insulin receptor gene had been deactivated. This mouse sample was administered a hyperinsulinaemic euglycaemic clamp. These mice had virtually terminated glucose transport and insulin-stimulated glucogen synthesis in their muscle tissue. However, they were able to maintain normal blood glucose levels at the expense of increased glucose transport in their adipose tissue, the level of which was definitely higher than in the control mice. This study showed that isolated selective defects that are responsible for insulin resistance in the muscle are capable of triggering substrate redistribution to other insulin-sensitive tissues such as adipose tissue and contribute to its development.

Comment Centrally distributed obesity is in particular frequently associated with insulin resistance, a condition that, in many people, is likely to contribute to the development of type 2 DM. Muscle tissue is responsible for most metabolic hormone resistance triggering defects. From this point of view, evaluation of the metabolic repercussions stemming from defects in the insulin receptor in the muscle is extremely important. The MIRKO transgenic mouse strain selectively inactivates the encoding insulin receptor gene in muscle cells. Consequently, this mouse presents drastically reduced glucogen muscle synthesis and insulin-stimulated glucose transport. Nevertheless, in this mouse strain, blood glucose levels both before and after meals stay normal.

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The apparently normalized glucose homeostasis is attributable to glucose metabolism potentiation in other insulin-sensitive tissues. Probably, as the authors of this paper suggested, muscle tissue releases some humoral factor and this helps to elevate insulin sensitivity in adipose tissue. However, obesity promotion is amongst the adverse changes that result. Conclusion The link between type 2 diabetes and increased cardiovascular risk has been established for many years. Fully understanding this association remains a challenge for clinical and laboratory researchers. Established vascular risk factors such as smoking, lipid abnormalities and hypertension play key roles, but can only account for approximately 70% of the increased risk. Attention has been directed towards other factors, including homocysteine, the fibrinolytic system and markers of inflammation such as C-reactive protein (CRP). The Hoorn study provided two reports that are summarized in Chapter 8. In the first, hyperhomocysteinaemia is shown to be associated with an increased risk of death in diabetes. The association was independent of other risk factors in multivariate analysis. Recent evidence suggests a biologically plausible mechanism for vascular injury because homocysteine promotes oxidant injury to the vascular endothelium, impairs endothelium-dependent vasomotor regulation and may also alter the coagulant properties of the blood. The Hoorn study also reported that levels of Von Willebrand factor, an endothelial-derived coagulation factor, that were in the upper tertile were associated with a threefold excess 5-year mortality in both diabetic and non-diabetic subjects. The Framingham Offspring study also provided important data on the relationship between hyperinsulinaemia and impaired fibrinolysis and hypercoagulability in subjects with NGT. Hence, these papers suggest that abnormalities of the coagulation pathways may be related to prevailing insulin concentrations and provide a further link between type 2 diabetes and vascular risk. The genesis of an atherosclerotic plaque depends on interplay of the cellular components of the immune system, such as monocytes, cytokines and cell adhesion molecules with lipids, platelets and endothelial cells. Inflammation may therefore play a central role in the progression of coronary artery disease. Several reports have linked the acute phase protein CRP with the future risk of coronary events independent of the traditional coronary artery disease risk factors. CRP has been positively linked to future cardiovascular events in healthy women, healthy men, elderly patients and high-risk individuals. In addition, reports have shown associations between CRP and peripheral vascular disease and stroke. The binding specificity of CRP for LDLs, for modified LDLs and for damaged and dead cells coupled with the capacity of bound CRP for activating complement and the presence of CRP in atheroma and acute myocardial infarction lesions all suggest a possible pathogenetic role of CRP. Further supportive data for a role of CRP in vascular disease in diabetes is provided in Chapter 8. The Third National Health and Nutrition Examination Survey analysis showed that patients with newly diagnosed or previously diagnosed diabetes had ORs of 1.84 and 1.59, respectively, for having a raised CRP. The Hoorn study reported a twofold excess mortality in patients with diabetes whose CRP levels are in the upper tertile. Hence, these papers support the suggestion that other factors, including abnormal coagulation pathways, inflammation and hyperhomocysteinaemia, are related to an increased risk of vascular disease and death in diabetes. These findings will prompt new avenues of research into drugs that can modulate these factors in order to determine whether clinical benefit in terms of reduced CVD will follow. Obesity and type 2 diabetes are inextricably linked. Approximately 70% of patients with type 2 diabetes are either overweight (BMI 25–30 kg/m2) or obese (BMI >30 kg/m2). Obesity is associated with increased insulin resistance, particularly when the excess weight accumulates in the abdominal region, which is

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termed central or android obesity. This is elegantly confirmed in the detailed prospective study of JapaneseAmericans. However, it is clear that many obese patients do not develop glucose intolerance or diabetes. Weyer et al. present interesting data showing the effect of weight gain or loss on insulin action in peripheral tissues and insulin secretion in a cohort of Pima Indians. Weight change was associated with similar changes in measures of insulin action in subjects with NGT or IGT, but marked differences in insulin secretion. Those with NGT were able to increase their insulin secretion to meet the demands of extra weight, whereas those with IGT experienced a fall in insulin secretion. These data elegantly emphasize the interaction between insulin resistance and B cell dysfunction in the aetiology of type 2 diabetes. It also supports the hypothesis that ‘offloading’ or ‘resting’ the B cell by reducing insulin resistance, either by life style changes or pharmacotherapy, may have clinical benefit and this is supported by the Diabetes Prevention Trial data summarized in Chapter 3. Pharmacological treatment of obesity has recently become a reality. Two trials that are summarized in this chapter report on the beneficial effects of the pancreatic lipase inhibitor orlistat in the prevention and treatment of type 2 diabetes. Improvements were seen as a result of weight loss in the progression of patients with IGT to diabetes over an 18-month follow-up period. In addition, vascular risk factors including lipid profiles and glucose tolerance improved with orlistat treatment, although neither of these studies were sufficiently large or long term enough to report clinical end-point data and a note of caution needs to be added before orlistat can be widely recommended. A recent health economic assessment of 14 published, randomized, controlled trials |3| assessed the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. Most of these trials showed greater weight loss and better weight maintenance with orlistat as compared to placebo. Most trials showed significant improvement in at least some lipid parameters and, in three, orlistat produced significant reductions in BP relative to placebo. Similar results were found in obese patients with type 2 diabetes, with some glycaemic and lipid control parameters improving. However, these benefits were obtained at an estimated cost per quality-adjusted life year of £45 881, which is a relatively expensive intervention. The authors concluded that, although many trials have demonstrated statistically significant differences between groups in terms of weight loss in favour of orlistat versus placebo, the differences may not always be of clinical significance. It seems clear that further studies are needed in order to evaluate the clinical significance of using orlistat in the treatment of obesity, type 2 diabetes and associated cardiovascular risk factors before it can be widely recommended. Similar comments apply to the use of sibutramine, which is a centrally acting appetite suppressant and promoter of thermogenesis. Sibutramine is associated with weight loss in type 2 diabetes and benefits in terms of improved glucose and lipid profiles flow from that. However, sibutramine is associated with a small increase in pulse and BP, which raises concerns in patients with type 2 diabetes, many of whom will have clinically overt or silent coronary artery disease. Short-term studies are important, but a long-term clinical outcome trial is needed in order to evaluate the potential benefits of weight loss associated with sibutramine with respect to cardiovascular end-points. References 1.

Hollander PA, Elbein SC, Hirsch IB, Kelley D, McGill J, Taylor T, Weiss SR, Crockett SE, Kaplan RA, Comstock J, Lucas CP, Lodewick PA, Canovatchel W, Chung J, Hauptman J. Role of orlistat in the treatment of obese patients with type 2 diabetes. A 1-year randomized double-blind study. Diabetes Care 1998; 21(8): 1288–94.

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2.

3.

4. 5. 6.

7.

8.

9.

10. 11. 12. 13. 14. 15.

16. 17.

193

Davidson MH, Hauptman J, DiGirolamo M, Foreyt JP, Halsted CH, Heber D, Heimburger DC, Lucas CP, Robbins DC, Chung J, Heymsfield SB. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: a randomized controlled trial. JAMA 1999; 281(3):235–42. O’Meara S, Riemsma R, Shirran L, Mather L, Ter Riet G. A rapid and systematic review of the clinical effectiveness and cost-effectiveness of orlistat in the management of obesity. Hlth Technol Assess 2001; 5(18): 1–81. Kolodziejczyk B, Duleba AJ, Spaczynski RZ, Pawelczyk L. Metformin therapy decreases hyperandrogenism and hyperinsulinemia in women with polycystic ovary syndrome. Fertility Sterility 2000; 73(6):1149–54. Nestler JE, Jakubowicz DJ, Evans WS, Pasquali R. Effects of metformin on spontaneous and clomipheneinduced ovulation in the polycystic ovary syndrome. N Engl J Med 1998; 338(26):1876–80. Gautier JF, Mourier A, De Kerviler E, Tarentola A, Bigard AX, Villette JM, Guezennec CY, Cathelineau G. Evaluation of abdominal fat distribution in noninsulin-dependent diabetes mellitus: relationship to insulin resistance. J Clin Endocrinol Metab 1998; 83(4):1306–11. Carey DG, Jenkins AB, Campbell LV, Freund J, Chisholm DJ. Abdominal fat and insulin resistance in normal and overweight women: direct measurements reveal a strong relationship in subjects at both low and high risk of NIDDM. Diabetes 1996; 45(5): 633–8. Chen G, Koyama K, Yuan X, Lee Y, Zhou YT, O’Doherty R, Newgard CB, Unger RH. Disappearance of body fat in normal rats induced by adenovirus-mediated leptin gene therapy. Proc Natl Acad Sci USA 1996; 93(25):14 795–9. Brüning JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR. Role of brain insulin receptor in control of body weight and reproduction. Science 2000; 289(5487): 2122–5. Li B, Nolte LA, Ju JS, Han DH, Coleman T, Holloszy JO, Semenkovich CF. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. Nat Med 2000; 6(10):1115–20. Poston II WS, Foreyt JP. Obesity is an environmental issue. Atherosderosis 1999; 146(2):201–9. Zimmet P. Globalization, coca-colonization and the chronic disease epidemic: can the Doomsday scenario be averted? J Intern Med 2000; 247(3):301–10. Poston II WS, Foreyt JP. Successful management of the obese patient. Am Family Phys 2000; 61(12):3615–22. Wing RR. Behavioral treatment of obesity. Its application to type II diabetes. Diabetes Care 1993; 16(1):193–9. Wing RR, Goldstein MG, Acton KJ, Birch LL, Jakicic JM, Sallis Jr JF, Smith-West D, Jeffery RW, Surwit RS. Behavioral science research in diabetes: lifestyle changes related to obesity, eating behavior, and physical activity. Diabetes Care 2001; 24(1):117–23. Williams KV, Mullen ML, Kelley DE, Wing RR. The effect of short periods of caloric restriction on weight loss and glycemic control in type 2 diabetes. Diabetes Care 1998; 21(1):2–8. Bray GA, Tartaglia LS. Medicinal strategies in the treatment of obesity. Nature 2000; 404:672–7.

Part V Diabetes and pregnancy

10 Diabetes and pregnancy

Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial The Diabetes Control and Complications Trial Research Group. Diabetes Care 2000; 23:1084–91. BACKGROUND. In order to assess the effect of pregnancy on the development and progression of retinopathy and microalbuminuria in type 1 diabetes, the authors compared intensive treatment with conventional diabetes therapy and studied 180 women who had 270 pregnancies and 500 women who did not become pregnant during an average of 6.5 years of follow-up. Fundus photography was performed every 6 months and the women’s urinary albumin excretion (UAE) rate was measured annually. Compared with non-pregnant women, pregnant women had a 1.63-fold greater risk of any worsening of their retinopathy from before to during pregnancy in the intensive treatment group and a 2.48-fold greater risk in the conventional group. The odds of a greater than three-step progression from the baseline retinopathy level in the conventional group was>2.9-fold among pregnant versus non-pregnant women. The level of UAE during pregnancy in the intensive group was significantly elevated from the level at baseline, albeit still being in the normal range. Pregnancy in type 1 diabetes induces a transient increase in the risk of retinopathy and increased ophthalmologic surveillance is needed during pregnancy and the first years post-partum.

Comment A major treatment goal in managing pregnancy in women with type 1 diabetes is optimizing their glycaemic control in order to reduce the risk of fetal macrosomia. Intensive insulin administration and blood glucose monitoring regimens are used and, in general, pregnant women are highly motivated towards achieving as near normoglycaemia as possible. This intensification usually results in a reduction in glycated haemoglobin, which is sometimes shifted from a significantly elevated level to normal or near normal levels. Several European insulin intervention trials in the 1980s reported a deterioration in retinopathy in patients whose glycaemic control improved over a short period of time. With longer term follow-up the prognosis favoured intensification, but some patients required laser photocoagulation for treating short-term retinal deterioration. The Diabetes Control and Complications Trial (DCCT) confirmed these smaller European trials in the secondary prevention cohort. © Clinical Publishing Services Ltd

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Table 10.1The risk of complications among women at the end of the study according to treatment group and pregnancy status during the DCCT Non pregnant Status at close-out Retinopathy ≥3-Steps worse Intensive Conventional SNPDR Intensive Conventional Nephropathy* Microalbuminuria Intensive Conventional Albuminuria Intensive Conventional

Pregnant

Total subjects

Events

Total subjects

Events

OR

95% Cl

P

249 246

28 (11.2) 74 (30.1)

94 84

9 (96) 22 (26.2)

0.84 0.82

0.38–1.84 0.47–1.44

NS NS

249 246

4 (1.6) 20 (8.1)

94 84

2 (2.1) 6 (7.1)

1.33 0.87

0.24–7.39 0.34–2.24

NS NS

242 235

13 (5.4) 19 (8 1)

85 83

4 (4.7) 11 (13.2)

0.87 1.74

0.28–2.74 0.79–3.82

NS NS

242 235

2 (0.8) 4 (1.7)

85 83

0 (0.0) 1 (1.2)

– 0.70

– 0.08–6 .39

– NS

The data are n values or n values with percentages in parentheses. *Women with a baseline AER rate≥40 mg/24 h were excluded from the analyses. Source: The Diabetes Control and Complications Trial Research Group (2000).

This trial looked at the effects of pregnancy on retinopathy progression in women enrolled in the intensive and conventional arms of the DCCT who became pregnant. Both groups were at an increased risk of deterioration during pregnancy compared with non-pregnant controls with the greatest risk being in those who were conventionally (less tightly) controlled. Usefulness of ambulatory blood pressure monitoring in pregnant women with type 1 diabetes L Flores, I Levy, E Aguilera, S Martinez, R Gomis et al. Diabetes Care 1999; 22(9):1507–11. BACKGROUND. This study sought to establish the blood pressure (BP) profiles for pregnant type 1 diabetic women using ambulatory BP (ABP) monitoring and determining whether BP patterns could define a population at risk of developing pregnancy-induced hypertension (PIH). ABP monitoring was carried out for one 24-hour period during each trimester in 22 normotensive pregnant type 1 diabetic and ten pregnant non-diabetic women. The incidence of PIH was fourfold greater in type 1 diabetic women than in control subjects. Diabetic women showed higher daily diastolic BP (DBP) in the third trimester compared with non-diabetic pregnant women. Diabetic Table 10.2 ABP monitoring measurement by trimester in patients who developed PIH and in patients who remained normotensive (non-PIH)

Mean 24-h BP

First trimester

Second trimester

Third trimester

Non-PIH

Non-PIH

Non-PIH

PIH

PIH

PIH

DIABETES AND PREGNANCY

Systolic Diastolic Daytime BP Systolic Diastolic Night time Systolic Diastolic

First trimester

Second trimester

Third trimester

Non-PIH

PIH

Non-PIH

PIH

Non-PIH

PIH

108.1±5.5 64.2±4.4

115.5±6.5* 67.1±4.8

107.9±5.6 63.9±4.1

118.7±10.0* 69.3±4.8*

113.2±5.0 68.7±4.2

129.7±4.9* 78.4±4.5*

110.8±5.7 66.5±4.2

118.1±7.1* 69.2±5.7

111.1±5.9 66.9±4.1

121.3±11 4* 71.5±5.7*

116.4±5.6 71.7±4.0

131.4±5.4* 80.1±5.7*

99.0±7.6 55.7±6.7

106.2±5.4* 59.6±4.4

97.4±8.0 53.8±6.4

109.7±7.0* 61.7±2.7*

104.0±7.3 60.0±6.9

124.2±8.2* 72.4±5.0*

197

The data are means±SDs. *P<0.05, PIH versus non-PIH. Source: Flores et al. (1999). women who developed PIH in the third trimester showed significantly higher BP profiles throughout gestation than those who remained normotensive. Receiver-Operator characteristic (ROC) curves for night-time systolic BP (SBP) showed the best predictive value for PIH, with a cut-off of>105 mmHg (85% sensitivity and 92% specificity).

Comment ABP monitoring has been used for screening for women at risk of PIH in non-diabetic pregnancy although it remains controversial as to whether abnormal recordings early in pregnancy can identify women at risk accurately. Hermida and Ayala |1| analysed 503 BP series from 71 healthy, pregnant women and 256 series from 42 women who developed gestational hypertension or pre-eclampsia. Forty-eight-hour BP monitoring was performed once every 4 weeks after the first obstetric consultation. The sensitivity ranged from 31.8% for DBP in the second trimester to 84.1% for SBP in the third trimester. However, the specificity was as low as 6.9% for DBP in the first trimester. The positive predictive value did not exceed 55% for any variable in any trimester. The higher relative risk was consistently obtained for SBP (4.9 in the third trimester). The authors concluded that, despite statistically significant differences in BP between healthy and complicated pregnancies in all trimesters, ABP monitoring did not provide a sufficiently sensitive method for identifying women at high risk of pre-eclampsia. Similar conclusions were drawn by Higgins et al. |2| in a large series of 1102 healthy primigravid women. Those authors found the best predictor for pre-eclampsia was secondtrimester 24-hour mean DBP, which gave a sensitivity of only 22% and a positive predictive value of 15%. More recently attempts have been made at improving the sensitivity of ABP monitoring data by describing the daily pattern of BP during the trimesters of preg nancy in clinically healthy women as well as in pregnant women who developed gestational hypertension or pre-eclampsia in detail. In a further report by Hermida et al. |3| 1494 48-hour ABP monitoring series were systematically sampled every 4 weeks after the first obstetric visit in 124 women with uncomplicated pregnancies, in 55 women with gestational hypertension and in 23 women with a final diagnosis of preeclampsia. The circadian pattern of BP variation for each group and trimester of gestation was established by population multiple-component analysis and significant differences were found between different groups. The authors concluded that differing changes in the circadian pattern of BP with advancing gestational age between healthy and complicated pregnancies

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could offer new and improved end-points for allowing the identification of hypertensive complications in pregnancy at an early stage. Women with type 1 diabetes are at greater risk of developing PIH than their non-diabetic counterparts. This study evaluated whether ABP monitoring is of greater use in this higher risk population and provided some interesting and novel clinical data. A 24-hour out-patient ABP monitoring series detected high BP profiles during the first trimester of pregnancy and a loss of circadian night rhythm during the second trimester of pregnancy. PIH was significantly more likely to develop if nocturnal SBP exceeded 105 mmHg and this observation had a high sensitivity and specificity. This study confirmed the early increase in BP in patients who will go on to develop PIH and suggested that night-time SBP>105 mmHg in the second trimester may be a useful predictor of PIH. ABP monitoring during the second trimester may be useful in screening for PIH in pregnant diabetic women. These conclusions need to be confirmed in larger prospective trials in women with type 1 diabetes. Post-partum reclassification of glucose tolerance in women previously diagnosed with gestational diabetes mellitus A Costa, F Carmona, S Martinez-Roman, L Quinto, I Levy, et al. Diabetic Med 2000;17:595–8. BACKGROUND. This study aimed to re-evaluate post-partum screening by comparing fasting plasma glucose (FPG) with an oral glucose tolerance test (OGTT) in Caucasian women with previous gestational diabetes mellitus (GDM). Once breast-feeding had finished, an OGTT was performed in 120 women with previous GDM. They were classified according to 1985 World Health Organization (WHO) and 1997 American Diabetes Association (ADA) criteria. The K-statistic measure of agreement was used for comparing both diagnostic categories. An ROC curve studied the FPG as a test for detecting abnormal glucose tolerance (AGT). Identical diabetes prevalence (2%) but quite different intermediate categories (12% impaired glucose tolerance (IGT) versus 3% impaired fasting glucose) were observed with both criteria. The ĸ-statistic (scaled from 0 to 1) was 0.38 (fair agreement) (P=0.000). The area of the ROC curve of the FPG was 0.65. FPG is an unsatisfactory method for evaluating the glucose tolerance of Caucasian women with previous GDM. An OGTT may be a better test for such a purpose.

Comment This project compared the diagnostic use of FPG, as recommended by the ADA, with a 75 g OGTT using 1985 WHO criteria during the post-partum and post-breast-feeding period in women who had gestational diabetes. FPG was considered an unsatisfactory way of defining glucose tolerance in this high-risk group of women. Other authors have drawn similar conclusions. Kousta et al. |4| studied 192 women with previous GDM who took an OGTT 1–86 months after delivery and classified them by 1985 WHO, 1997 ADA (fasting glucose) and revised 1998 WHO guidelines. Although all diagnostic criteria identified a similar prevalence of diabetes, one-third of women showed a classification discrepancy between 1985 WHO and 1997 ADA criteria, including 44 with normal fasting glucose (NFG) by 1997 ADA criteria, but abnormal 2-hour glucose by 1985 WHO criteria (40 with IGT and four with diabetes). Hence, based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) 60% of women with abnormal 2-hour glucose levels would

DIABETES AND PREGNANCY

199

not be identified. Screening women with previous GDM (and, by analogy, other groups at high risk of diabetes) with a single fasting glucose screen appears to have low sensitivity for the detection of AGT. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria S Ellard, F Beards, L Allen, M Shepherd, E Ballantyne, et al. Diabetologia 2000; 43:250–3. BACKGROUND. Patients with glucokinase mutations are characterized by mild, persistent fasting hyperglycaemia, a small increment in glucose in response to an oral load and a dominant family history. We assessed whether the selection of gestational diabetes subjects by clinical criteria would result in a high detection rate of glucokinase mutations. Caucasian gestational diabetes subjects from the UK who had fasting hyperglycaemia in pregnancy but who did not meet the diagnostic criteria for maturity onset diabetes of the young (MODY) were selected for direct sequencing of the glucokinase gene if they fulfilled some criteria. Twelve (80%) of the 15 patients with all these clinical criteria had glucokinase gene mutations. These included four previously unreported mutations (N180K, R191W, Y215X and L288-1G→A). Phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene as previous studies have suggested a prevalence of 2.5% (range 0–6%). Table 10.3 Selection criteria and mutations detected in the glucokinase gene in subjects with gestational diabetes Patient reference Fasting glucose after Pregnancy mmol/l

Smallest increment on OGTT mmol/l

n relatives fasting plasma glucose >5.5 mmol/l

Mutation found

BDA 07 BDA 31 BDA 49 BDA 50 BDA 57

6.7 6.5 7.1 7.0 6.0

2.8 1.0 0.1 2.6 2.5

1 2 1 1 1

BDA 58 BDA 117 BDA 165 BDA 189

6.7 5.7 6.5 6.5

2.8 2.2 2.2 2.4

2 2 3 1

BDA 199 BDA 224 BDA 286 BDA 67 BDA 76 BDA 93

5.9 6.4 5.9 6.1 6.3 6.4

1.3 1.6 2.8 1.1 2.6 2.4

1 4 2 2 5 3

F150S (exon 4) A259T (exon 7) A384T (exon 9) R403 fsdelC (exon 9) K161+2del 15 (intron 4) N180K (exon 5) C382Y (exon 9) Y215X (exon 6) K161+2del 15(intron 4) E40 ins 21 (exon 2) R191W (exon 5) L288-1G>A (intron 7) none none none

Source: Ellard et al. (2000).

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Comment Mutations of the glucokinase gene result in early onset familial type 2 (non-insulin-dependent) diabetes mellitus ((NID)DM). Several rnembers of the mutant glucokinase kindreds were originally diagnosed as having gestational diabetes. Previous studies have examined the glucokinase gene in unselected women with GDM. For example, Chiu et al. |5| studied 270 Black American women, including 94 with gestational diabetes whose diabetes resolved after pregnancy (gestational diabetes only), 77 with gestational diabetes who developed type 2 diabetes after pregnancy (overt diabetes) and 99 normal control subjects who were recruited during the peripartum period. Two simple, sequence, repeat polymorphisms flanking either end of the glucokinase gene were evaluated. No association was found between glucokinase alleles and gestational diabetes only or overt diabetes after adjustment for multiple comparisons. Stoffel et al. |6| screened a group of women with gestational diabetes who also had a first-degree relative with DM for the presence of mutations in this gene. They identified two mutations among 40 subjects, thereby suggesting a prevalence of approximately 5% in this group. Extrapolating from this result, the prevalence of glucokinase-deficient NIDDM among Americans may be approximately onein2500. This study refined this approach because the authors used more detailed clinical criteria for identifying a subgroup of women with GDM who may be more likely to have glucokinase mutations. The four clinical criteria selected were (1) persisting fasting hyperglycaemia outside pregnancy (5.5–8 mmol/l), (2) a small increment (<4.6 mmol/l) during a 2-hour OGTT, (3) insulin treatment during at least one pregnancy, but subsequently controlled by diet and (4) a history of type 2 DM, gestational diabetes or fasting hyperglycaemia (>5.5 mmol/l) in a first-degree relative. Unlike the situation with unselected women with GDM those who met these four clinical criteria had a high probability of having glucokinase mutations (Table 10.3) The authors concluded that phenotypic selection of subjects with gestational diabetes greatly increases the likelihood of detecting a mutation in the glucokinase gene in comparison with previous studies that have suggested a prevalence of 2.5% (range 0–6%). Glycaemic control is associated with pre-eclampsia but not pregnancy-induced hypertension in woman with type 1 diabetes mellitus V.Hiilesmaa, L Suhonen, K Terano. Diabetologia 2000; 43:1534–9. BACKGROUND. In order to investigate the association between glycaemic control and hypertensive pregnancy complications, the authors followed up 683 consecutive, non-selected pregnancies in women with type 1 DM from 1988 to 1997. Glycaemic control was assessed using glycosylated haemoglobin (HbA1c) measurements. Pre-eclampsia was defined as DBP exceeding 90 mmHg at the end of pregnancy with an increase of at least 15 mmHg combined with proteinuria of 0.3 g or more for 24 h. PIH was defined similarly but without proteinuria. The same criteria were applied to a control group of 854 nonselected, non-diabetic women. Pre-eclampsia developed in 12.8% of the women with diabetes, excluding those with nephropathy before pregnancy and 2.7% of the controt women, which was a 5.2-fold increase in risk. The adjusted odds ratios (ORs) for pre-eclampsia were 1.6 for each 1% increment in the HbA1c values at 4-14 weeks of gestation and 0.6 for each 1% decrement achieved during the first half of pregnancy with no statistically significant associations detected in the second half of pregnancy. Poor glycaemic control is associated with an increased risk of pre-eclampsia but not with a risk of PIH in women with type 1 DM.

DIABETES AND PREGNANCY

201

Comment Pregnant women with type 1 DM have a higher risk of developing pre-eclampsia particularly when their diabetes is complicated by nephropathy. This paper implicated poor glycaemic control during the first half of pregnancy in women with Table 10.4 The frequency of pre-eclampsia and PIH in subgroups of type 1 diabetic women without pre-pregnancy nephropathy in control subjects

n

n

HbA1c in early pregnancy <5.6% (<mean+2 SD) 5.6–6.8% (mean+2 to 5.9 SD) 6.9–8.0% (mean+6 to 9.9 SD) ≥8.1% (≥mean+10 SD) Not known Duration of diabetes <15 years ≥15 years Retinopathy No Yes White’s class B C D R Women with diabetes, total Women without diabetes (control subjects) *χ2 test and Armitage test for trend: P<0.0001. †χ2 test: P=0.004. χ2 test: P<0.0001. Other differences were not statistically significant. Source: Hiilesmaa et al. (2000).

Total

Pre-eclampsia

PIH

%

n

%

41 154 221 171 29

2 11 30 34 2

4.9* 7.1* 13.6* 19.8* 6.9

4 14 31 16 5

9.8 9.1 14.0 9.4 17.2

319 297

29 50

9.1† 16.8†

39 31

12.2 10.4

431 185

44 35

10.2† 18.9†

49 21

11.4 11.4

157 175 237 47 616 854

9 23 35 12 79 23

5.7* 13.1* 14.8* 25.5* 12. 8 2.7

17 23 23 7 70 48

10.8 13.1 9.7 14.9 11. 4 5.6

type 1 diabetes as a strong risk factor for subsequent pre-eclampsia. Multiple logistic regression analysis also identified nulliparity, retinopathy and the duration of diabetes as statistically significant independent predictors of pre-eclampsia (Tables 10.4 and 10.5). Hanson and Persson |7| undertook a nationwide collaborative study of 491 type 1 diabetic pregnancies between 1983 and 1985. A blood sample for the determination of HbA1c was obtained in early gestation (median 9 weeks and range 5–16 weeks). They reported a PIH/pre-eclampsia rate of 20.6% in type 1 diabetic pregnancies as compared to 5.0% in the background population. The type 1 diabetic pregnancies complicated by PIH/pre-eclampsia were associated with a significantly longer duration of diabetes, higher

202

V · DIABETES AND PREGNANCY

initial HbA1c (8.1 versus 7.4%) (P<0.01) and higher rates of nephropathy and retinopathy. Discriminant analysis confirmed that the occurrence of nephropathy (P<0.001), retinopathy (P<0.01) and high HbA1c (P< Table 10.5 Factors associated with pre-eclampsia in 616 type 1 diabetic women without pre-pregnancy nephropathy (White’s classes B, C, D and R)

Nulliparity Retinopathy Duration of diabetes HbA1c in early pregnancy HbA1c improvement until mid-pregnancy

Unadjusted

Adjusted

OR

95% Cl

OR

95% Cl

P

2.9 3.0 1.3* 1.3† 1.0

1.9–4.5 2.0–4.5 1.2–1.5 1.1–1.5 0.9–1.2

2.7 2.0 1.2* 1.6† 0.6

1.7–4.3 1.2–3.3 1.0–1.5 1.3–2.0 0.5–0.8

<0.0001 0.0001 0.02 <0.0001 <0.0001

*Increase of risk for each additional 5 years’ duration. †Increase of risk for each 1% increment in HbA1c. Reduction of risk for each 1% decrement In HbAlc during the first half of pregnancy. Source: Hiilesmaa et al. (2000).

0.01) in early pregnancy were independently and significantly associated with the occurrence of PIH/preeclampsia. In conclusion, both studies confirmed that poor glycaemic control in early pregnancy is associated with an increased risk of pre-eclampsia in non-proteinuric type 1 diabetic pregnancies. Pre-diabetes and perinatal mortality S Wood, R Sauve, S Ross, R Brant, E Love. Diabetes Care 2000; 23:1752–4. BACKGROUND. The objective of this study was to assess the relationship between the time to diabetes and the perinatal outcome of pre-diabetic pregnancies in a contemporary population of women with adult onset diabetes. A population of 403 diabetic women from two recruitment sites completed a pre-tested questionnaire. Details of 1181 pregnancy outcomes were obtained comprising 1024 live births, 22 stillbirths and eight early neonatal deaths. Crude analysis suggested a relationship between a time to diabetes (latency) of≤20 years and both perinatal death and stillbirth: the ORs (95% confidence interval (Cl)) were 2.41 (1.17–4.95) and 2.15 (0.93–4.98). Generalized additive modelling (GAM) revealed a nonlinear relationship between the variables time to diabetes and maternal age and perinatal outcome. This final analysis documented a significant association between a time to diabetes of≤20 years and both perinatal death and stillbirth. There appeared to be an increased risk of perinatal death and stillbirth in pregnancies occurring in the previous 20 years before the diagnosis of diabetes.

Table 10.6 Association between a time to diabetes of<20 years and perinatal death Time to diabetes

Perinatal death

No perinatal death

Stillbirth

Live birth

Total

≤20 years to diabetes >20 years to diabetes

13 (5.0)

247

9 (3.5)

251

260

17 (2.1)

777

13 (1.6)

781

794

DIABETES AND PREGNANCY

203

Fig. 10.1 Parametric smoothed functions for (a) maternal age, (b) year of birth and (c) timeto diabetesforthe outcome perinatal death. The y-axis indicates the non-parametric estimates of the log ORs. Source: Wood et al. (2000). Time to diabetes

Perinatal death

No perinatal death

Stillbirth

Live birth

Total

Total

30

1024

22

1032

1054

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V · DIABETES AND PREGNANCY

Time to diabetes

Perinatal death

No perinatal death

Stillbirth

Live birth

Total

The data are n values or n values with percentages in parentheses. Perinatal death: risk ratio (95% Cl) 2.34 (1.15–4.74), OR (95% Cl) 2.41 (1.17–4.95) and two-sided Fisher’s exact P=0.0288. Stillbirth: risk ratio (95% Cl) 2.11 (0. 91–4.89), OR (95% Cl) 2.15 (0.93–4.98) and two-sided Fisher’s exact P=0.0826. Source: Wood et al. (2000).

Comment GAM is a relatively new statistical method for investigating non-linear relationships and was used in this study for correlating the pre-diabetes period (diabetes undiagnosed) with perinatal mortality due to the fact that these women have a high risk of developing gestational diabetes in subsequent pregnancies. The perinatal mortality associated with this type of pregnancy is possibly explained by the fact that these women are suffering from an illness and that they have not undergone proper examination. This is plausible given that diabetes develops some years prior to diagnosis (Table 10.6 and Fig. 10.1). In conclusion this report suggests that there is an increased risk of perinatal death and stillbirth in pregnancies occurring in the 20 years before the diagnosis of type 2 DM. Risks of pre-eclampsia and adverse neonatal outcomes among women with pre-gestational diabetes mellitus B M Sibai, S Caritis, J Hauth, M Lindheimer, J P VanDorsten, et al. Am J Obstet Gynecol 2000; 182:364–9. BACKGROUND. This study was undertaken in order to determine the prevalence of pre-eclampsia and adverse neonatal outcomes among women with pre-gestational DM (PDM). This was a prospective observation of pregnancy outcomes among 462 women with PDM and singleton pregnancies who were enrolled in a multicentre trial for pre-eclampsia prevention. Ninety-two (20%) of the 462 women with pre-gestational diabetes (White’s classes B-F) had pre-eclampsia. The pre Table 10.7 White’s classification of diabetes Classification

Criteria (%)

Risk of pre-eclampsia

Class A Class B Class C Class D Classes R+F

Diabetes treated with diet or drugs Age at onset>20 years and disease duration<10 years Age at onset 10–19 years or duration 10–19 years Age at onset<10 years and disease duration>20 years Nephropathy (R) and proliferative retinopathy (F)

11 22 21 36

P<0.0001. Source: Sibai et al. (2000).

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Table 10.8 Neonatal outcome according to the presence or absence of pre-eclampsia Pre-eclampsia present (n=92)

Pre-eclampsia absent (n=370)

Odds ratio

Outcome

No.

%

No.

%

Adjusted* 95% Confidence interval

Statistical significance

Delivery at<37 wk Delivery at<35 wk Birth weight<10th percentile Birth weight>90th percentile Birth weight>4000 g Admission to neonatal intensive care unit Perinatal death

52

56.5

123

33.2

2.5

1.5–4.0

P=.0002

18

19.6

57

15.4

1.2

0.7–2.2

P=.532

5

5.4

17

4.7

0.9

0.5–4.3

P=.871

34

37.0

125

35.0

1.2

0.8–2.0

P=413

13

14.1

58

16.1

1.0

0.5–1.9

P=.903

60

65.2

162

46.2

2.0

1.3–3.3

P=.0036

1

1.1

10

2.7

0.4

0.1–2.9

P=.3321

*The ORs were adjusted for the presence or absence of proteinuria at baseline. Source: Sibai et al. (2000). eclampsia frequency rose significantly with increasing severity of diabetes according to White’s classification. Pre-eclampsia was also more common among women who had proteinuria at baseline (28 versus 18%) (OR=1.75 and 95% Cl= 1.02–3.01). The frequency of pre-term delivery at<35 weeks’ gestation rose greatly with increasing severity of diabetes (P=0.0002). Women with proteinuria at baseline were significantly more likely to be delivered at<35 weeks’ gestation (29 versus 13%) (OR=2.6 and 95% Cl=1.5–4.6) and to have infants that were small for their gestational age (14 versus 3%) (OR=5. 4 and 95% Cl=2.7–17.7) and were less likely to have infants that were large for their gestational age (14 versus 40%) (OR=0.2 and 95% Cl=0.1–0.5).

Comment This prospective trial established a 20% prevalence of pre-eclampsia in women with pre-gestational diabetes. The risk increased with increasing severity of diabetes according to White’s classification (Table 10.7). The pre-eclampsia frequency rose significantly (p<0.001) with increasing severity of diabetes according to White’s classification. Other studies have confirmed the increased risk of pre-eclampsia and adverse pregnancy outcomes with increasing severity of diabetes. In a prospective nation-wide study in Sweden conducted during 1982–1985

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the rates of hypertensive disorders and perinatal mortality and morbidity were studied in 491 type 1 diabetic pregnancies using White’s classes (class B rate=164, class C rate=129, class D rate= 172 and class F rate=26) compared with the total population of 279 000 |8|. The rates of PIH or pre-eclampsia were almost identical (20.6%). PIH or pre-eclampsia occurred significantly (P<0.01) more frequently in patients with diabetic micro-angiopathy. It can be concluded that, among women with PDM, the frequency of pre-eclampsia increases with increasing severity of diabetes particularly when microvascular complications are present. Proteinuria early in pregnancy was particularly associated with marked increases in adverse neonatal outcomes independent of pre-eclampsia development. Patterns of congenital anomalies and relationship to initial maternal fasting glucose level in pregnancies complicated by type 2 and gestational diabetes U Schaefer-Graf, T Buchanan, A Xiang, G Songster, M Montoro, et al. Am J Obstet Gynecol 2000; 182:313–20. BACKGROUND. The authors sought to determine the types of congenital anomalies affecting the infants of women with GDM or type 2 diabetes and to examine the relationship between those malformation types and measures of the initial glycaemia of the women with type 2 diabetes at entry into prenatal care or at the time of diagnosis in the women with GDM. A total of 4180 pregnancies complicated by GDM (n=3764) or type 2 diabetes (n=416) that were delivered after 20 weeks of gestation were reviewed for the presence of congenital malformations that were diagnosed before hospital discharge. Anomalies were categorized as being absent, minor, major, genetic syndromes or aneuploidies. The number and type of the affected organ systems were used for categorizing major anomalies further. The women’s initial fasting serum glucose (FSG) and HbA1c levels were significantly higher in pregnancies with major (n=143) and minor (n=112) anomalies and genetic syndromes (n=9) as compared with pregnancies with no anomalies (n= 3895). Congenital anomalies in the offspring of women with gestational and type 2 diabetes affected the same organ systems that have been previously Table 10.9 Glycaemic parameters according to the anomaly status of the offspring in a cohort of women with gestational and type 2 diabetes (reported as means±SDs) Anomaly classification

None

Mean*

Major†

Genetic syndrome

Aneuploidy

Initial fasting serum glucose level (mg/dL) Highest fasting serum glucose level (mg/dL)¶ Glycosylated haemoglobin level (SD)**

114.6±37.2

132.1±58.5§II

144.6±56.8§

152.2±59.2§

115.2±37.9

119.9±40.0

138.4±61.3§#

150.3±58.7§

156.3±60.9§

123.2±41.4

1.91±3.64

3.35±5.02§

3.60±3.80§

3.92±2.50§

3.65±5.7

*Minor anomalies not associated with major anomalies, a genetic syndrome or aneuploidy. †At least one major anomaly not associated with a genetic syndrome or aneuploidy. At the time of the diagnosis of GDM or initial pre-natal visit in women with type 2 diabetes. §P<0.0001 compared with the no anomaly group. IIP=0.01 compared with the major anomaly group. ¶Before the initiation of insulin therapy only in women who required this therapy. #P=0.03 compared with the major anomaly group.

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Anomaly None Mean* Major† Genetic Aneuploidy classification syndrome **HbA1c available in 1705 subjects, all of whom required insulin, expressed as the number of standard deviations from the normal population mean for the assay. Source: Schaefer-Graf et al. (2000). Table 10.10 Maternal clinical and historical variables according to the anomaly status of the offspring (sample size) in a cohort of women with GDM and type 2 diabetes (reported as means and SDs or frequencies)

Infants with anomalies (No. and rate) Current pregnancy Maternal age (y) Parity Pre-pregnancy body mass index (kg/m2) Gestational age at initial prenatal visit (wk) Gestational age at initial fasting serum glucose (wk) Substance abuse§ during pregnancy (% and No.) First-trimester exposure to sulfonylurea agents II (% and No.) Prior pregnancy GDM (%) Anomalous infant (%) Stillbirth Macrosomia¶

No anomaly

Minor*

Major†

Genetic syndrome Aneuploidy

3895 (93.2%)

112 (2.7%)

143 (3.4%)

9 (0.2%)

21 (0.5%)

31.7±5.8 2.2±1.8 29.5±5.7

31.2±5.9 2.3±1.9 31.0±6.0

31.5+5.9 2.6±2.1 31.4±6.5

27.9±7.03 2.6±1.10 30.4±3.8

38.6±4.8 3.4±2.6 31.4±5.5

17.3±7.3

17.0±8.0

17.6±7.8

21.6±6.9

18.8±8.9

24.5±8.6

22.6±9.2

22.2±8.9

25.2±8.7

22.6±9.3

1.5 (59)

0.9 (1)

1.4 (2)

0 (0)

0 (0)

3.7 (142)

9.1 (10)

12.9 (18)

22 (2)

5 (1)

18.6 2.8 4.6 28.5

20.6 3.7 8.3 31.5

32.8 3.0 7.4 34.1

0 0 12.5 0

42.1 0 5.8 41.2

* Minor anomalies not associated with major anomalies, a genetic syndrome or aneuploidy. †Anomalies not associated with a genetic syndrome or aneuploidy. P<0.05 compared with the no anomaly group. § Alcohol, illicit drugs or tobacco. II Exposure to sulphonylurea agents during the first 8 weeks of pregnancy in 173 of the 416 pregnancies complicated by type 2 diabetes. ¶ Birth weight>4000g. Source: Schaefer-Graf et al. (2000). described in pregnancies complicated by type 1 diabetes. Pregnancies with major anomalies affecting multiple organ systems had significantly higher initial FSG levels (166±64 mg/dl) as compared with pregnancies in which only one organ system was affected (141±55 mg/dl) (P<0.04) or no organ system was affected (115±38 mg/dl) (P<0.0001).

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Comment For some years, hyperglycaemia during the embryogenic period has been linked with fetal malformations of the central nervous system (CNS), heart and major blood vessels, kidneys and skeleton in the children of mothers with type 1 DM. Relatively few studies of expectant mothers with type 2 DM or gestational diabetes have been published. In this study, the most commonly affected organ systems in those pregnancies with major anomalies were the cardiac system (37.6%), the musculoskeletal system (14.7%) and the CNS (9.8%) and anomalies involving multiple organ systems (16%). There was no increased predominance of any specific organ system involvement seen with increasing FSG levels in pregnancies with major congenital anomalies. Congenital anomalies in the offspring of women with gestational and type 2 diabetes affected the same organ systems that have been previously described in pregnancies complicated by type 1 diabetes. A study of 3743 pregnancies complicated by GDM delivered at>20 weeks of gestation that investigated the presence of congenital malformations that were diagnosed before hospital discharge has also been reported |9|. One or more major congenital anomalies were present in 108 (2.9%) of the newborns and an additional 91 (2.4%) had minor anomalies. The risk of major congenital anomalies was related to a history of GDM and the highest FSG level was found to be the best independent predictor. The FSG level at diagnosis gave similar predictive information about the risk of major anomalies. Stratification of the women into subgroups of FSG level at diagnosis revealed a major anomaly risk of 2.1% with an FSG level of<120 mg/ dl (2973 pregnancies), 5.2% with an FSG level of 121–260 mg/dl (747 pregnancies) and 30.4% with an FSG level of> 260 mg/dl (23 pregnancies). Both studies, which were based on large populations of women without a diagnosis of diabetes before pregnancy, suggested that the maternal FSG concentration at diagnosis is a useful predictor of the risk of major anomalies in their offspring. Increasing hyperglycaemia at diagnosis or presentation for care was associated with an increased risk of anomalies in general and with anomalies involving multiple organ systems without a preferential increase in the involvement of a specific organ system. Is insulin lispro associated with the development or progression of diabetic retinopathy during pregnancy? A Buchbinder, M Miodovnik, S McElvy, B Rosenn, G Kranias, et al. Am J Obstet Gynecol 2000; 183:1162–5. BACKGROUND. This study was designed for determining whether there is an association between the use of insulin lispro during pregnancy and the development or progression of diabetic retinopathy (DR). This observational cohort study included women with type 1 DM (n=12) who were enrolled in our DM in pregnancy programme and who were treated with insulin lispro during pregnancy. We compared these women with a historical cohort (n=42) that was treated with regular insulin during pregnancy. Whereas none of the patients in the insulin lispro group showed any change in retinopathy status, six patients in the regular insulin group (14%) demonstrated changes in retinopathy status. These preliminary findings provide no evidence that insulin lispro treatment during pregnancy is associated with the development or progression of DR.

Comment Insulin lispro is not licensed for use during pregnancy, although many diabetologists maintain regimens based on insulin lispro if these were used prior to pregnancy and optimal glycaemic control was achieved.

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Some studies have linked insulin lispro to the development of retinopathy based on the hypothesis that it could act as a growth factor |10, 11|. However, various Table 10.11Glycaemic control: HbA1c concentrations according to the insulin type used Insulin lispro (n=12) Regular insulin (n=42) Statistical significance Glycohaemoglobin A1 concentration* (mean ± SD) At enrolment First trimester Second trimester Third trimester Post partum Change from enrolment to second trimester Rapid normalization† (No.)

3.2±1.9 3.1±3.0 1.2±1.8 1.2±3.0 2.6±1.8 −2.1±2.1

2.5±2.4 1.9±2.0 0.1±1.5 −0.2±1.3 1.4±2.7 −2.3±2.2

P=.39 P=.27 P=.06 P=35 P=.20 P=.74

2 (17%)

10 (28%)

P=.41

*The HbA1c concentrations are expressed in SDs from the the means of the population with normal glycaemic control. †Defined as a decrease from enrolment to the second trimester in HbA1c concentrations of more than four SDs. Source: Buchbinder et al. (2000).

confounding factors, such as other hormones, vascular complications, poor metabolic control and rapid blood glucose correction, could be influential at this stage, making any risk attributable to insulin lispro difficult to prove with certainty. Although this report provided no evidence to support an adverse effect of insulin lispro on the development or progression of retinopathy in pregnancy the small numbers of patients taking insulin lispro and the resulting limited power of the study suggested the conclusions must be interpreted with caution. Further prospective trials are needed in order to evaluate this area. The fetal and childhood growth of persons who develop type 2 diabetes T Forsen, J Eriksson, J Tuomilehto, A Reunanen, C Osmond, et al. Ann Intern Med 2000; 133:176–82. BACKGROUND. This study aimed to examine the relation of type 2 diabetes to birth weight and, in particular, to the pattern of childhood growth. The authors studied men (n=3639) and women (n=3447) who were born at the Helsinki University Central Hospital between 1924 and 1933 and who attended school in Helsinki and who still lived in Finland in 1971. Growth data was obtained from school records. Four hundred and seventy-one men and women who had developed type 2 diabetes were identified using the national Social Insurance Institution’s register of all persons in Finland who were receiving longterm therapy with medication. The main explanatory measurements were size at birth and childhood growth in terms of height, weight and body mass index (BMI). The cumulative incidence of type 2 diabetes was 7.9% (n=286) in men and 5.4% (n=185) in women. The incidence increased with decreasing birth weight, birth length, ponderal index and placental weight. The mean weights and heights at 7 years of age of the children who later developed type 2 diabetes were approximately average. Thereafter, their growth in weight and height was accelerated until 15 years of age. The OR for the development of type 2 diabetes was 1.39 (95% Cl=1.21–1.61) (P<0.001) for each standard deviation increase in weight between 7 and 15 years of age. The OR increased to 1.83 (95% Cl=1.37–2.45) (P<0.001) in an analysis restricted to persons whose birth weights were below 3000g. Children of both sexes whose mothers had a high BMI in pregnancy had more rapid growth during childhood and an increased incidence of type 2 diabetes.

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These findings are consistent with the hypothesis that type 2 diabetes is programmed in utero in association with low rates of fetal growth. The increased risk of type 2 diabetes associated with small size at birth is further increased by high growth rates after 7 years of age.

Comment This report is one of a series that investigated the relationship between birth weight and a range of cardiovascular risk factors in a cohort of Finnish men whose anthro Table 10.12 Cumulative incidence of type 2 diabetes according to size at birth Size at birth

Men

Women

% (n) Birthweight ≤2500 g 2501–3000 g 3001–3500 g 3501–4000 g >4000 g P value for trend Length at birth ≤48 cm 48.1–49.0 cm 49.1–50.0 cm 50.1–51.0 cm >51.0 cm P value for trend Placental weight ≤450 g 451–550 g 551–650 g 651–750 g >750 g P value for trend

All %

8.3 (145) 10.9 (552) 7.7 (1318) 7.5 (1153) 5.9 (444) 0.002

10.0 (190) 5.3 (704) 5.1 (1411) 5.2 (879) 4.4 (248) 0.08

9.3 7.7 6.4 6.5 5.3 <0.005

10.5 (497) 7.9 (518) 8.1 (993) 8.1 (749) 6.1 (841) 0.009

6.4 (719) 4.7 (593) 5.4 (1071) 5.1 (588) 4.9 (449) 0.11

8.1 6.2 6.7 6.8 5.7 0.002

11.2 (251) 7.7 (845) 8.6 (1181) 6.7 (836) 6.9 (496) 0.05

10.1 (257) 5.5 (855) 4.9 (1106) 4.9 (789) 4.5 (418) 0.02

10.6 6.6 6.8 5.8 5.8 0.002

Source: Forsen et al. (2000).

pomorphic measurements at birth were available from hospital records between 1924 and 1933. In addition to an increased risk of type 2 diabetes in later life, low-birth weight infants are also more likely to experience hypertension, heart disease and stroke in later life |12–14|. Type 2 DM therefore appears to form part of a group of illnesses that are the consequences of fetal adaptation to an adverse intra-uterine environment and provides further support for the well known Barker-Hales hypothesis |15|, which established that low-birth weight infants who became obese in adult life had an increased risk of type 2 diabetes. In this study a low birth weight also predicted type 2 diabetes, with an OR of 1.38 for every 2 kg

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decline in birth weight. In addition, diabetes risk was compounded by an increased growth rate over 7 years of age, particularly in those subjects who had a low birth weight. The benefits, risks, costs and patient satisfaction associated with insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus S G Gabbe, E Holing, P Temple, Z A Brown. Am J Obstet Gynecol 2000; 182:1283–91. BACKGROUND. Glycaemic control, perinatal outcomes and health care costs were evaluated among women with type 1 DIVI who began insulin pump therapy during pregnancy (group 1) (n=24), who were treated with multiple insulin injections during pregnancy (group 2) (n=24) or who were already using an insulin pump before pregnancy (group 3) (n=12). A retrospective review of maternal and neonatal medical records was performed and a questionnaire was sent to patients after delivery. No differences in HbA1c levels were observed among groups 1–3 in the first, second or third trimesters. No deterioration in glycaemic control was noted during the 2- to 4-week period after the start of pump treatment. No significant differences in perinatal outcomes or health care costs were observed among groups 1–3. After delivery 94.7% of the women in group 1 continued to use the pump because it provided better glycaemic control and a more flexible life style. Insulin pump therapy was initiated during pregnancy without a deterioration in glycaemic control and was associated with maternal and perinatal outcomes and health care costs that were comparable to those among women who were already using the pump before pregnancy or who received multiple-dose insulin therapy.

Comment Continuous subcutaneous insulin infusion (CSII) pumps give greater time flexibility and improve the quality of some patients’ lives. CSII is associated with significant improvements in glucose control in nonpregnant subjects that is often achieved with lower daily doses of insulin as compared with multiple insulin regimens |16|. Some but not all studies have suggested a lower risk of severe hypoglycaemia with CSII |17, 18|. There is increasing experience of CSII therapy during pregnancy, when the treatment goal is optimal glycaemic control in order to avoid fetal macrosomia. This report assessed the feasibility of introducing CSII therapy during pregnancy and provided evidence that it is both feasible and effective. CSII was confirmed as a good method of improving and maintaining metabolic control during pregnancy. Transfer to CSII was undertaken at a mean of 16.8 weeks’ gestation and 17 (70.8%) began therapy as out-patients. Importantly, no deterioration in glycaemic control was noted during the 2- to 4-week period after the start of pump treatment. It is important to educate women using CSII about the importance of monitoring for ketones since, in the event of catheter malfunction, ketoacidosis can develop very quickly with well-established adverse risks for the fetus. With appropriate education a patient can switch to subcutaneous insulin therapy while the CSII is Table 10.13 HbA1c values

1st trimester 2nd trimester 3rd trimester Post partum

Group 1 (n=24)

Group 2 (n=24)

Group 3 (n=12)

Statistical significance

Mean Range

Mean Range

Mean Range

All 3 groups

Group 1 vs group 2

7.6 6.2 6.1 7.2*

8.4 6.5 6.6 9.1*

7.1 6.1 6.3 7.1†

NS, P=.06 NS NS P=.02

NS, P=.15 NS NS P=.03

5.6–10.2 5.1–7.6 4.8–7.0 5.3–12.7*

5.2–11.1 4.7–10.3 4.7–9.5 5.4–15.7*

5.7–9.7 5.4–6.9 5.3–7.5 5.9–9.0†

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Group 1 (n=24)

Group 2 (n=24)

Group 3 (n=12)

Statistical significance

Mean Range

Mean Range

Mean Range

All 3 groups

Group 1 vs group 2

The data are HbA1c concentrations as percentages. NS, not significant. *n=16. †n=10. Source: Gabbe et al. (2000).

replaced. In the study reported, two episodes of ketoacidosis occurred in group 1 and no episodes occurred in groups 2 and 3, but no significant differences in perinatal outcomes or health care costs were observed among groups 1–3. The study also suggested benefits in terms of a reduced risk of severe hypoglycaemia. Eight of the women in group 1 had at least one episode of severe hypoglycaemia before starting pump therapy, but only one had such an episode after this treatment was begun. The results obtained for mothers and the unborn and in terms of health costs were similar to those for pregnant women treated with multiple doses of insulin. In conclusion, insulin pump therapy was initiated during pregnancy without a deterioration in glycaemic control and was associated with maternal and perinatal outcomes and health care costs that were comparable to those among women who were already using the pump before pregnancy or who received multiple-dose insulin therapy. Women who began pump therapy in pregnancy were highly likely to continue pump use after delivery and preferred the flexible life style that this treatment allowed. Conclusion The interaction between diabetes and pregnancy that is summarized in the Introduction to Part V is complex and occurs at many levels. The report by Sibai et al. (p. 253) emphasizes that the risk of pre-eclampsia increases with increasing severity of diabetes, particularly when microvascular complications are present. Proteinuria early in pregnancy was in particular associated with marked increases in adverse neonatal outcomes independent of pre-eclampsia development. This paper rein-forces the need for a rigorous assessment of all women with diabetes who become pregnant. The identification of established complications should alert the clinical team to the need for intensive supervision of such women during their pregnancies. In addition, the relationship between glycaemic control and pre-eclampsia that is identified by Hiilesmaa et al. (p. 249) is also partly explained by coexistant renal disease, retinopathy and diabetes duration and these are all factors that must be assessed in pre-conceptual clinical assessment. Similar clinical messages flow from the DCCT report (p. 243), which confirms a strongly held clinical belief that pregnancy causes a transient deterioration in retinopathy. As a minimum requirement women with preconception diabetes require retinal screening in each trimester in order to detect progressive retinopathy and perhaps more frequently in those with established retinopathy at conception. It is reassuring that this deterioration is transient and the long-term outlook remains better if optimal glycaemic control can be maintained. The use of BP measurements in identifying patients at risk of pre-eclampsia or PIH is an important clinical issue. ABP monitoring has been evaluated in this regard although a review of the literature showed inconsistent results. The report by Flores et al. (p. 244) analyses the ABP profiles in each trimester in women with diabetes and finds that PIH was significantly more likely to develop if their nocturnal SBP exceeded 105 mmHg. This observation had a high sensitivity and specificity, but requires confirmation in

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larger cohorts of unselected patients. It is also essential for robust normal ranges in women with uncomplicated pregnancy to be developed for each trimester of pregnancy. There must also be doubts about the practicality of repeated ABP monitoring measurements in pregnant women with diabetes in many units since the test is somewhat uncomfortable for patients. CSII is being increasingly considered as an option for insulin therapy in pregnancy. Women are generally well motivated, undertaking self-monitored blood glucose measurements regularly and are in frequent contact with the diabetes team. It is important for the clinical diabetes team to be confident about the use of CSII. Incorrect use, for example with blocking of the administration tubing, will lead to the rapid development of ketoacidosis, a metabolic complication with grave implications for the health of the fetus. The report from Gabbe et al. (p. 262) is therefore reassuring in showing that women were able to maintain diabetic control with CSII or transfer successfully to pump therapy with no increased risk of ketoacidosis during pregnancy. CSII should be considered as an option for achieving glycaemic control in selected women attending selected clinical teams. Women diagnosed with gestational diabetes should have their glucose tolerance re-assessed in the postpartum period. The majority will have returned to normal glucose tolerance although the type of test that should be used for determining glucose tolerance has been subject to doubt with the introduction of the ADA criteria (as summarized in Chapter 1 on pp. 51 and 52). The report by Costa et al. (p. 246) echoes the concerns expressed by many other authors about the validity of fasting glucose. Their finding that fasting glucose was an unsatisfactory way of defining glucose tolerance in this high-risk group of women supports the work of other authors. Kousta et al. |4| studied 192 women with previous GDM who took an OGTT 1– 86 months after delivery and classified them by 1985 WHO, 1997 ADA (fasting glucose) and revised 1998 WHO guidelines. Although all diagnostic criteria identified a similar prevalence of diabetes, one-third of women showed a classification discrepancy between the 1985 WHO and 1997 ADA criteria, including 44 with NFG by the 1997 ADA criteria, but abnormal 2-hour glucose by the 1985 WHO criteria (40IGT and four diabetes). Hence, based on a single fasting glucose screen (and a threshold of 6.1 mmol/l) 60% of women with abnormal 2-hour glucose levels would not be identified. Screening women with previous gestational diabetes (and, by analogy, other groups at high risk of diabetes) with a single fasting glucose screen appears to have low sensitivity for the detection of AGT. Finally, the clinical screening tool used for identifying women who may have MODY due to glucokinase mutations is of interest. The authors relied on fasting and 2-hour post-load glucose results together with a family history of type 2 or gestational diabetes for identifying women with a much higher probability of having MODY. Clearly the identification of the MODY phenotype in the situation where diabetes has been identified during gestation has proven a sensitive means of identifying new cases. This result has clinical implications for the patient as well as her family and offspring. References 1. 2.

3.

Hermida RC, Ayala DE. Diagnosing gestational hypertension and preeclampsia with the 24-hour mean of blood pressure. Hypertension 1997; 30(6):1531–7. Higgins JR, Walshe JJ, Halligan A, O’Brien E, Conroy R, Darling MR. Can 24-hour ambulatory blood pressure measurement predict the development of hypertension in primigravidae? Br J Obstet Gynaecol 1997; 104(3): 356–62. Hermida RC, Ayala DE, Mojon A, Fernandez JR, Alonso I, Silva I, Ucieda R, Iglesias M. Blood pressure patterns in normal pregnancy, gestational hypertension, and preeclampsia. Hypertension 2000; 36(2):149–58.

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4.

5.

6.

7. 8. 9.

10. 11. 12. 13. 14. 15. 16.

17.

18.

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Kousta E, Lawrence NJ, Penny A, Millauer BA, Robinson S, Dornhorst A, De Swiet M, Steer PJ, Grenfell A, Mather HM, Johnston DG, McCarthy MI. Implications of new diagnostic criteria for abnormal glucose homeostasis in women with previous gestational diabetes. Diabetes Care 1999; 22(6):933–7. Chiu KC, Go RC, Aoki M, Riggs AC, Tanizawa Y, Acton RT, Bell DS, Goldenberg RL, Roseman JM, Permutt MA. Glucokinase gene in gestational diabetes mellitus: population association study and molecular scanning. Diabetologia 1994; 37(1):104–10. Stoffel M, Bell KL, Blackburn CL, Powell KL, Seo TS, Takeda J, Vionnet N, Xiang KS, Gidh-Jain M, Pilkis SJ. Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes 1993; 42(6): 937–40. Hanson U, Persson B. Epidemiology of pregnancy-induced hypertension and preeclampsia in type 1 (insulindependent) diabetic pregnancies in Sweden. Acta Obstet Gynecol Scand 1998; 77(6):620–4. Hanson U, Persson B. Outcome of pregnancies complicated by type 1 insulin-dependent diabetes in Sweden: acute pregnancy complications, neonatal mortality and morbidity. Am J Perinatol 1993; 10(4):330–3. Schaefer UM, Songster G, Xiang A, Berkowitz K, Buchanan TA, Kjos SL. Congenital malformations in offspring of women with hyperglycemia first detected during pregnancy. Am J Obstet Gynecol 1997; 177(5): 1165–71. Kitzmiller J, Main E, Theiss T, Peterson D. Insulin lispro and the development of proliferative diabetic retinopathy during pregnancy. Diabetes Care 1999; 22:874–6. Bhattacharyya A, Vice PA. Insulin lispro, pregnancy and retinopathy. Diabetes Care 1999; 22:2101–2. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth and coronary heart disease in later life: longitudinal study. BMJ 2001; 322(7292):949–53. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Early growth, adult income, and risk of stroke. Stroke 2000; 31(4):869–74. Eriksson JG, Forsen T, Tuomilehto J, Osmond C, Barker DJ. Fetal and childhood growth and hypertension in adult life. Hypertension 2000; 36(5):790–4. Hales CN, Barker DJ, Clark PM, Cox LJ, Fall C, Osmond C, Winter PD. Fetal and infant growth and impaired glucose tolerance at age 64. BMJ 1991; 303(6809):1019–22. Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care 2000; 23(9):1232– 5. Boland EA, Grey M, Oesterle A, Fredrickson L, Tamborlane WV. Continuous subcutaneous insulin infusion. A new way to lower risk of severe hypoglycemia, improve metabolic control, and enhance coping in adolescents with type 1 diabetes. Diabetes Care 1999; 22(11):1779–84. Coustan DR, Reece EA, Sherwin RS, Rudolf MC, Bates SE, Sockin SM, Holford T, Tamborlane WV. A randomized clinical trial of the insulin pump vs intensive conventional therapy in diabetic pregnancies. JAMA 1986; 255(5):631–6.

Part VI Diabetes research

Diabetes research

Introduction This part of the book summarizes important research in the field of basic science as applied to the clinical problems of diabetes. Whilst many of these reports have no current clinical application they are intrinsically of great interest and they also give a flavour of future directions of genetic and cellular research that may ultimately yield important breakthroughs.

11 Diabetes research

Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen A M Shapiro, J R Lakey, E A Ryan, G S Korbutt, E Toth, et al. N Engl J Med 2000; 343(4):230–8. BACKGROUND. Seven consecutive patients with type 1 diabetes and a history of severe hypoglycaemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium and transplanted immediately by means of a percutaneous transhepatic portal embolization. All seven patients quickly attained sustained insulin independence after transplantation of a mean islet mass of 11 547 islet equivalents per kilogram of body weight (median follow-up 11.9 months). All recipients required islets from two donor pancreases and one required a third transplant from two donors in order to achieve sustained insulin independence. The mean glycosylated haemoglobin (HbA1c) values were normal after transplantation in all recipients. Complications were minor and there were no significant increases in lipid concentrations during follow-up. These observations in patients with type 1 diabetes indicated that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoidfree immunosuppression is combined with the infusion of an adequate islet mass.

Comment Islet transplantation was begun as a treatment for type 1 diabetes in 1972. The results to date have been unsatisfactory with only 8% of those patients given an islet transplant remaining insulin independent for more than 1 year. This low success rate has been attributed to the toxic effect of the immunosuppressive drugs that are used for preventing acute rejection or to diabetic autoimmune disease relapse. This article has generated worldwide interest and fresh hopes that islet transplantation may be an alternative treatment for patients with type 1 diabetes who find difficulty in exercising metabolic control. In this study, seven patients with labile type 1 diabetes received an islet transplantation. © Clinical Publishing Services Ltd

All of the patients achieved insulin independence during a maximum monitoring period of 15 months. The basic characteristics determining the success of this treatment protocol were probably the following.

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1. Transplantation of an adequate number of fresh cells. Patients were given an average of 11 547+1604 islet equivalents per kilogram of body weight (where an islet equivalent is the number of islets with a standard diameter of 150 mm) entailing two implants of approximately 50% purity (islets/exocrine) and two different donors per patient. 2. A new non-corticoid immunosuppressive drug regimen. Since this initial report the authors have published further data on twelve type 1 diabetic patients with brittle diabetes or problems with hypoglycaemia who received islet transplantation |1|. The median and longest follow-ups were 10.2 and 20 months, respectively. Glucose control was significantly improved (pre-transplant fasting and meal tolerance-stimulated glucose levels of 12.5±1.9 and 20.0±2.7 mmol/1 and post-transplant fasting and meal tolerance-stimulated glucose levels of 6.3±0.3 and 7.5±0.6 mmol/1, respectively) (P<0.006). The mean HbA1c leveldecreasedfrom 8.3±0. 5% to 5.8±0.1% (P<0.001). Four patients had normal glucose tolerance (NGT), five had impaired glucose tolerance (IGT) and three had post-islet transplant diabetes (two of whom needed oral hypoglycaemic drugs and low-dose insulin of<10 U/day). All patients continued to have sustained insulin production, as evidenced by the most current baseline Cpeptide levels of 0.66±0.06 nmol/1 increasing to 1.29± 0.25 nmol/1 90 min after the meal tolerance test. Three patients had a temporary increase in their liver function tests. One patient had a thrombosis of a peripheral branch of the right portal vein and two of the early patients had bleeding from the hepatic needle puncture site, but these technical problems were resolved. The acute insulin response and the insulin area under the curve (AUC) after an intravenous glucose tolerance test (IVGTT) were consistently maintained over time. Importantly, in vivo insulin secretion was shown to correlate with the number of islets transplanted and with the cold ischaemia time prior to organ harvesting. The success of the Edmonton group using their protocol must be confirmed in other laboratories covering larger patient populations and a longer follow-up. Insulin independence is probably attainable when an adequate cellular mass is implanted and an immunosuppressor regimen with a lower diabetogenic effect is employed. Genetic and clinical characterization of maturity onset diabetes of the young in Spanish families A Costa, M Bescos, G Velho, J Chevre, J Vidal, et al. EurJ Endocrinol 2000; 142:380–6. BACKGROUND. The aim of this study was to investigate the frequencies of the major maturity onset diabetes of the young (MODY) subtypes in a panel of

Spanish families and to assess phenotypic differences in patients with the different subtypes of MODY. Mutations in the glucokinase and hepatic nuclear factor 1-α (HNF-lα) genes were observed in five (25%) and seven (35%) families, respectively. The insulin secretion capacity was similar in the three groups and the insulin sensitivity was decreased in MODY-X subjects. The glucose levels were significantly higher and insulin levels significantly lower throughout an oral glucose tolerance test (OGTT) in MODY-3 as compared with MODY-2 subjects. Mutations in the glucokinase/MODY-2 and HNF-lα/MODY-3 genes account for the majority of cases. The relative frequencies and the clinical characteristics of these MODY subtypes are in agreement with data previously reported in other European populations. MODYX patients seem to present a heterogeneous clinical profile.

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Comment In this article, the authors detailed the characteristics of MODY in a Spanish family sample. In the population studied, MODY-2 and MODY-3 gene mutations were found to be the commonest causes of MODY, MODY-3 being the commoner of the two. The relative frequencies and the clinical characteristics of the families studied were similar to those already reported for other European countries. It was not possible to identify the causal gene mutation for a large number of the families presenting MODYtype diabetes’ clinical characteristics. They were therefore labelled MODY-X. The authors suggested that, in such families, the clinically heterogeneous diabetes probably originated from mutations positioned in unidentified zones of the genome. This study is noteworthy in that reactions to an OGTT were used for identifying the possible genotype for each of the MODY families. Finally, this article is interesting in that it provides more information about the characteristics of this type of monogenic diabetes in yet another region of Europe. Identification and functional analysis of mutations in the hepatocyte nuclear factor 1-α gene in antiislet autoantibody-negative Japanese patients with type 1 diabetes E Kawasaki, Y Sera, K Yamakawa, T Abe, M Ozaki, et al. J Clin Endocrinol Metab 2000; 85:331–5. BACKGROUND. The aim of this study was to estimate the prevalence of MODY-3 in anti-islet autoantibody-negative patients with type 1 diabetes. Twenty-eight patients who lacked islet cell autoantibodies were identified from a large population-based sample of unrelated Japanese patients with type 1 diabetes. Two (7.1%) of these 28 autoantibody-negative patients with diabetes had mutations in the HNF-lα gene. One patient carried a frameshift mutation (Pro379fsdelCT) in exon 6 and another patient carried a novel 2 bp substitution at nucleotides 45 (G to A) and 46 (C to A) from the transcriptional site of the promoter region. These mutations were identified

in heterozygous form and were not identified in 64 unrelated healthy control subjects or 54 unrelated islet autoantibody-positive patients with type 1 diabetes.

Comment Mutations in the HNF-1α gene are the cause of MODY-3. MODY-3 is characterized by a severe impairment of insulin secretion and early disease onset, which may present with typical clinical features of type 1 diabetes. Although the majority of patients with type 1 diabetes have type 1A immune-mediated diabetes, a significant percentage have no evidence of an autoimmune disorder at diagnosis and are currently classified as type 1B. This and other studies |2| have estimated the prevalence of MODY-3 patients who have been misclassified as having type 1 diabetes. Moller et al. |2| reported 39 (6.7%) patients from a large populationbased sample of unrelated Danish Caucasian type 1 diabetic patients with an affected first-degree relative who did not carry high-risk human leucocyte antigen haplotypes, i.e. DR3 or DR4 or both were studied for mutations of the HNF-lα gene. Four of the 39 patients (10%) carried mutations in the HNF-lα gene all of which were in heterozygous form, segregated with diabetes and were not identified in 84 unrelated, healthy subjects. Furthermore, the family history in three of the four families showed diabetes in four consecutive generations, which is suggestive of an autosomal dominant inheritance.

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Fig. 11.1 Proposed model for coupling glucose metabolism to insulin secretion in the β cell. Glycolysis converts glucose to pyruvate (Pyr), which enters the mitochondrion and the tricarboxylic acid (TCA) cycle resulting in the transfer of reducing equivalents (red. equ.) to the electron (e-) transport chain, hyperpolarization of ∆ψc and generation of ATP. Subsequently, closure of the ATP-sensitive potassium channels depolarizes ∆ψc, which opens the voltagesensitive Ca2+ channels, thereby raising [Ca2+]c and triggering insulin exocytosis. Atthis time, underconditions of elevated [Ca2+]m, hyperpolarized Aψm increases [Ca2+]m, further activating the TCA cycle. Glutamate is then formed from α-ketoglutarate (aKG) by GDH. Glutamate uptake bygranules leads tothe second phase of insulin secretion. Source: Maechler and Wollheim (1999).

The discovery of mutation carriers in the HNF- lα gene in two out of 28 (7%) type 1B diabetic patients (i.e. with autoimmunity marker negativity) from the Japanese cohort and 10% in the Danish Caucasian cohort suggested that some diabetic patients initially classified as idiopathic are in reality suffering from MODY-3 diabetes. Clinical awareness of a family history of diabetes and mode of inheritance might help to identify and reclassify these diabetic subjects as MODY-3 patients. Mitochondrial glutamate acts as a messenger in glucose-induced insulin secretion P Maechler, C B Wollheim. Nature 1999; 402(6762):685–9. BACKGROUND. Insulin is stored in secretory granules and is released from pancreatic p cells by exocytosis. In the consensus model of glucose-stimulated insulin secretion, ATP is generated by mitochondrial metabolism, thus promoting the closure of ATP-sensitive potassium channels, which depolarizes the plasma membrane. Subsequently, opening of voltage-sensitive Ca2+ channels increases the cytosolic Ca2+ concentration ([Ca2+]c), which constitutes the main trigger initiating insulin exocytosis. Nevertheless, the Ca2+ signal alone is not sufficient for sustained secretion. A mitochondrial messenger must therefore exist which is distinct from ATP. The authors identified this as glutamate. They showed that glucose generates glutamate

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221

from β cell mitochondria. A membrane-permeable glutamate analogue sensitizes the glucose-evoked secretory response, acting downstream of mitochondrial metabolism. Added glutamate directly stimulates insulin exocytosis in permeabilized cells under conditions of fixed [Ca2+]c, independently of mitochondrial function. Glutamate uptake by the secretory granules is likely to be involved, as inhibitors of vesicular glutamate transport suppress the glutamate-evoked exocytosis. These results demonstrate that glutamate acts as an intracellular messenger that couples glucose metabolism to insulin secretion.

Comment This relevant article postulated the presence of a mitochondrial factor other than ATP for β cell insulin secretion. Maechler et al. held glutamate to be the likely candidate forming the link between glucose metabolism and insulin secretion. Glutamate is the product of the a-keto-glutarate amination reaction that is catalysed by glutamate dehydrogenase (GDH). The results showed that glutamate levels increased with increasing glucose concentration. Glutamate activated insulin secretion on entering the secretion granules. Consequently, glutamate in the β cell acted as an intracellular messenger during the exocytosis of glucose-dependent insulin release. Another recently published paper |3| showed that glutamate did not act as an insulin secretion messenger. Glucose and other secretogogues were not found to increase intracellular glutamate. Furthermore, insulin secretion did not increase when glutamine was added to the fluid although the glutamate levels were raised. Current evidence suggests that insulin secretion is associated with GDH flow, not towards glutarate formation, but towards oc-ketoglutarate formation. The two articles have been published in respected scientific journals and the working hypothesis and conclusions drawn by both appear to be correct. More experiments need to be carried out and the results reexamined for confirmation or revision purposes. Nevertheless, this does not detract from the fact that the theory is a very attractive and interesting one that merits further research. Hypoinsulinaemia, glucose intolerance and diminished β-cell size in SGKl-deficient mice M Pende, S C Kozma, M Jaquet, V Oorschot, R Burcelin, et al. Nature 2000; 408:994-7. BACKGROUND. Insulin controls glucose homeostasis by regulating glucose use in peripheral tissues and its own production and secretion in pancreatic (3 cells. These responses are largely mediated downstream of the insulin receptor substrates IRS-1 and IRS-2 through distinct signalling pathways, but their roles in mediating glucose homeostasis are poorly defined. Here the authors showed that mice that were deficient in S6 kinase 1 (S6K1), an effector of the phosphatidylinositide-3-OH kinase signalling pathway, are hypoinsulinaemic and glucose intolerant. Whereas insulin resistance is not observed in isolated muscle, such mice exhibit a sharp reduction in glucose-induced insulin secretion and in pancreatic insulin content. This is not due to a lesion in glucose sensing or insulin production, but to a reduction in pancreatic endocrine mass, which is accounted for by a selective decrease in P cell size. The observed phenotype closely parallels those of pre-clinical type 2 diabetes meUitus (DM), in which malnutrition-induced hypoinsulinaemia predisposes individuals to glucose intolerance.

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Comment In this study, the authors demonstrated the potential implication of S6K1 in type 2 DM in a model of S6Kldeficient mice. These animals are hypoinsulinaemic and intolerant to glucose and also present a reduced glucose-induced insulin secretion as well as reduced pancreatic insulin content. Since insulin transcription, insulin sensitivity and glucose uptake were not altered, the reduced size of insulin-secreting β cells seems to be the major cause of the diabetic phenotype in these animals. This suggests that S6K1, an effector of insulin action that is sensitive to nutrients such as glucose and amino acids, might be responsible for impaired β cell growth and, therefore, along with other factors, contributes to the development of type 2 diabetes. In vitro cultivation of human islets from expanded ductal tissue S Bonner-Weir, M Taneja, G C Weir, K Tatarkiewicz, K H Song, et al. Proc Natl Acad Sci USA 2000; 97(14):7999–8004. BACKGROUND. A major obstacle to successful islet transplantation for both type 1 and 2 diabetes is an inadequate supply of insulin-producing tissue. This need for transplantable human islets has stimulated efforts at expanding existing pancreatic islets and/or growing new ones. In order to test the hypothesis that human adult duct tissue could be expanded and differentiated in vitro to form islet cells, digested pancreatic tissue that is normally discarded from eight human islet isolations was cultured under conditions that allowed expansion of the ductal cells that formed three-dimensional structures of ductal cysts from which 50 to 150 jnm diameter islet-like clusters of pancreatic endocrine cells budded. The insulin content per flask increased ten- to 15-fold over 3- to 4-weeks culture as the DNA content increased up to sevenfold. The cultivated human islet buds were shown to consist of cytokeratin 19positive duct cells and hormone-positive islet cells by immunofluorescence. Double staining of insulin and non-β cell hormones in occasional cells indicated immature cells still in the process of differentiation. Insulin secretion studies were done over 24 h in culture. Compared with their basal secretion at 5 mlVI glucose, cysts/cultivated human islet buds exposed to stimulatory 20 mM glucose had a 2.3-fold increase in secreted insulin. Thus, duct tissue from human pancreas can be expanded in culture and then be directed to differentiate into glucose-responsive islet tissue in vitro. This approach may provide a potential new source of pancreatic islet cells for transplantation.

Comment The need for an adequate supply of quality β cells for transplantation into patients with types 1 and 2 DM prompted the search for alternative sources of this material. The adult islet, even under optimal in vitro conditions, has a very low replication capacity |4| and, in addition, is associated with the loss of insulin output. This project showed how, with adequate external stimuli, pancreatic cell ducts are able to lose their phenotype specificity and, on proliferating, revert to multipotential cells and succeed in differentiating into endocrine tissue arranged into a structure closely resembling that of the islets with endocrine cells. Laboratory work revealed how, over a 3- to 4-week period, researchers were able to expand human ductal tissue in vitro and make them differentiate into insulin-secreting and insulin-producing cells and endocrine cells. They were also capable of elevating the secretory response on exposure to higher glucose concentration. One disadvantage was that the quantity obtained was limited. Although the project has only just started, this system, once optimized, could generate sufficient quantities for having an impact on β cell replacement therapy in a large number of diabetic patients.

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This optimization would need to include greater expansion of the ductal tissue and/or a greater tissue differentiating capability. Expression of neurogenin-3 reveals an islet cell precursor population in the pancreas V M Schwitzgebel, D W Scheel, J R Conners, J Kalamaras, J E Lee, et al. Development 2000; 127:3533–42. BACKGROUND. Differentiation of early gut endoderm cells into the endocrine cells forming the pancreatic islets of Langerhans depends on a cascade of gene activation events controlled by transcription factors, including the basic helix-loop-helix (bHLH) proteins. In order to delineate this cascade, the authors began by establishing the position of neurogenin-3, which is a bHLH factor found in the pancreas during fetal development. They detected neurogenin-3 immunoreactivity transiently in scattered ductal cells in the fetal mouse pancreas, peaking at embryonic day 15.5. Although not detected in cells expressing islet hormones or the islet transcription factors Isll, Brn4, Pax6 or PDXl, neurogenin-3 is detected along with the early islet differentiation factors Nkx6.l and Nkx2.2, thereby establishing that it is expressed in immature cells in the islet lineage. These data support a model in which neurogenin-3 acts upstream of other islet differentiation factors, initiating the differentiation of endocrine cells, but switching off prior to final differentiation. The ability to identify islet cell precursors uniquely by neurogenin-3 expression allows the position of other islet transcription factors in the differentiation cascade to be determined and a map for the islet cell differentiation pathway to be proposed.

Comment The endocrine cells of the islets of Langerhans in the mammalian pancreas, including the A, B, D and pancreatic polypeptide cells as well as the exocrine cells, derive from foregut endodermal progenitors. Recent genetic studies |5| have identified a network of transcription factors, including Pdxl, Isll, Pax4, Pax6, NeuroD, Nkx2.2 and Hlxb9, that regulate the development of islet cells at different stages, but the molecular mechanisms controlling the specification of pancreatic endocrine precursors remain unknown. Neurogenin-3 is a member of a family of bHLH transcription factors that is involved in the determination of neural precursor cells in the neuroectoderm. Neurogenin-3 is expressed in discrete regions of the nervous system and in scattered cells in the embryonic pancreas. This article is a new contribution towards understanding islet of Langerhans differentiation. The protein neurogenin-3 is detectable at embryonic stage 11.5 in certain epithelial cells of the pancreatic bud, achieves peak expression at embryonic day 15.5 and diminishes at embryonic day 18.5, but is undetectable in adult pancreatic islets. At embryonic day 15.5 there is no neurogenin-3 coexpression with none of the islet hormones or transcription factors expressed in fully differentiated cells, thereby suggesting that the neurogenin-3 function is silenced before terminal differentiation. Studies conducted on animals with mutations or ‘targeted disruptions’ in different transcription factors implied in the differentiation process locate neurogenin-3 at the initial stages of this process |6|. The role suggested for neurogenin-3 is shown in Fig. 11.2. However, cells expressing neurogenin-3 do not constitute cstem cells’ as over-expression causes accelerated differentiation and does not lead to a non-differentiation state like the one occurring by defmition in stem cells. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells V K Ramiya, M Maraist, K E Arfors, D A Schatz, A B Peck, et al. Nature Med 2000; 6:278-82.

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Fig. 11.2 Model for the role of neurogenin-3 in endocrine differentiation in the mouse pancreas. The proposed position for each transcription factor is based on its timing of expression, its timing of its predominant functional role or both. Clearly some factors function at several steps, but a single step is shown for simplicity. Source: Schwitzgebel et al. (2000). BACKGROUND. Ductal structures of the adult pancreas contain stem cells that differentiate into islets of Langerhans. Here, the authors grew pancreatic ductal epithelial cells isolated from pre-diabetic, adult, non-obese mice in long-term cultures, where they were induced to produce functioning islets containing α, β and δ cells. These in vitro-generated islets reversed insulin-dependent diabetes after being implanted into diabetic, non-obese diabetic (NOD) mice. The ability to control the growth and differentiation of islet stem cells provides an abundant islet source for β cell reconstitution in type 1 diabetes.

Comment Stem cells are defined as clonogenic cells that are capable of both self-renewal and multilineage differentiation. Such cells can be expanded in vivo or in vitro and differentiated in order to produce the desired cell type. Several sources of stem cells have been demonstrated to give rise to pluripotent cell lines: (1) embryonic stem cells, (2) embryonic germ cells, (3) embryonic carcinoma cells and (4) adult stem cells. Embryonic stem cells can be differentiated into specific cell lineages using techniques of in vitro differentiation and selection protocols with subsequent selection using genetic techniques. All types of endocrine cells in the islets of Langerhans (α, β, γ and δ cells) originate from sequential differentiation of the same ductal epithelial stem cell. Recently, the possibility has been suggested that differential stem cells be used in the treatment of different illnesses including type 1 diabetes. This study shows how pluripotential stem cells isolated from the pancreatic ducts of pre-diabetic NOD mice differentiate to form glucose-responsive islets and how they are able to reverse the illness, once they have been implanted, encapsulated or otherwise, in diabetic NOD mice. The results of this study are similar to those obtained by Soria et al. |7| in which differentiated stem cells were shown to normalize glycaemia in type 1 diabetic mice.

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Fig. 11.3 Reversal of IDD in NOD mice with subcapsular kidney or subcutaneous implantation of IPC-derived islets. (a) Approximately 300 IPC-derived islets from IPSC cultures that had been producing islets for 6–8 months were injected into the kidney subcapsular regions of eight female, diabetic NOD/Uf mice. The animals were weaned from insulin over 5–7 days and their blood glucose levels were determined. The data represent mice monitored for the 55 days of the experiment. Control diabetic female mice did not receive implants, but were weaned from insulin using the same protocol (grey circles). (b) Approximately 5000 IPC-derived islets from IPSC cultures that had been producing islets for 18–21 months were implanted subcutaneously into three female diabetic NOD/Uf mice. Hyaluronic acid-based gel (Hy) was first injected into the pocket in two mice, followed by the islet clusters in order to encapsulate the implants. Then, 2 days after the implantation, the animals were weaned from insulin. Their blood glucose levels were determined at the same time every second day throughoutthe experiment. Source: Ramiya et al. (2000).

The use of stem cell-derived, insulin-producing cells combined with autotransplantation opens up huge potential for the treatment of type 1 diabetes. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue H C Lee, S J Kim, K S Kim, H C Shin, J W Yoon.

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Nature 2000; 408(6811):483–8. BACKGROUND. A cure for diabetes has long been sought using several different approaches, including islet transplantation, the regeneration of β cells and insulin gene therapy. Standard insulin therapy may not maintain blood glucose concentrations within the relatively narrow range that occurs in the presence of normal pancreatic β cells. The authors used a recombinant adeno-associated virus (rAAV) that expresses a single-chain insulin analogue (SIA), which possesses biologically active insulin activity without enzymatic conversion, under the control of a hepatocyte-specific L-type pyruvate kinase (LPK) promoter, which regulates SIA expression in response to blood glucose levels. The authors show that SIA produced from the gene construct rAAV-LPK-SIA caused remission of diabetes in streptozotocininduced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent sideeffects. This new SIA gene therapy may have potential therapeutic value for the cure of autoimmune diabetes in humans.

Comment This article described a new approach to type 1 diabetes: gene therapy using the recombinant adenovirus in the specifk positional genome as a vector. An insulin analogue was employed (SIA) with similar biological activity expressed in the liver in glucose level-regulated form. Diabetes remission and non-observance of liver damage in mammalian animal models such as mice and rats commend this method as a possible field of study for type 1 diabetes therapy in humans. The common PPAR-γ Prol2Ala polymorphism is associated with decreased risk of type 2 diabetes D Altshuler, J N Hirschhorn, M Klannemark, C M Lindgren, M-C Vohl, et al. Nature Genet 2000; 26(1):76–80. BACKGROUND. The authors evaluated 16 published genetic associations to type 2 diabetes and related subphenotypes using a family-based design for controlling for population stratification and replication samples for increasing the power. They were able to confirm only one association, that of the common Prol2Ala polymorphism in peroxisome proliferator-activated receptor gamma (PPAR-γ) with type 2 diabetes. By analysing over 3000 individuals, they found a modest (1.25-fold) but significant (P=0. 002) increase in diabetes risk associated with the more common proline allele (85% frequency). The data implicate inherited variation in PPAR-γ in the pathogenesis of type 2 diabetes. Because the risk allele occurs at such high Table 11.1 Characteristics of the study populations

TDT trios (Scandinavia ) DM/IGT/ IFG NGT

Sex (male/ female)

Age (y)

Age at onset BMI (kg/ of diabetes m2 ) (y)

HbA1c (%)

Fasting plasma glucose (mmol/l)

Plasma glucose at (mmol/l)

176/157

39±9

37±9

27±5

5.9±1.8

7.2±2.6

8.5±2.9

187/192

31±10

–

24±5

5.1±0.5

5.2±0.5

5.611.1

DIABETES RESEARCH

Sibships (Scandinavia ) DM/severe IGT sibling NGT sibling Case control (Scandinavia ) DM severe IGT subjects NGT subjects Case control (SLSJ) DM subjects NGT subjects

Sex (male/ female)

Age (y)

Age at onset BMI (kg/ of diabetes m2 ) (y)

HbA1c (%)

Fasting plasma glucose (mmol/l)

Plasma glucose at (mmol/l)

283/329

65±10

56±11

29±5

7.3±1.7

9.4±3.5

14.2±5.5

216/302

62±10

–

26±3

5.4±0.6

5.4±0.4

6.0±1.0

252/229

61±10

54±11

28±5

7.5±1.8

9.7±3.2

15.3±5.5

252/229

60±10

–

27±4

5.4±0.5

5.5±0.6

6.2±1.5

70/57 70/57

53±8 52±8

ND

29±5 29±4

6.5±1.9 5.1±0.6

6.4±1.8 5.1±0.6

12.8±2.1 6.1±1.1

227

The data are presented as means±SDs. Plasma glucose was measured at baseline (fasting) and 2 h after an OGTT. DM, type 2 diabetes; IGT, impaired glucose tolerance; IFG, impaired fasting glucose; NGT, normal glucose tolerance; severe IGT, 10.0 mmol/l>120 min blood glucose>8.5 mmol/l; SLSJ, Saguenay-Lac-St-Jean. ND, not determined. Source: Altshuler et al. (2000). frequency, its modest effect translates into a large population attributable risk, influencing as much as 25% of type 2 diabetes in the general population.

Comment Peroxisome proliferator-activator receptor gamma (PPARG) encodes PPAR-γ, which is a nuclear hormone receptor and adipogenesis regulator that is targeted by the thiazolidinedione class of insulin-sensitizing drugs that are used for treating type 2 diabetes. The population study structure is shown in Table 11.1. Associations were tested primarily in 333 trios of parents and Scandinavian descendants with type 2 diabetes and abnormal glucose homeostasis, using the transmission disequilibrium test (TDT) that eliminates false positives due to population stratification. So far, the results of association in the 16 variants published indicate that only the lower incidence of the insulin autoantibodies (IAA) allele (16%) is associated with a reduced risk of diabetes. This project reflected the PPAR-γ Pro/IAA association with the risk of diabetes in three independent samples, with a statistically significant value of P=0.002. The relative risk of this genotype was estimated at 1.25, corresponding to an overall population risk of 25%. Despite this population impact, linkage analysis would have failed to detect the risk allele contribution owing to allele donation by both parents.

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Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus Y Horikawa, N Oda, N J Cox, X Li, M Orho-Melander, et al. Nature Genet 2000; 26(2):163–75. BACKGROUND. Type 2 or non-insulin-dependent DM (NIDDM) is the most common form of diabetes worldwide, affecting approximately 4% of the world’s adult population. It is multifactorial in origin with both genetic and environmental factors contributing to its development. A genome-wide screen for type 2 diabetes genes carried out in Mexican-Americans localized a susceptibility gene, designated NIDDM-1, to chromosome 2. Here we describe the positional cloning of a gene located in the NIDDM-1 region that shows an association with type 2 diabetes in Mexican-Americans and a Northern European population from the Botnia region of Finland. This putative diabetes-susceptibility gene encodes a ubiquitously expressed member of the calpain-like cysteine protease family, calpain-10. This finding suggests a novel pathway that may contribute to the development of type 2 diabetes.

Comment Earlier studies in this same series |8, 9| have already discovered an area of the 2 chromosome susceptible to type 2 DM (NIDDM-1). This new study searched this area for the polymorphisms associated with type 2 DM with ‘linkage’ evidence. A gene associated with type 2 diabetes was discovered in the NIDDM-1 region. This gene encodes a protein conventionally expressed as calpain-10. This was a really novel discovery; hitherto no relationship has been discovered between calpain-10 and type 2 DM. This suggests that a new avenue of research focusing on the study of the biochemical fanction of this protein should be explored in order to determine whether there could be some connection, for example, with blood sugar level control. The putative effect of genetic variations of calpain-10 on type 2 DM could also be explored. This same group |10| has already begun an investigation along these lines. Another interesting aspect for investigation would be protein-inhibited or protein-activated calpain-10 substrates. In this project, it was important to highlight the successful description of a gene associated with type 2 DM in a Mexican and Northern European population by positional cloning. This technique is widely used for the localization of monogenic illnesses, but not for illnesses of multifactorial origin, as is the case with type 2 DM. This could pave the way for discovery of the genes responsible for other illnesses dependent on various factors, both genetic and environmental. As mentioned earlier, genetic variations of calpain-10 affect type 2 DM susceptibility in a Mexican and Northern European population. However, it would be interesting to extend this study to other populations in order to confirm whether these genetic variations can be extrapolated to the type 2 DM population at large. The lipid phosphatase SHIP2 controls insulin sensitivity S Clément, U Krause, F Desmedt, J-FTanti, J Behrends, et al. Nature 2001; 409:92. BACKGROUND. Insulin is the primary hormone involved in glucose homeostasis and impairment of insulin action and/or secretion has a critical role in the pathogenesis of DM. Type 2 SH2 domaincontaining inositol 5-phosphatase or SHIP2 is a member of the inositol polyphosphate 5-phosphatase family. In vitro studies have shown that SHIP2, in response to stimulation by numerous growth factors and insulin, is closely linked to signalling events mediated by both phosphoinositide-3-OH kinase and Ras/ mitogen-activated protein kinase. Here the authors reported the generation of mice lacking the SHIP2

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gene. The results showed that SHIP2 is a potent negative regulator of insulin signalling and insulin sensitivity in vivo.

Comment This knock-out study was important as it provided new insights into the molecular mechanisms involved in insulin signalling. A lack of the SHIP2 gene triggers increased sensitivity to insulin that is characterized by severe neonatal hypoglycaemia causing perinatal mortality and deregulation of the genes involved in glucogenesis. In heterozygote adults (SHIP2±), in creased sensitivity to insulin is associated with an increase in glucose transporter protein-4 (GLUT-4) translocation and skeletal muscle glycogen synthesis. Since the SHIP2 enzyme is widely expressed, the authors analysed what effect the absence of this enzyme might have on other tissues; they failed to discover any abnormality. Consequently, SHIP2 is not a negative regulator of any of the growth factors eliciting its response, but is involved mainly in the control of the insulin cascade, as it is a negative regulator of insulin and of in vivo insulin sensitivity. SHIP2 has been suggested as a therapeutic tool for treating type 2 diabetes and as a possible illness susceptibility gene. Apolipoprotein E isoform polymorphisms are not associated with insulin resistance: the Framingham Offspring Study J B Meigs, J M Ordovas, L A Cupples, D E Singer, D M Nathan, et al. Diabetes Care 2000; 23:669–74. BACKGROUND. Participants in the Framingham Offspring Study underwent a clinical examination and an OGTT with measurement of their fasting and 2-hour glucose, insulin levels and fasting lipid levels during 1991–1995. The authors measured insulin resistance using the homeostasis model assessment (HOMA), in which insulin resistance=fasting insulin×glucose/ 22.5. Apolipoprotein (apo) E isoforms and phenotypes were determined in 1983–1987 using isoelectric focusing of plasma very lowdensity lipoprotein (LDL). Subjects with type 2 diabetes were excluded. The remainder were classified with features of the insulin resistance syndrome including IGT, hypertension, obesity (body mass index>85th percentile), a high waist to hip ratio (>85th percentile) and high triglyceride (TG) and low high-density lipoprotein levels. The data were analysed with contingency tables and age-and sex-adjusted logistic regression models. The mean age among the 1916 subjects was 55 years (range 28–83 years) and 51% were women. The median HOMA insulin resistance was 6.4 (interquartile range 5.2–8.2) and the allele frequencies were 7.8, 79.9 and 12.4% for apo E alleles e2, e3 and e4, respectively There were no differences in the proportions of apo E isoforms or alleles across increasing quintiles of HOMA insulin resistance. A less dramatic increase in the proportions occurred with elevated TGs associated with increasing HOMA insulin resistance among those with apo E isoforms 2/2 and 2/3 compared with the others (P≤0.01 for interaction). Otherwise, apo E did not substantially modify the associations between insulin resistance and features of the insulin resistance syndrome.

Comment Apo E plays a critical part in clearing residual atherogenic lipoproteins in the vascular space that is linked to the LDL and LDL receptor-related protein receptor and involved in cholesterol reverse transport. The apo E human gene is polymorphic, as three different alleles (e2, e3 and e4) have been identified in the apo E locus sited in chromosome 19, encoding three different isoforms (apo E2, apo E3 and apo E4). These would

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produce six different phenotypes (apo E2/2, apo E2/3, apo E3/3, apo E4/2, apo E4/3 and apo E4/4). The allele frequencies for e2, e3 and e4 in the Caucasian population are 8, 77 and 15%, respectively. The current thinking is that apo E polymorphisms constitute one of the most important genetic determinants for ischaemic coronary disease in the general population; the E4 isoform in particular confers an elevated risk of coronary illness |11|. On the other hand, insulin resistance is currently regarded as a risk factor for ischaemic coronary disease, although the mechanism for this association is unknown. The authors pursued a very attractive goal, claiming to have analysed the association between these two important cardiovascular risk factors, namely insulin resistance and apo E phenotype, in a generous population consisting of approximately 2000 individuals (participants in the Framingham Offspring Study). Nevertheless, the authors did not detect any relationship between the insulin resistance index and the different apoE2, apoE3 and apoE4 isoforms, concluding that the two factors are independent of cardiovascular risk. The main criticism levelled at this project is the methodological concept used for evaluating insulin resistance, namely the HOMA method. Most authors consider that the main technique involved in evaluating insulin sensitivity is the euglycaemic clamp technique |12|. A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes M Tawata, J I Hayashi, K Isobe, E Ohkubo, M Ohtaka, et al. Diabetes 2000; 49:1269–72. BACKGROUND. The authors investigated a 69-year-old type 2 diabetes woman from a family of 16 diabetic patients with typical maternal inheritance. The proband showed no major deletions in her mitochondrial DNA. Direct sequencing revealed seven mis-sense and five ribosomal RNA homoplasmic nucleotide substitutions when compared with the Cambridge Sequence and its recent revision. When compared with the control cybrid cells, the proband’s cybrid cells showed six nucleotide substitutions. Among these, 14577 T/C, which turned out to be 98.9% heteroplasmic, was a new mis-sense substitution. The authors also observed two other patients with 14577 T/C substitution from another group of 252 unrelated diabetic patients, whereas no individual from a group of 529 control subjects had 14577 T/C substitution. Furthermore, these six substitutions were in linkage disequilibrium. The mitochondrial respiratory chain complex I activity and o2 consumption rates of the proband cybrid cells, which were obtained by the

fusion of mitochondrial DNA-deleted (rhoO) HeLa cells and mitochondrial DNA from the proband, showed 64.5 and 61.5% reductions, respectively, compared with control cybrid cells.

Comment The aetiopathogenesis of the conventionally termed maternally inherited diabetes and deafness, which is nowadays identified as diabetes linked to mitochondrial DNA mutations |13|, is basically associated with punctual mutations of the coding gene for RNA leukin transference (tRNALEU (UUR)) and more rarely with major deletions of mitochondrial DNA |14|. It is the most frequently detected A3243G mutation. This project described the presence of a new mutation detected in the mitochondrial DNA of a Japanese population that affects a complex in which, to date, no sequence variations have been detected.

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This 14577 T/C mutation causes valine amino acid substitution by isoleucine in codon 33 of the 6-NADH dehydrogenase gene. In vitro studies have established the presence of a severe decline in mitochondrial I complex activity of the respiratory chain in the mutant structure as opposed to the control structure. However, just how malfunction of the mitochondrial I complex leads to the development of diabetes has yet to be determined. Nonsense mutation of the islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history H Shimomura, T Sanke, T Hanabusa, K Tsunoda, H Furuta, et al. Diabetes 2000; 49:1597–600. BACKGROUND. The authors scanned the islet-1 gene in 77 Japanese type 2 diabetic patients with a family history and found a heterozygous nonsense mutation (Q310X) in one diabetic patient. The mutation was not found in 180 non-diabetic subjects. This mutation is located in the putative transactivation domain and deletes 40 amino acids of the COOH-terminal lesion. The Q310X mutant exhibited a 50% reduction in activity compared with the wild-type when tested for stimulation of the transcription of a human amylin promoter-linked luciferase reporter gene in β TC3 cells. The patient was a 49-year-old non-obese man who was diagnosed as having type 2 diabetes at 32 years of age and has been treated with sulphonylureas. The mutation was found in his mother, who has type 2 diabetes and in his 14-year-old daughter, who has NGT but a relatively low insulin response. This is the first reported finding of an islet-1 gene mutation in type 2 diabetes.

Comment Islet-1 is a transcription factor belonging to the LIM/homeodomain protein family that plays a critical part in differentiating the pancreatic islet endocrine cells |15|. The coding gene for islet-1 was identified in the 5q chromosome between markers D5S395 and D5S407 and consists of six exons |16|. This article described the first mutation detected in the islet-1 gene, mutation Q310X, which was located at exon 5 of the gene, in a family of Japanese origin with type 2 diabetes. This mutation was located within the islet-1 transcriptional activity domain. In vitro experiments on β TC3 cells using the luciferase reporter system have shown that the Q310X mutation produces a severe decline in gene transcriptional activity, suggesting that this mutation may have a potential role in the pathogenesis of type 2 diabetes. Nevertheless, in view of the low frequency of this mutation on the population studied (one out of 77 individuals with type 2 diabetes), it does not appear to be a putative major suspect in the development of diabetes amongst the general population. On the other hand, the main criticism levelled at this project is the sparse size of the population sample investigated, which is an obstacle to the achievement of adequate statistical strength. The gene MAPK8IP1 encoding islet-brain-1 is a candidate for type 2 diabetes G Waeber, J Delplanque, C Bonny, V Mooser, M Steinmann, et al. Nature Genet 2000; 24:291–5. BACKGROUND. The authors evaluated the role of islet-brain-1 (IB-1) in β cells by expression of a MAPK8IP1 anti-sense RNA in a stable insulinoma β cell line. A 38% decrease in the IB-1 protein content resulted in 49 and 41% reductions in the glucose transporter 2 gene SLC2A2 and INS (encoding insulin) mRNA expression, respectively. In addition, the authors detected MAPK8IP1 transcripts and IB-1 protein in human pancreatic islets. These data established MAPK8IP1 as a candidate gene for human

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diabetes. Sib pair analyses performed on 149 multiplex French families with type 2 diabetes excluded MAPK8IP1 as a major diabetogenic locus. However, the authors did identify a mis-sense mutation located in the coding region of MAPK8IP1 that segregated with diabetes in one family. In vitro this mutation was associated with an inability of IB-1 for preventing apoptosis induced by MAPK/ERK kinase kinase 1 and a reduced ability for counter-acting the inhibitory action of the activated c-Jun amino-terminal kinase (JNK) pathway on INS transcriptional activity. Identification of this novel, nonMODY form of diabetes demonstrates that IB-1 is a key regulator of β cell function.

Comment The MAPK8IP1 gene, which is located in the Ilpll.2-pl2 chromosome and contains 12 exons, has recently been imputed to be the gene responsible for the aetiopathogenesis of type 2 diabetes. MAPK8IP1 encodes the IB-1 transcription factor, basically expressing itself as brain and pancreatic islets. IB-1 is a 714 amino acids protein associated with JNK protein-1 inhibitor and its apparent mode of action is therefore to block the c-jun activation pathway, i.e. it is an insulin gene expression repressor |17|. IB-1 also appears to regulate the transcriptional activity of the GLUT-2 glucose-transporting gene by uniting its promoter to the GTII element |18|. This article described a French family with a high incidence of type 2 diabetes, which is the first mutation identified in the MAPK8IP1 gene. This mutation involves an AGC→AAC change at exon 2, resulting in serine being replaced by as-paragine at codon 59 (S59N mutation), as all diabetic members of this family were heterozygotes. In vitro studies have shown that the mutation causes the inhibiting effect of IB-1 in the c-Jun pathway to disappear and have indicated that impairment of the IB-1 function could make the p cell more susceptible to apoptotic stimuli. Glucose modulation of insulin mRNA levels is dependent on the transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+ W M Macfarlane, R M Shepherd, K E Cosgrove, R F James, M J Dunne, et al. Diabetes 2000; 49(3):418–23. BACKGROUND. The availability of a human β-like cell line, NES2Y, which lacks pancreatic and duodenal homeobox factor 1 (PDX-1), but expresses the insulin gene, allowed us to determine whether PDX-1 was essential for the stimulatory effect of glucose on insulin mRNA levels. Glucose had no effect on the insulin gene promoter linked to a firefly luciferase reporter or on endogenous insulin mRNA levels in NES2Y cells. However, in NES2Y cells stably transfected with PDX-1 (NES-PDX-1 cells), glucose exhibited a marked stimulatory effect on both the insulin promoter (5±0.2-fold) (n=6) and insulin mRNA levels (4.8±0.5-fold) (n=4). The NES2Y cells lacked operational ATP-sensitive potassium channels, which resulted in a failure to control depolarization-dependent intracellular Ca2+ signalling. Despite the loss of control of Ca2+ channel activity, NES-PDX-1 cells maintained normal glucoseresponsive insulin gene regulation.

Comment The stimulation of insulin gene transcriptional activity in pancreatic β cells in response to glucose is partly measured by the PDX-1 transcription factor (which is also called insulin promoter factor 1 or insulin upstream factor 1). The latter is an essential factor in the embryonic development of the pancreatic islets and in the regulation of specific gene transcription in adult pancreatic tissue such as insulin genes, GLUT-2,

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glucokinase and amyline in β cells and the somatostatin gene in γ cells. The intracellular signalling pathway linking glucose metabolism with the regulation of the PDX-1/ADN union and with insulin promoter activity has recently been described |19|. According to this model, glucose appears to stimulate the activity of phosphatidylinositol 3-kinase, which eventually appears to activate protein kinase-2 (which is also called p38 or SAPK2). This appears to lead to phosphorylation and activation of the cytoplasmic form of PDX-1 (an inactive 31 kDa protein), which produces an active form of the protein (46 kDa) that appears to migrate to the nucleus, where ultimately it activates insulin gene transcription by interaction with the A boxes. However, the part played by calcium in the regulation of insulin gene transcription is open to conjecture |20|. In their study, the authors analysed this signalling pathway using the NES2Y β cell line that expresses the insulin gene, but lacks both PDX-1 and functional ATP-dependent potassium canals, from a patient who had suffered from persistent hyperinsulinaemic hypoglycaemia since infancy. Glucose was unable to stimulate insulin gene transcriptional activity in the NES2Y cells. However, when this cell line was transfected with PDX-1, the insulin promoter response to glucose stimulation was re-established, despite the absence of an integral calcium signalling pathway. These results supported the theory that glucose-stimulating activity in the insulin gene promoter depends on PXD-1, but is independent of intracellular calcium concentrations. Pancreatic and duodenal homeobox gene 1 induces the expression of insulin genes in the liver and ameliorates streptozotocin-induced hyperglycaemia S Ferber, A Halkin, H Cohen, I Ver, Y Einav, et al. Nature Med 2000; 6:568–72. BACKGROUND. The insulin gene is restricted to islet β cells of the mammalian pancreas through specific control mechanisms that are mediated in part by specific transcription factors. PDX-1 is central in regulating pancreatic development and islet cell function. PDX-1 regulates insulin gene expression and is involved in islet cell-specific expression of various genes. The involvement of PDX-1 in islet cell differentiation and function has mainly been demonstrated by ‘loss of function’ studies. The authors used a ‘gain of function’ approach for testing whether PDX-1 could endow a non-islet tissue with pancreatic β cell characteristics in vivo. Recombinant adenovirus-mediated gene transfer of PDX-1 to the livers of BALB/C and C57BL/6 mice activated expression of the endogenous otherwise silent genes for mouse

insulin 1 and 2 and pro-hormone convertase 1/3. Hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active and it ameliorated hyperglycaemia in diabetic mice treated with streptozotocin. These data indicated the capacity of PDX-1 for reprogramming extra-pancreatic tissue towards a β cell phenotype and may provide a valuable approach for regenerating 'self surrogate β cells that are suitable for replacing impaired islet cell function in diabetics.

Comment The restoration of islet β cells in type 1 diabetes offers the opportunity of curing metabolic abnormalities and preventing long-term complications. Islet cell transplantation provides one approach to achieving this objective, but is currently limited by the availability of donor organs and the need for lifelong immunosuppression. The identification of pluripotent stem cells that are capable of generating various cell

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types in the body in combination with advanced genetic and cell-engineering techniques may enable the design of custom tissues and organs and, thus, solve the problems associated with conventional transplantation. This article described a new approach in the development of insulin-producing tissue since the authors succeeded in expressing PDX-1, the pancreas-specific transcription factor, in liver cells. As a consequence of expression of this factor the insulin gene produced a mature and, even more importantly, biologically active protein. The results provided evidence in support of the existence of an undifferentiated cell subpopulation that is apparently reprogrammed by PDX-1 so that they become differentiated into insulin-producing cells. One interesting aspect of this work was that, during expression of this ‘ectopic’ insulin, healthy mice did not experience hypoglycaemia. However, hyperglycaemia was reversed in diabetic mice. This article described a new strategy for producing insulin-producing cells, which may, in the future, be used in the therapy of type 1 diabetes. The many new technologies of the past few years have set the stage for novel human therapeutic methods. Identification of pluripotent stem cells as being capable of generating various cell types in the body, together with advanced genetic and cell-engineering techniques, may enable the design of custom tissues and organs and, thus, solve the problem of donor organ scarcity and the need for immune compatibility and immunosuppression in order to avoid graft rejection. One of the most prevalent metabolic disorders that will benefit from such technologies is IDDM. The purpose of this study was to review potential future methods of curing metabolic disorders such as diabetes and analyse the capacity for genetically manipulating the developmental fate of a tissue in vivo using ‘master regulator’ genes. The authors systemically delivered the homeobox gene PDX-1 to the liver of mice by recombinant adenovirus technology and analysed whether it induced a developmental shift towards a β cell phenotype. The authors demonstrated that PDX-1 is sufficient for activating the endogenous otherwise silent mouse insulin 1 and 2 and pro-insulin convertase gene expression in the liver. PDX-1 expression in the liver resulted in a 25-fold increase in the hepatic immunoreactive insulin content and a threefold increase in plasma immunoreactive insulin levels as compared to control adenovirus-treated mice. The hepatic immunoreactive insulin induced by PDX-1 was processed to mature mouse insulin 1 and 2 and was biologically active and it ameliorated hyperglycaemia in streptozotocin-treated diabetic mice. PDX-1 has the capacity for reprogramming extrapancreatic tissue towards a β cell phenotype. The data provided a valuable approach to generating ‘self’ surrogate β cells that are suitable for replacing impaired islet cell function in diabetics. Adipose tissue is required for the anti-diabetic but not for the hypolipidemic effect of thiazolidinediones L Chao, B Marcus-Samuels, M M Mason, J Moitar, C Vinson, et al. J Clin Invest 2000; 106:1221–8. BACKGROUND. The thiazolidinediones are PPAR-γ nuclear receptor agonists. These receptors are found mainly in adipose tissue and, to a lesser extent, in other tissues such as the liver and muscle. This study evaluated the effects of the thiazolidinediones on a strain of mouse with severe lipoatrophy that develops diabetes, insulin resistance, hyperlipidaemia and a fatty liver. The authors noted that, in this form, the thiazolidinediones did not have the anticipated effect on glucose homeostasis. Surprisingly, the thiazolidinediones continued to affect TGs. They reduced TG levels and increased fatty acid oxidation despite substantial lipoatrophy. Finally, the authors further observed that the thiazolidinediones raised the fat contained in the livers of these animals.

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Comment The thiazolidinediones are a new family of drugs with the ability to lower insulin resistance and blood glucose levels and to improve lipid metabolism anomalies. These drugs act through PPAR-γs. However, little is known about their mode of action. The PPAR-γs distributed throughout adipose tissue are invariably present in very low concentrations in the liver and muscle, two locations on which the thiazolidinediones have considerable impact. Adipose tissue plays an important part in the development of type 2 DM and adipocyte cells are specifically targeted by the thiazolidinediones. A strain of mouse with severe lipoatrophy was used for establishing that the absence of adipose tissue affects thiazolidinedione action on glucose metabolism and resistance to insulin. Nevertheless, the thiazolidinediones continue to affect the lipid profile of the animal whilst elevating TG deposits in the liver. It should be remembered that these results have not been reproduced in other mouse strains with less severe lipoatrophy and that certain clinical data have proved that, in human lipoatrophy, the thiazolidinediones improve hydrocarbonate, lipid and adipose tissue redistribution metabolism. Despite the different results observed in the different animal strains investigated, there is no doubt that each provides information about the how these new drugs work. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice O Gavrilova, B Marcus-Samuels, D Graham, J K Kim, G I Shulman, et al. J Clin Invest 2000; 105:271–8. BACKGROUND. The lack of adipose tissue in partial or generalized lipodystrophy is linked to insulin resistance and DM. In this study, the authors investigated the possible physiopathological mechanisms responsible for lipodystrophic diabetes. This project examined an A-ZIP/F-1 (diabetic and lipodystrophic) mouse sample. The authors transplanted white adipose tissue. The outcome was twofold: the mice had lower blood glucose levels and substantially improved sensitivity to insulin. These results were accompanied by a parallel disappearance of hepatic steatosis. The lipid profile of these mice improved slightly. Surprisingly, regardless of the source of this tissue, whether central or peripheral, the results depended on the total quantity of adipose tissue transplanted.

Comment Type 2 DM is often associated with obesity and insulin resistance. Lipodystrophy, however, is an interesting form of DM in that insulin resistance is present despite a reduction in adipose tissue. The (A-ZIP/F-1) transgenic strain of mice has hardly any adipose tissue and is thus ideally suited for investigation of the relationship between adipose tissue and insulin sensitivity. When adipose tissue was transplanted and the changes observed in this strain of mice had been reversed, the authors found that these morphological and metabolic changes were attributable to a lack of adipose tissue. The triggering physiopathological mechanisms are still unknown. One astonishing fact to emerge was the efficacy of the amount of adipose tissue transplanted, regardless of origin. Although the results obtained on transplanting adipose tissue into these mice are interesting, the amount of tissue for transplantation may be a limitation if this technique is to be used as a lipidystrophy treatment for humans.

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Conclusion Despite the improvements in insulin preparations together with advances in pen and meter technology achieving normal glucose control remains elusive in type 1 diabetes other than by the restoration of endogenous insulin production by the transplantation of functioning islets into patients. A seminal paper is reviewed in this chapter describing the dramatically improved outcome of islet cell transplantation from the Edmonton unit in Canada (p. 271). Prior to this report islet cell transplantation had a poor record of success in achieving insulin independence due, amongst other things, to problems extracting and purifying donor islets and problems in controlling rejection. The Edmonton group have improved a number of stages of the purification process for obtaining functioning islets from cadaveric donor pancreatic tissue. Importantly, they have also used a non-steroid based immunosuppressive regimen and have achieved dramatically improved results. This work has stimulated worldwide interest in islet cell transplantation and many centres in the developed world are currently trying to reproduce these findings. Despite the success of the Edmonton protocol the restoration of functioning islet tissue to patients with type 1 diabetes remains a challenge due to the shortage of donor organs. Several papers that are reviewed in this chapter address this issue by trying to develop islets from stem cells derived from the pancreatic duct. Such cells are shown to be capable of reversing insulin-dependent diabetes in animal models and offer a novel way ahead in terms of tissue engineering for the treatment of type 1 diabetes (p. 280). Lee et al. suggested an alternative approach (p. 282). They used an rAAV that expresses an SIA, which possesses biologically active insulin activity without enzymatic conversion, under the control of a hepatocyte-specific LPK promoter, which regulates SIA expression in response to blood glucose levels. The authors showed that the SIA produced from the gene construct caused the remission of diabetes in streptozotocin-induced diabetic rats and autoimmune diabetic mice for a prolonged time without any apparent side-effects. Considerable further developmental work is obviously needed before any of these approaches could be used in clinical trials in humans. Further insights into the genetic abnormalities and clinical phenotypes associated with MODY are unravelled in two reports. Spanish authors have summarized their experience of MODY in a Spanish family sample (p. 272). They found that the clinical characteristics of families with MODY-2 (which is glucokinase related) and MODY-3 (which is HNF- 1α related) were similar to those described in other European countries. Japanese authors have reported interesting observations in a group of patients with clinically diagnosed type 1 diabetes who did not have anti-islet autoantibodies (p. 273) (this is also reviewed in Chapter 3 on p. 129). Twenty-eight patients who lacked islet cell autoantibodies were identified in a large population-based sample of unrelated Japanese patients with type 1 diabetes. Two (7.1%) of these 28 autoantibody-negative patients with diabetes had mutations in the HNF-α gene. Mutations in the HNF-la gene are the cause of MODY-3. MODY-3 is characterized by a severe impairment of insulin secretion and early disease onset, which may present with typical clinical features of type 1 diabetes. The discovery of mutation carriers in the HNF-α gene in two of the 28 (7%) type 1B diabetic patients (i.e. with autoimmunity marker negativity) from the Japanese cohort and in 10% of a Danish Caucasian cohort suggested that some diabetic patients initially classified as idiopathic are, in reality, suffering from MODY-3 diabetes. Clinical awareness of their family history of diabetes and the mode of inheritance might help in identifying and reclassifying these diabetic subjects as MODY-3 patients. Certain discoveries made over the last year may be relevant to a better understanding of the aetiology of type 2 DM. Calpain, for example, the function of which is still unknown, has been regarded as a promising gene for type 2 DM. Horikawa et al. undertook a genome-wide screening for type 2 diabetes genes in Mexican-Americans and succeeded in localizing a susceptibility gene, which is designated NIDDM-1, to chromosome 2 (p. 284). This putative diabetes-susceptibility gene encodes a ubiquitously expressed member

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of the calpain-like cysteine protease family, calpain-10. This finding suggests a novel pathway that may contribute to the development of type 2 diabetes. Other research in type 2 diabetes is included, including new studies on polymorphic regions of the PPAR receptor, which suggest that this receptor may be of great importance in insulin signalling and in lipid metabolism and other putative genetic associations with type 2 diabetes, including MAPK81P1 encoding IB-1 and the islet 1 gene Q310X. These papers serve to emphasize the complexity of the genetics of type 2 diabetes and suggest that further subclassifkation, as has happened with MODY, will occur in the future. This chapter is intended to provide an overview of important basic science research that may have little or no current clinical application. Hopefully, however, the summary articles presented here will prompt the interested clinical reader to explore new fields of diabetes research. References 1.

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5. 6. 7. 8.

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11. 12. 13. 14.

Ryan EA, Lakey JR, Rajotte RV, Korbutt GS, Kin T, Imes S, Rabinovitch A, Elliott JF, Bigam D, Kneteman NM, Warnock GL, Larsen I, Shapiro AM. Clinical outcomes and insulin secretion after islet transplantation with the Edmonton protocol. Diabetes 2001; 50(4):710–19. Moller AM, Dalgaard LT, Pociot F, Nerup J, Hansen T, Pedersen O. Mutations in the hepatocyte nuclear factor-a gene in Caucasian families originally classified as having type 1 diabetes. Diabetologia 1998; 4:1528–31. MacDonald MJ, Fahien LA. Glutamate is not a messenger in insulin secretion. JBiol Chem 2000; 275(44):34 025–7. Brelje TC, Sharp DW, Lacy PE, Ogren L, Talamantes F, Robertson M, Frieses HG, Sorenson RL. Effect of homologous placental lactogens, prolactins, and growth hormones on islet β cell division and insulin secretion in rat, mouse, and human islets: implication for placental lactogen regulation of islet function during pregnancy Endocrinology 1993; 132:879–87. Gradwohl G, Dierich A, Le Meur M, Guillemot F. Neurogenin3 is required for the development of the four endocrine cell linages of the pancreas. Proc Natl Acad Sci USA 2000; 97:1607–11. Huang H-P, Liu M, El-Hodiri HM, Chu K, Jamrich M, Tsai MJ. Regulation of the pancreatic islet-specific gene BETA2 (neuroD) by neurogenin 3. Mol Cell Biol 2000; 20:3292–307. Soria B, Roche E, Berná G, León-Quinto T, Reig JA, Martin F. Insulin-secreting cells derived from embryonic stem cells normalize glycemia in streptozotocin induced diabetic mice. Diabetes 2000; 49(2):157–62. Hanis CL, Boerwinkle E, Chakraborty R, Ellsworth DL, Concannon P, Stirling B, Morrison VA, Wapelhorst B, Spielman RS, Gogolin-Ewens KJ, Shepard JM, Williams SR, Risch N, Hinds D, Iwasaki N, Ogata M, Omori Y, Petzold C, Rietzch H, Schroder HE, Schulze J, Cox NJ, Menzel S, Boriraj W, Chen X. A genome-wide search for human non-insulin-dependent (type 2) diabetes genes reveals a major susceptibility locus on chromosome 2. Nature Genet 1996; 13:161–6. Cox NJ, Frigge M, Nicolae DL, Concannon P, Hanis CL, Bell GI, Kong A. Loci on chromosomes 2 (NIDDMl) and 15 interact to increase susceptibility to diabetes in Mexican Americans. Nature Genet 1999; 21:213–15. Baier LI, Permana PA, Yang X, Pratley RE, Hanson RL, Shen GQ, Mott D, Knowler WC, Cox NJ, Horikawa Y, Oda N, Bell GI, Bogardus C. A calpein-10 gene polymorphism is associated with reduced muscle mRNA levels and insulin resistance. J Clin Invest 2000; 106:R69–73. Davignon J, Cohn JS, Mabile L, Bernier L. Apolipoprotein E and atherosclerosis: insight from animal and human studies. Clin Chim Acta 1999; 286:115–43. Ferrannini E. Insulin resistance versus insulin deficiency in non-insulin-dependent diabetes mellitus: problems and prospects. Endocrine Rev 1999; 19:477–90. American Diabetes Association: 1997. Wollheim CB. Beta-cell mitochondria in the regulation of insulin secretion: a new culprit in type II diabetes. Diabetologia 2000; 43:265–77.

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20.

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Karlsson O, Thor S, Norberg T, Ohlsson H, Edlund T. Insulin gene enhancer binding protein Isl-1 is a member of a novel class of protein containing both a homeo- and a cys-his domain. Nature 1990; 344:879–82. Tanizawa Y, Riggs AC, Dagogo-Jack S, Vaxillaire M, Froguel P, Liu L, Donis-Keller H, Permutt MA. Isolation of the human LIM/homeodomain gene Islet-1 and identification of a simple sequence repeat polymorphism. Diabetes 1994; 43:935–41. Mooser V, Maillard A, Bonny C, Steinmann M, Shaw P, Yarnall DP, Burns DK, Schorderet DF, Nicod P, Waeber G. Genomic organization, fine-mapping and expression of the human Islet-brain 1 (IBl)/c-Junaminoterminal kinase interacting protein-1 (JIP-1). Genomics 1999; 55:202–8. Bonny C, Nicod P, Waeber G. IBl, a JIP-1-related nuclear protein present in insulin-secreting cells. J Biol Chem 1998; 273:1843–6. MacFarlane WM, McKinnon CM, Felton-Edkins ZA, Cragg H, James RF, Docherty K. Glucose stimulates translocation of the homeodomain transcription factor PDXl from the cytoplasm to the nucleus in pancreatic betacells. J Biol Chem 1999; 274:1011–16. MacFarlane WM, Campbell SC, Elric LJ, Oates V, Bermano G, Lindley KJ, Aynsley-Green A, Dunne MJ, James RF, Docherty K. Glucose regulates islet amyloid polypeptide gene transcription in a PDXl- and calciumdependent manner. J Biol Chem 2000; 275:15 330–5.

List of abbreviations

A II ABCD ABP ACE ADA ADI ADMIT ADNc AGT AN apo ARB AUC BARI BI BMI BP BSA CABG CHD CNS CPS-1 CRP CSII CT CV CVD DAISY

angiotensin IIA Appropriate Blood presssure Control in Diabetes ambulatory blood pressure angiotensin-converting enzyme American Diabetes Association acceptable daily intake Arterial Disease Multiple Intervention Trial adenovirus c abnormal glucose tolerance autonomic neuropathy apolipoprotein angiotensin receptor blocker area under the curve Bypass Angioplasty Revascularization Investigator/ Investigation bovine insulin body mass index blood pressure bovine serum albumin coronary artery bypass grafting coronary heart disease central nervous system Cancer Prevention Study 1 C-reactive protein continuous subcutaneous insulin infusion computerized tomography coefficient of variance cardiovascular disease/cerebrovascular disease Diabetes Autoimmunity Study in the Young

240

LIST OF ABBREVIATIONS

DBP DCCT DIABHYCAR DM DMGT DN DPP DPS DPT-1 DR EDC EDIC ESRD ESRF EURODIAB FACET FBG FDA FOS FPG FPIR FSG FSIGT GAD GADA GAM GCT GDH GDM GFR GH GHb GHBP GHTP GLUT-4 HbA1c

diastolic blood pressure Diabetes Control and Complications Trial Non-insulin-dependent diabetes, hypertension, microalbuminuria or proteinuria, cardiovascular event and ramipril diabetes mellitus diabetes mellitus glucose tolerance diabetic nephropathy Diabetes Prevention Program Diabetes Prevention Study Diabetes Prevention Trial of Type 1 Diabetes diabetic retinopathy Epidemiology of Diabetes Complications Epidemiology of Diabetes Interventions and Complications end-stage renal disease end-stage renal failure European Community-funded Concerted Action Programme into the epidemiology and prevention of Diabetes Fosinopril versus Amlodipine Cardiovascular Events randomized Trial fasting blood glucose Food and Drug Administration Framingham Offspring Study fasting plasma glucose first-phase insulin response fasting serum glucose frequently sampled intravenous glucose tolerance test glutamic acid decarboxylase Glutamic acid decarboxylase antibodies generalized additive modelling glucose challenge test glutamate dehydrogenase gestational diabetes mellitus glomerular filtration rate growth hormone glycated haemoglobin growth hormone-binding protein growth hormone-transporting protein glucose transporter protein-4 glycohaemoglobin A

LIST OF ABBREVIATIONS

HCV HDL HLA HM HMG CoA HNF-lα HOMA HOPE 2-hPG IAA ICA IDDM IDNT IFG IGF-1 IGT IIEF IL INS IRMA 2 IRS ITT IVGTT LADA LDL LOCF LTPA MDI MI MICRO-HOPE MIRKO MNT MODY mRNA MUFA NAVIGATOR NCEP

241

hepatitis C virus high-densitylipoprotein human leucocyte antigen high mixture 3-hydroxyl-3-methylglutaryl coenzyme A reductase hepatic nuclear factor 1-α homeostasis model assessment Heart Outcomes Prevention Evaluation 2-hour post-load plasma glucose insulin autoantibodies islet cell antibodies insulin-dependent diabetes mellitus Irbesartan Type II Diabetic Nephropathy Trial impaired fasting glucose insulin-like growth factor 1 impaired glucose tolerance International Index of Erectile Function interleukin gene coding for insulin Irbesartan microalbuminuria type 2 diabetes trial insulin resistance score intention to treat Intravenous glucose tolerance test latent autoimmune diabetes of adults low-densitylipoprotein last observation carried forward leisure time physical activity multiple daily inj ection myocardial infarction Microalbuminuria, Cardiovascular and Renal Outcomes Heart Outcomes Prevention Evaluation muscle insulin receptor knockout medical nutrition therapy maturity onset diabetes of the young mitochondrial RNA monounsaturated fatty acids Nateglinide and Valsartan in impaired glucose tolerance outcomes research National Cholesterol Education Program

242

LIST OF ABBREVIATIONS

NDS NEFA NFG NGF NGT NHANESIII NIDDM NIRKO NO NOD NPH NPL NRT OGTT PAI-1 PCOS PDE PDM PIH PPAR PPARG PRIME PRP PTCA PVD PZI RENALL rhNGF ROC RR SAT SBP SFA SHBG SLC2A2 SMBG S6K1 STOP-NIDDM

neuropathy disability score non-esterified fatty acid normal fasting glucose nerve growth factor normal glucose tolerance Third National Health and Nutrition Examination Survey non-insulin-dependent diabetes mellitus heuron-specific insulin receptor knockout nitric oxide non-obese diabetic neutral protamine Hagedorn neutral protamine lispro nicotine replacement therapy oral glucose tolerance test plasminogen activator inhibitor 1 polycystic ovary syndrome phosphodiesterase pre-gestational diabetes mellitus pregnancy-induced hypertension peroxisome proliferator-activated receptor peroxisome proliferator-activated receptor gamma Programme for Irbesartan Mortality and morbidity Evaluation panretinal photocoagulation percutaneous transluminal coronary angioplasty peripheral vascular disease protamine zinc insulin Renal Losartan protection trial recombinant human nerve growth factor receiver-operator characteristic relative risk subcutaneous adipose tissue systolic blood pressure saturated fatty acids sex hormone-binding globulin gene coding for the glucose transporter 2 self-monitoring of blood glucose S6 kinase 1 Study to Prevent Non-insulin-dependent Diabetes Mellitus

LIST OF ABBREVIATIONS

SWM TCA TDT TG tHcy TNF TSH TTPA UAE UCP UKPDS VAT VLDL WT WCH WHO

Semmes-Weinstein monofilament tricarboxylic acid transmission disequilibrium test triglyceride total homocysteine tumour necrosis factor thyroid-stimulating hormone tissue-type plasminogen activator urinary albumin excretion uncoupling protein United Kingdom Prospective Diabetes Study visceral adipose tissue very low-density lipoprotein vibration perception threshold white coat hypertension World Health Organization

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Index of Papers Reviewed

Part I Diabetes management guidelines American Diabetes Association. Continuous subcutaneous insulin infusion. Diabetes Care 2000; 23(Suppl 1): S90. 47 American Diabetes Association. Diabetes mellitus and exercise. Diabetes Care 2000; 23(Suppl 1): S50. 18 American Diabetes Association. Diabetic nephropathy. Diabetes Care 2000; 23(Suppl 1): S69. 32 American Diabetes Association. Diabetic retinopathy. Diabetes Care 2000; 23(Suppl 1): S73. 35 American Diabetes Association. Gestational diabetes mellitus. Diabetes Care 2000; 23(Suppl 1): S77. 36 American Diabetes Association. Hospital admission guidelines for diabetes mellitus. Diabetes Care 2000; 23 (Suppl 1): S83. 41 American Diabetes Association. Insulin administration. Diabetes Care 2000; 23(Suppl 1): S86. 44 American Diabetes Association. Management of dyslipidaemia in adults with diabetes. Diabetes Care 2000; 23(Suppl 1): S57. 25 American Diabetes Association. Nutrition recommendations and principles for people with diabetes mellitus. Diabetes Care 2000; 23(Suppl 1): S43. 10 American Diabetes Association. Pancreas transplantation for patients with type 1 diabetes. Diabetes Care 2000; 23(Suppl 1): S85. 43 American Diabetes Association. Pre-conception care of women with diabetes. Diabetes Care 2000; 23(Suppl 1): S65. 29

American Diabetes Association. Preventive foot care in people with diabetes. Diabetes Care 2000; 23(Suppl 1): S55. 23 American Diabetes Association. Role of fat replacers in diabetes medical nutrition therapy. Diabetes Care 2000; 23(Suppl 1):S96. 48 American Diabetes Association Screening for type 2 diabetes. Diabetes Care 2000; 23(Suppl): 20–3. 5 American Diabetes Association. Smoking and diabetes. Diabetes Care 2000; 23(Suppl 1): S63. 28 American Diabetes Association. Standards of medical care for patients with diabetes mellitus. Diabetes Care 2000; 23(Suppl 1): S32. 6 American Diabetes Association. Tests of glycaemia in diabetes. Diabetes Care 2000; 23(Suppl): 80–2. 39 Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus Diabetes Care 2000; 23(Suppl 1): S4–19. 54 Gabir M M, Hanson R L, Dabelea D, Imperatore G, Roumain J, et al. The 1997 American Diabetes Association and 1999 World Health Organization criteria for hyperglycemia in the diagnosis and prediction of diabetes. Diabetes Care 2000; 23(8):1108– 12. 51

Part II Clinical trials Apfel SC, Schwartz S, Adornato BT, Freeman R, Biton V, Rendell M, Vinik A, Giuliani M, Stevens JC, Barbano R, Dyck PJ. Efficacy and safety of recombinant human nerve growth factor in patients with

diabetic polyneuropathy: a randomized controlled trial. JAMA 2000; 284:2215–21. 106 Aronoff S, Rosenblatt S, Braithwaite S, Egan JW, Mathisen AL, Schneider RL. The Pioglitazone 001 Study Group. Pioglitazone hydrochloride monotherapy 244

INDEX OF PAPERS REVIEWED

improves glycaemic control in the treatment of patients with type 2 diabetes: a 6-month randomized, placebocontrolled, dose-response study. The Pioglitazone 001 Study Group. Diabetes Care 2000; 23(11):1605–11. 117 Bastyr III EJ, Stuart CA, Brodows RG, Schwartz S, Graf CJ, Zagar A, Robertson KE. Therapy focused on lowering postprandial glucose, not fasting glucose, may be superior for lowering HbA1c. IOEZ Study Group. Diabetes Care 2000; 23(9):1236–41. 85 Bode BW, Strange P. Efficacy, safety and pump compatibility of insulin aspart used in continuous subcutaneous insulin infusion therapy in patients with type 1 diabetes. Diabetes Care 2001; 24:69–72. 116 Chaillous L, Lefevre H, Thivolet C, Boitard C, Lahlou N, Atlan-Gepner C, Bouhanick B, Mogenet A, Nicolino M, Carel JC, Lecomte P, Marechaud R, Bougneres P, Charbonnel B, Sai P. Oral insulin administration and residual β cell function in recent-onset type 1 diabetes: a multicentre randomized controlled trial. Lancet 2000; 356:545–9. 100 Chiasson JL, Gomis R, Hanefeld M, Josse RG, Karasik A, Laakso M. The STOP-NIDDM trial: an international study on the efficacy of an α-glucosidase inhibitor to prevent type 2 diabetes in a population with impaired glucose tolerance: rationale, design and preliminary screening data. The Study to Prevent Non-insulindependent Diabetes Mellitus. Diabetes Care 1998; 21: 1720–5. 70 Damsbo P, Marbury TC, Hatorp V, Clauson P, Muller PG. Flexible prandial glucose regulation with repaglinide in patients with type 2 diabetes. Diabetes Res Clin Pract 1999; 45:31–9. 115 Diabetes Prevention Program Research Group. The Diabetes Prevention Program: baseline characteristics of the randomized cohort. Diabetes Care 2000; 23: 1619–9. 69 Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C, Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on lipid and lipoprotein levels and glycemic control in patients with diabetes and peripheral arterial disease: the ADMIT study. A randomized trial. Arterial Disease Multiple Intervention Trial. JAMA 2000; 284 (10):1263–70. 104 Eriksson J, Lindstrom J, Valle T, Aunola S, Hamalainen H, Ilanne-Parikka P, Keinanen-Kiukaanniemi S, Laakso M, Lauhkonen M, Lehto P, Lehtonen A, Louheranta A, Mannelin M, Martikkala V, Rastas M, Sundvall J, Turpeinen A, Viljanen T, Uusitupa M, Tuomilehto J.

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Prevention of type 2 diabetes in subjects with impaired glucose tolerance: the Diabetes Prevention Study in Finland. Study design and 1 -year interim report on the feasibility of the life style intervention programme. Diabetologia 1999; 42:793–801. 72 Fonseca V, Rosenstock J, Patwardhan R, Salzman A. Effect of metformin and rosiglitazone combination therapy in patients with type 2 diabetes mellitus: a randomized controlled trial. JAMA 2000; 283(13):1695– 702. 78 Grant MB, Mames RN, Fitzgerald C, Hazariwala KM, Cooper-DeHoff R, Caballero S, Estes KS. The efficacy of octreotide in the therapy of severe non-proliferative and early proliferative diabetic retinopathy: a randomized controlled study. Diabetes Care 2000; 23: 504–9. 114 Hanaire-Broutin H, Melki V, Bessieres-Lacombe S, Tauber JP. Comparison of continuous subcutaneous insulin infusion and multiple daily injection regimens using insulin lispro in type 1 diabetic patients on intensified treatment: a randomized study. The Study Group for the Development of Pump Therapy in Diabetes. Diabetes Care 2000; 23(9):1232–5. 92 Heart Outcomes Prevention Evaluation (HOPE) Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000; 355:253–9. 94 Holman RR, Cull CA, Turner RC. A randomized, doubleblind trial of acarbose in type 2 diabetes shows improved glycaemic control over 3 years. Diabetes Care 1999; 22:960–4. 76 Horton ES, Clinkingbeard C, Gatlin M, Foley J, Mallows S, Shen S. Nateglinide alone and in combination with metformin improves glycaemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care 2000; 23(11): 1660–5. 82 Janssen MM, Snoek FJ, Masurel N, Hoogma RP, Deville WL, Popp-Snijders C, Heine RJ. Optimized basal bolus therapy using a fixed mixture of 75% lispro and 25% NPL insulin in type 1 diabetes patients: no favourable effects on glycaemic control, physiological responses to hypoglycaemia, well-being or treatment satisfaction. Diabetes Care 2000; 23:629– 33. 97 Jovanovic L, Dailey III G , Huang WC , Strange P, Goldstein BJ. Repaglinide in type 2 diabetes: a 24week, fixed-dose efficacy and safety study. J Clin Pharmacol 2000; 40(1):49–57. 89

246

INDEX OF PAPERS REVIEWED

Jovanovich L, Ilic S, Pettitt D, Hugo Karen, Gutierrez M, Bowsher R, Bastyr E. Metabolic and immunological effects of insulin lispro in gestational diabetes. Diabetes Care 1999; 22(9): 1422–7. 96 Kaufman FR, Halvorson M, Kim C, Pitukcheewanont P. Use of insulin pump therapy at night-time only for children of 7–10 years of age with type 1 diabetes. Diabetes Care 2000; 23:579–82. 99 Langer O , Conway DL, Berkus MD, Xenakis EM, Gonzales O. A comparison of glyburide and insulin in women with gestational diabetes mellitus. N Engl J Med 2000; 343:1134–8. 111 Marre M, Lievre M, Vasmant D, Gallois Y, Hadjadj S, Reglier JC, Chatellier G, Mann J, Viberti GC, Passa P. Determinants of elevated urinary albumin in the 4937 type 2 diabetic subjects recruited for the DIABHYCAR Study in Western Europe and North Africa. Diabetes Care 2000; 23(Suppl 2): B40–8. 67 Paolisso G, Barbagallo M, Petrella G, Ragno E, Barbieri M, Giordano M, Varricchio M. Effects of simvastatin and atorvastatin administration on insulin resistance and the respiratory quotient in aged dyslipidemic noninsulin-dependent diabetic patients. Atherosclerosis 2000; 150(1):121–7. 107 Raskin P, Guthrie RA, Leiter L, Riis A, Jovanovic L. Use of insulin aspart, a fastacting insulin analog, as the mealtime insulin in the management of patients with type 1 diabetes. Diabetes Care 2000; 23(5):583–8. 84 Ratner RE, Hirsch IB, Neifing IL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. US Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 2000; 23(5):639–43. 87 Rendell MS, Rajfer J, Wicker PA, Smith MD. Sildenafil in the treatment of erectile dysfunction in men with

diabetes: a randomized, controlled trial. Sildenafil Diabetes Study Group. JAMA 1999; 281: 421–6. 110 Rodby RA, Rohde RD, Clarke WR, Hunsicker LG, Anzalone DA, Atkins RC, Ritz E, Lewis E, for the Collaborative Study Group. The Irbesartan Type 2 Diabetic Nephropathy Trial: study design and baseline patient characteristics. Nephrol Dial Transplant 2000; 15:487–97. 65 Rosenfalck AM, Thorsby P, Kjems L, Birkeland K, Dejgaard A, Hanssen KF, Madsbad S. Improved postprandial glycaemic control with insulin aspart in type 2 diabetic patients treated with insulin. Acta Diabetol 2000; 37(1):41–6. 77 Skyler JS, Cefalu WT, Kourides IA, Landschulz WH, Balagtas CC, Cheng SL, Gelfand RA, for The Inhaled Insulin Phase II Study Group. Efficacy of inhaled human insulin in type 1 diabetes mellitus: a randomized proof-of-concept study. Lancet 2001; 357:331–5. 105 Taylor R, Davies R, Fox C, Sampson M, Weaver JU, Wood L. Appropriate insulin regimens for type 2 diabetes: a multi-center, randomized, cross-over study. Diabetes Care 2000; 23:1612–18. 112 Tuomilehto J, Lindstrom J, Erikkson J G, ValleT T, Hamalainen H, Ilanne-Parikka P, KeinanenKiukaanniemi S, Laakso M, Louheranta A, Rastas M, Salminem V, Uusitupa M. Prevention of type 2 diabetes mellitus by changes in life style among subjects with impaired glucose tolerance. N Engl J Med 2001; 344: 1390–2. 72 Willms B, Ruge D. Comparison of acarbose and metformin in patients with type 2 diabetes mellitus who are insufficiently controlled with diet and sulphonylureas: a randomized, placebo-controlled study. Diabetic Med 1999; 16:755–61. 75

Part III Advances in type 1 diabetes mellitus Adler A, Stratton I, Neil A, Yudkin J, Matthews D, Cull C, Wright A, Turner R, Holman R on behalf of the UK Prospective Diabetes Study Group. Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36): a prospective observational study. BMJ 2000; 321:412–19. 151 Biesenbach G, Margreiter R, Konigsrainer A, Bosmuller C, Janko O, Brucke P, Gross C, Zazgornik J. Comparison of the progression of macrovascular diseases after kidney transplantation or pancreas and kidney transplantation in diabetic patients with endstage renal disease. Diabetologia 2000; 43:231–4. 156

Bode BW, Gross TM, Thornton KR, Mastrotaro JJ. Continuous glucose monitoring used for adjusting diabetes therapy improves glycosylated haemoglobin: a pilot study. Diabetes Res Clin Pract 1999; 46:183–90. 170 Canga N, De Irala J, Vara E, Duaso M, Ferrer A, Martinez-Gonzalez M. Intervention study for smoking cessation in diabetic patients. Diabetes Care 2000; 23: 1455–60. 165 Carlsson A, Sundkvist G, Groop L, Tuomi T. Insulin and glucagon secretion in patients with slowly progressing autoimmune diabetes. J Clin Endocrinol Metab 2000; 85 (1):76–80. 134

INDEX OF PAPERS REVIEWED

3 Chandalia M, Garg A, Lutjohann D, von Bergmann K, Grundy SM, Brinkley LJ. Beneficial effects of high dietary fiber intake in patients with type 2 diabetes mellitus. N Engl J Med 2000; 342(19): 1392–8. 166 Detre KM, Lombardero MS, Brooks MM, Hardison RM, Holubkov R, Sopko G, Frye RL, Chaitman BR. The effect of previous coronary artery bypass surgery on the prognosis of patients with diabetes who have acute myocardial infarction. The Bypass Angioplasty Revascularization Investigation. N Engl J Med 2000; 342(14):989–97. 147 Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes 4 years after a trial of intensive therapy. N Engl J Med 2000; 342(6):381– 9. 145 Flores L, Recasens M, Gomis R, Esmatjes E. White coat hypertension in type 1 diabetic patients without nephropathy. Am J Hypertens 2000; 13: 560–3. 148 Geerlings SE, Stolk RP, Camps MJ, Netten PM, Hoekstra JB, Bouter KP, Bravenboer B, Collet JT, Jansz AR, Hoepelman AI. Asymptomatic bacteriuria may be considered a complication in women with diabetes. Diabetes Care 2000; 23:744–9. 159 Greenbaum CJ, Cuthbertson D, Krischer JP, and the Diabetes Prevention Trial of Type 1 Diabetes Study Group. Type 1 diabetes manifested solely by a 2-hour oral glucose tolerance test criteria. Diabetes 2001; 50: 470–6. 139 Imagawa A, Hanafusa T, Miyagawa J, Matsuzawa Y. A novel subtype of type 1 diabetes mellitus characterized by a rapid onset and an absence of diabetes-related antibodies. Osaka IDDM Study Group. N EnglJMed 2000; 342(5):301–7. 129 Karamanos B, Porta M, Songini M, Metelko Z, Kerenyi Z, Tamas G, Rottiers R, Stevens L, Fuller J, and the EURODIAB IDDM Complications Study Group. Different risk factors for micro-angiopathy in patients with type 1 diabetes mellitus of short versus long duration. The EURODIAB IDDM Complications Study. Diabetologia 2000; 43:348–55. 153 Karvonen M, Viik-Kajander M, Moltchanova E, Libman I, LaPorte R, Tuomilehto J. Incidence of childhood type 1 diabetes worldwide. Diabetes Mondiale (DiaMond) Project Group. Diabetes Care 2000; 23(10):1516–26. 131 Lafferty AR, Werther GA, Clarke CR Ambulatory blood pressure, micro-albuminuria and autonomic neuropathy

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in adolescents with type 1 diabetes. Diabetes Care 2000; 23(4):533–8. 161 Madigan C, Ryan M, Owens D, Collins P, Tomkin GH. Dietary unsaturated fatty acids in type 2 diabetes: higher levels of postprandial lipoprotein on a linoleic acid-rich sunflower oil diet compared with an oleic acid-rich olive oil diet. Diabetes Care 2000; 23(10): 1472–7. 178 Menzin J, Langley-Hawthorne C, Friedman M, Boulanger L, Cavanaugh R. Potential short-term economic benefits of improved glycaemic control: a managed care perspective. Diabetes Care 2001; 24: 51–5. 173 O’Byrne S, Forte P, Roberts LJ, Morrow JD, Johnston A, Anggard E, Leslie RD, Benjamin N. Nitric oxide synthesis and isoprostane production in subjects with type 1 diabetes and normal urinary albumin excretion. Diabetes 2000; 49(5):857–62. 158 Paronen J, Knip M, Savilahti E, Virtanen S, Ilonen J, Akerblom H, Vaarala O, and the Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group. Effect of cow’s milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Diabetes 2000; 49:1657–65. 137 Pearce IA, Ilango B, Sells RA, Wong D. Stabilization of diabetic retinopathy following simultaneous pancreas and kidney transplants. Br J Ophthalmol 2000; 84(7): 736–40. 149 Pham H, Armstrong DG, Harvey C, Harkless LB, Giurini JM, Veves A. Screening techniques for identifying people at high risk of diabetic foot ulceration: a prospective multicenter trial. Diabetes Care 2000; 23: 606–11. 155 Pugliese A, Brown D, Garza D, Murchinson D, Zeller M, Redondo M, Diez J, Eisenbarth GS, Patel DD, Ricordi C. Self-antigen-presenting cells expressing diabetesassociated autoantigens exist in both the thymus and peripheral lymphoid organs. J Clin Invest 2001; 107: 555–64. 140 Sabbah E, Savola K, Ebeling T, Kulmala P, Vahsalo P, Ilonen J, Salmela P, Knip M. Genetic, autoimmu-ne and clinical characteristics of childhood and adult onset type 1 diabetes. Diabetes Care 2000; 23:1326–32. 135 Sharma K, Eltayeb B, McGowan T, Dunn S, Alzahabi B, Rohde R, Ziyadeh F, Lewis E. Captopril-induced reduction of serum levels of transforming growth factor-β correlates with long-term renoprotection in insulin-dependent diabetic patients. Am JKidneyDis 1999; 34:818–23. 152

248

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Snehalatha C, Ramachandran A, Satyavani K, Vijay V. Limitations of glycosylated haemoglobin as an index of glucose intolerance. Diabetes Res Clin Pract 2000; 47 (2):129–33. 171 Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE, Cull CA, Hadden D, Turner RC, Holman RR. Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): a prospective observational study. 5M/ 2000; 321(7258): 405–12. 157 Torn C, Landin-Olsson M, Ostman J, Schersten B, Arnqvist H, Blhme G, Bjork E, Bolinder J, Eriksson J, Littorin B, Nystrom L, Sunndkvist G, Lernmark A. Glutamic acid decarboxylase antibodies are the most important factor in the prediction of insulin therapy within 3 years in young adult diabetic patients not classified as type 1 diabetes on clinical grounds. Diabetes Metab Res Rev 2000; 16:442–7. 136 Wamala SP, Lynch J, Horsten M, Mittleman MA, Schenck-Gustafsson K, Orth-Gomer K. Education and the metabolic syndrome in women. Diabetes Care 1999; 22:1999–2003. 174 Wei M, Gibbons L W, Kampert JB, Nichaman MZ, Blair SN. Low cardiorespiratory fitness and physical

inactivity as predictors of mortality in men with type 2 diabetes. Ann Intern Med 2000; 132:605–11. 167 Weitgasser R, Gappamyer B, Pichler M. Newer portable glucose meters: analytical improvement compared with previous generation devices? Clin Chem 1999; 45(10): 1821–5. 169 Williams KV, Erbey JR, Becker D, Arslanian S, Orchard TJ. Can clinical factors estimate insulin resistance in type 1 diabetes? Diabetes 2000; 49:626–32. 141 Yu L, Robles DT, Abiru N, Kaur P, Rewers M, Kelemen K, Eisenbarth GS. Early expression of anti-insulin autoantibodies of humans and the NOD mouse: evidence for early determination of subsequent diabetes. Proc Natl Acad Sci USA 2000; 15:1701–6. 142 Ziyadeh F, Hoffman B, Cheol D, Iglesias M, Won S, Isono M, Chen S, Mc Gowan T, Sharma K. Long-term prevention of renal insufficiency, excess matrix gene expression and glomerular mesangial matrix expansion by treatment with monoclonal anti-transforming growth factor-p antibody in db/db diabetic mice. Proc Natl Acad Sci USA 2000; 97:8015– 20. 154

Part IV Insulin resistance: type2 diabetes mellitus and obesity Boyko EJ, Fujimoto WY, Leonetti DL, Newell-Morris L. Visceral adiposity and the risk of type 2 diabetes: a prospective study among Japanese-Americans. Diabetes Care 2000; 23:465–71. 222 Briining JC, Gautam D, Burks DJ, Gillette J, Schubert M, Orban PC, Klein R, Krone W, Muller-Wieland D, Kahn CR. Role of the brain insulin receptor in the control of body weight and reproduction. Science 2000; 289:2122– 8. 225 Buchanan TA, Xiang AH, Peters RK, Kjos SL, Berkowitz K, Marroquin A, Goico J, Ochoa C, Azen SP. Response of pancreatic (3 cells to improve insulin sensitivity in women at high risk of type 2 diabetes. Diabetes 2000; 49:782–8. 202 Fernandez-Real JM, Broch M, Vendrell J, Richart C, Ricart W. Interleukin 6 gene polymorphism and lipid abnormalities in healthy subjects. J Clin Endocrinol Metab 2000; 85:1334–9. 195 Fernandez-Real JM, Granada ML, Ruzafa A, Casamitjana R, Ricart W. Insulin sensitivity and secretion influence the relationship between growth hormone-binding protein and leptin. Clin Endocrinol 2000; 52:159–64. 205

Fernandez-Real JM, Vendrell J, Ricart W, Broch M, Gutierrez C, Casamitjana R, Oriola J, Richart C. Polymorphism of the tumor necrosis factor-oc receptor 2 gene is associated with obesity, leptin levels and insulin resistance in young subjects and diet-treated type 2 diabetic patients. Diabetes Care 2000; 23:831–7. 204 Ford ES. Body mass index, diabetes and C-reactive protein among US adults. Diabetes Care 1999; 22(12): 1971–7. 196 Foreyt JP, Poston WS. The challenge of diet, exercise and life style modification in the management of the obese diabetic patient. Int J Obesity Relat Metab Disord 1999; 23 (Suppl 7):85–11. 227 Fujioka K, Seaton TB, Rowe E, Jelinek CA, Raskin P, Lebovitz HE, Weinstein SP and the Sibutramine/ Diabetes Clinical Study Group. Weight loss with sibutramine improves glycaemic control and other metabolic parameters in obese patients with type 2 diabetes mellitus. Diabetes Obesity Metab 2000; 2:175– 87. 217 Gress T, Nieto J, Shahar E, Wofford M, Brancati F for the Atherosclerosis Risk in Communities Study. Hypertension and anti-hypertensive therapy as risk

INDEX OF PAPERS REVIEWED

factors for type 2 diabetes mellitus. N Engl J Med 2000; 342:905–12. 199 Haffner SM, Mykkanen L, Festa A, Burke JP, Stern MP. Insulin-resistant pre-diabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the pre-diabetic state. Circulation 2000; 101:975–80. 201 Heilbronn LK , Noakes M, Clifton PM. Effect of energy restriction, weight loss and diet composition on plasma lipids and glucose in patients with type 2 diabetes. Diabetes Care 1999; 22:889–95. 230 Heymsfield SB, Segal KR, Hauptman J, Lucas CP, Boldrin MN, Rissanen A, Wilding JP, Sjostrom L. Effects of weight loss with orlistat on glucose tolerance and progression to type 2 diabetes in obese adults. Arch Intern Med 2000; 160(9): 13 321–6. 213 Hoogeveen EK, Kostense PJ, Jakobs C, Dekker JM, Nijpels G, Heine RJ, Bouter LM, Stehouwer CD. Hyperhomocysteinemia increases the risk of death, especially in type 2 diabetes: 5-year follow-up of the Hoorn Study. Circulation 2000; 101(13): 1506–11. 193 Jager A, van Hinsbergh VW, Kostense PJ, Emeis JJ, Yudkin JS, Nijpels G, Dekker JM, Heine RJ, Bouter LM, Stehouwer CD. Von Willebrand factor, C-reactive protein and 5-year mortality in diabetic and nondiabetic subjects: the Hoorn Study. Arterioscler Thromb Vasc Biol 1999; 19(12): 3071–8. 198 Kim JK, Michael MD, Previs SF, Peroni OD, MauvisJarvis F, Neschen S, Kahn BB, Khan CR, Shulman GI. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. J Clin Invest 2000; 105:1791–7. 235 Lehto S, Ronnemaa T, Pyorala K, Laakso M. Cardiovascular risk factors clustering with endogenous hyper-insulinaemia predict death from coronary heart disease in patients with type 2 diabetes. Diabetologia 2000; 43:148–55. 200 Li B, Nolte A, Ju JS, Han DH, Coleman T, Holloszy JO, Semenkovich CF. Skeletal muscle respiratory uncoupling prevents diet-induced obesity and insulin resistance in mice. NatureMed. 2000; 6(10). 226 Liao D, Shofer JB, Boyko EJ, McNeely MJ, Leonetti DL, Kahn SE, Fujimoto WY. Abnormal glucose tolerance

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and increased risk of cardiovascular disease in Japanese-Americans with normal fasting glucose. Diabetes Care 2001; 24:39–44. 208 Lindgarde F. The effect of orlistat on body weight and coronary heart disease risk profile in obese patients: the Swedish Multimorbidity Study. J Intern Med 2000; 248: 245–54. 214 Mehta SH, Brancati FL, Sulkowski MS, Strathdee SA, Szklo M, Thomas DL. Prevalence of type 2 diabetes mellitus among persons with hepatitis C virus infection in the USA. Ann Intern Med 2000; 133:592–9. 197 Meigs JB, Mitleman MA, Nathan DM, Tofler GH, Singer DE, Murphy-Sheehy PM, Lipinska I, D’Agostino RB, Wilson PWF. Hyperinsulinemia, hyperglycemia and impaired hemostasis. The Framingham Offspring Study. JAMA 2000; 283(2):221–8. 194 Pasquali R, Gambineri A, Biscotti D, Vicennati V, Gagliardi L, Colitta D, Fiorini S, Cognigni GE, Filicori M, Morselli-Labate AM. Effect of long-term treatment with metformin added to a hypocaloric diet on body composition, fat distribution and androgen and insulin levels in abdominally obese women with and without polycystic ovary syndrome. J Clin Endocrinol Metab 2000; 85:2767– 74. 216 Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerlee RR, Wrigth CM, Patel H, Ahima R, Lazar M. The hormone resistin links obesity to diabetes. Nature 2001; 409:307– 12. 222 Weyer C, Bogardus C, Mott DM, Pratley RE. The natural history of insulin secretory dysfunction and insulin resistance in the pathogenesis of type 2 diabetes mellitus. J Clin Invest 1999; 104: 787–94. 210 Weyer C, Hanson K, Bogardus C, Pratley RE. Long-term changes in insulin action and insulin secretion associated with gain, loss, regain and maintenance of body weight. Diabetologia 2000; 43:36– 46. 220 Williamson DF, Thompson TJ, Thun M, Flanders D, Pamuk E, Byers T. Intentional weight loss and mortality among overweight individuals with diabetes. Diabetes Care 2000; 23:1499– 504. 232 Zhou YT, Wang ZW, Higa M, Newgard CB, Unger RH. Reversing adipocyte differentiation: implications for the treatment of obesity. Proc. Natl Acad. Sci USA 1999; 96:2391–5. 224

Part V Diabetes and pregnancy Buchbinder A, Miodovnik M, McElvy S, Rosenn B, Kranias G, Khoury J, Siddiqi TA. Is insulin lispro associated with the development or progression of

diabetic retinopathy during pregnancy? Am J Obstet Gynecol 2000; 183:1162–5. 259 Costa A, Carmona F, Martinez-Roman S, Quinto L, Levy I, Conget I. Post-partum reclassification of glucose

250

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tolerance in women previously diagnosed with gestational diabetes mellitus. Diabetic Med 2000; 17: 595–8. 246 Diabetes Control and Complications Trial Research Group. Effect of pregnancy on microvascular complications in the Diabetes Control and Complications Trial. Diabetes Care 2000; 23:1084–91. 243 Ellard S, Beards F^Allen L, Shepherd M, Ballantyne E, Harvey R, Hattersley A. A high prevalence of glucokinase mutations in gestational diabetic subjects selected by clinical criteria. Diabetologia 2000; 43:250– 3. 247 Flores L, Levy I, Aguilera E, Martinez S, Gomis R, Esmatjes E. Usefulness of ambulatory blood pressure monitoring in pregnant women with type 1 diabetes. Diabetes Care 1999; 22(9):1507–11. 244 Forsen T, Eriksson J, Tuomilehto J, Reunanen A, Osmond C, Barker D. The fetal and childhood growth of persons who develop type 2 diabetes. Ann Intern Med 2000; 133:176–82. 260 Gabbe SG, Holing E, Temple P, Brown ZA. The benefits, risks, costs and patient satisfaction associated with

insulin pump therapy for the pregnancy complicated by type 1 diabetes mellitus. Am J Obstet Gynecol 2000; 182:1283–91. 262 Hiilesmaa V, Suhonen L, Terano K. Glycaemic control is associated with preeclampsia but not pregnancyinduced hypertension in woman with type 1 diabetes mellitus. Diabetologia 2000; 43: 1534–9. 249 Schaefer-Graf U, Buchanan T, Xiang A, Songster G, Montoro M, Kjos S. Patterns of congenital anomalies and relationship to initial maternal fasting glucose level in pregnancies complicated by type 2 and gestational diabetes. Am J Obstet Gynecol 2000; 182:313–20. 255 Sibai BM, Caritis S, Hauth J, Lindheimer M, VanDorsten JP, MacPherson C, Klebanoff M, Landon M, Miodovnik M, Paul R, Meis P, Dombrowski M, Thurnau G, Roberts J, McNellis D. Risks of preeclampsia and adverse neonatal outcomes among women with pre-gestational diabetes mellitus. Am J Obstet Gynecol 2000; 182: 364–9. 253 Wood S, Sauve R, Ross S, Brant R, Love E. Pre-diabetes and perinatal mortality. Diabetes Care 2000; 23:1752– 4. 251

Part VI Diabetes research Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPAR-y Prol2Ala polymorphism is associated with decreased risk of type 2 diabetes. Nature Genet2000; 26(1):76– 80. 282 Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, Sharma A, O’Neil JJ. In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci USA 2000; 97(14): 7999– 8004. 277 Chao L, Marcus-Samuels B, Mason MM, Moitar J, Vinson C, Arioglu E, Gavrilova O, Reitman ML. Adipose tissue is required for the anti-diabetic but not for the hypolipidemic effect of thiazolidinediones. /C/w/ ttvesf 2000; 106:1221–8. 293 Clement S, Krause U, Desmedt F, Tanti J-F, Behrends J, Pesesse X, Sasaki T, Penninger J, Doherty M, Malaisse W, Dumont JE, Le Marchand-Brustelk J, Erneux C, Hue L, Schurmans S. The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 2001; 409:92. 285 Costa A, Bescos M, Velho G, Chevre J, Vidal J, Sesmilo G, Bellanne-Chantelot C, Froguel P, Casamitjana R, Rivera-Fillat F, Gomis R, Conget I. Genetic and clinical characterization of maturity onset diabetes of the

young in Spanish families. Eur J Endocrinol 2000; 142: 380–6. 272 Ferber S, Halkin A, Cohen H, Ver I, Einav Y, Goldberg I, Barsahack I, Seijffers R, Kopolovic J, Kaiser N, Karasik A. Pancreatic and duodenal homeobox gene 1 induces the expression of insulin genes in the liver and ameliorates streptozotocin-induced hyperglycaemia. Nature Med 2000; 6:568–72. 291 Gavrilova O, Marcus-Samuels B, Graham D, Kim JK, Shulman GI, Castle AL, Vinson C, Eckhaus M, Reitman ML. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. J Clin Invest 2000; 105: 271–8. 294 Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, Lindner TH, Mashima H, Schwarz PE, del Bosque-Plata L, Horikawa Y, Oda Y, Yoshiuchi I, Colilla S, Polonsky KS, Wei S, Concannon P, Iwasaki N, Schulze J, Baier LJ, Bogardus C, Groop L, Boerwinkle E, Hanis CL, Bell GI. Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. NatureGenet 2000; 26(2):163–75. 284 Kawasaki E, Sera Y, Yamakawa K, Abe T, Ozaki M, Uotani S, Ohtsu N, Takino H, Yamasaki H, Yamaguchi Y, Matsuura N, Eguchi K. Identification and functional

INDEX OF PAPERS REVIEWED

analysis of mutations in the hepatocyte nuclear factor 1a gene in anti-islet autoantibody-negative Japanese patients with type 1 diabetes. J Clin Endocrinol Mete & 2000;85:331–5. 273 Lee HC, Kim SJ, Kim KS, Shin HC, Yoon JW. Remission in models of type 1 diabetes by gene therapy using a single-chain insulin analogue. Nature 2000; 408(6811): 483–8. 282 Macfarlane WM, Shepherd RM, Cosgrove KE, James RF, Dunne MJ, Docherty K. Glucose modulation of insulin mRNA levels is dependent on the transcription factor PDX-1 and occurs independently of changes in intracellular Ca2+. Diabetes 2000; 49(3):418–23. 290 Maechler P, Wollheim CB. Mito-chondrial glutamate acts as a messenger in glucose-induced insulin secretion. Nature 1999; 402(6762):685–9. 274 Meigs JB, Ordovas JM> Cupples LA, Singer DE, Nathan DM, Schaefer EJ, Wilson PW. Apolipoprotein E isoform polymorphisms are not associated with insulin resistance: the Framingham Offspring Study. Diabetes Care 2000; 23: 669–74. 286 Pende M, Kozma SC, Jaquet M, Oorschot V, Burcelin R, Le Marchand-Brustel Y, Klumperman J, Thorens B, Thomas G. Hypoinsulinaemia, glucose intolerance and diminished B cell size in S6Kl-deficient mice. Nature 2000; 408: 994–7. 276 Ramiya VK, Maraist M, Arfors KE, Schatz DA, Peck AB, Cornelius JG. Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nature Med 2000; 6:278–82. 280 Schwitzgebel VM, Scheel DW, Conners JR, Kalamaras J, Lee JE, Anderson DJ, Sussel L, Johnson JD and German MS. Expression of neurogenin-3 reveals an islet cell precursor population in the pancreas. Development200ty 127:3533–42. 278 Shapiro AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N Engl J Med 2000; 343(4):230–8. 271 Shimomura H, Sanke T, Hanabusa T, Tsunoda K, Furuta H, Nanjo K. Nonsense mutation of the islet-1 gene (Q310X) found in a type 2 diabetic patient with a strong family history. Diabetes 2000; 49: 1597–600. 288 Tawata M, Hayashi JI, Isobe K, Ohkubo E, Ohtaka M, Chen J, Aida K, Onaya T. A new mitochondrial DNA mutation at 14577 T/C is probably a major pathogenic mutation for maternally inherited type 2 diabetes. Diabetes 2000; 49:1269–72. 287

251

Waeber G, Delplanque J, Bonny C, Mooser V, Steinmann M, Widmann C, Maillard A, Miklossy J, Dina C, Hani EH, Vionnet N, Nicod P, Boutin P, Froguel P. The gene MAPK8IP1 encoding islet-brain-1 is a candidate for type 2 diabetes. Nature Genet 2000; 24:291–5. 289

General Index

A abdominal obesity 237 and polycystic ovary syndrome 217 and risk of type 2 diabetes 222–3 see also obesity acarbose 120 clinical trials 75–6 STOP-NIDDM trial 70–1 ACE (angiotensin-converting enzyme) inhibitors 10, 121–2 renoprotective effect 34, 65–7, 68, 152 use in pregnancy 31 see also captopril; lisinopril; ramipril acesulphame K 15 Actrapid, comparison with insulin aspart 77–78 ADA see American Diabetes Association adenosine triphosphate see ATP adenovirus-induced hyperleptinaemia 224 adipocytes endocrinology of 191 effect of hyperleptinaemia 224 and resistin 191, 222 and thiazolidinediones 293–4 adipose tissue transplantation in lipodystrophic diabetes 294 ADMIT (Arterial Disease Multiple Intervention Trial) 104–5 adolescent type 1 diabetics 161–2 aetiology of diabetes 56–7 type 1 181–2 type 2 189 age, as risk factor in type 2 diabetes 5 albuminuria see mico-albuminuria; nephropathy; proteinuria alcohol 16

ambulatory blood pressure monitoring 148–9 use in adolescent type 1 diabetics 161–2 use in pregnancy 244–6, 264 American Diabetes Association (ADA) 1 diagnostic criteria 51–3, 208–10, 246–7, 265 amlodipine, in Irbesartan Type II Diabetic Nephropathy Trial 65–7 android obesity see abdominal obesity angiotensin II receptor antagonists 121–2 see also irbesartan angiotensin-converting enzyme inhibitors see ACE inhibitors anti-obesity drugs see orlistat; sibutramine antihypertensives and risk of type 2 diabetes 199–200 apolipoprotein E polymorphisms 286–7 Arterial Disease Multiple Intervention Trial (ADMIT) 104–5 aspartame 15 aspartic insulin see insulin aspart aspirin, use in peripheral vascular disease 25 asymptomatic bacteriuria 159–161 atheroma, role of endothelial dysfunction 191 atorvastatin, use in type 2 diabetics 107–10 ATP, role in insulin secretion 274–5 autoantibodies 181–2 and age of onset of type 1 diabetes 137–8 anti-insulin 142–3 in diagnosis of type of diabetes 136–7 lack in type 1 diabetes 129–31, 273–4, 295 autoantigens, presence in thymus 140–1 autoimmune diabetes 54 slowly progressing 134 autonomic neuropathy in adolescent type 1 diabetics 161– 2 and exercise 20 see also neuropathy 252

GENERAL INDEX

A-ZIP-F1 mice 294 B β cell antigens 181 presence in thymus 141–2 β cell replacement therapy see islet transplantation β cells function and oral insulin administration 100–3 conservation 137, 237 effect of glitazones 81–2 growth, and S6 kinase 1 (S6K1) 276–7 offloading 237 effect of thiazolidinediones 202–4 see also islet cell antibodies; islet cell differentiation; islet transplantation bacteriuria, asymptomatic 159–161 Bedford study 63, 72 beta blockers, and type 2 diabetes risk 199–200 β TC3 cells 288, 89 big babies 36, 39 and risk of type 2 diabetes 5 birth weight, and risk of type 2 diabetes 260–1 blood glucose levels, and alcohol 16 blood glucose meters 184 accuracy 169 use in screening 6 blood glucose monitoring 41–3 blood pressure 127–128 ambulatory monitoring in pregnancy 244–6, 264 effect of exercise 21 and nephropathy 33, 34 effect of orlistat 237 and risk of complications in type 2 diabetes 151–2 effect of weight loss 230 see also hypertension body mass index association with C-reactive protein 196– 7 and tumour necrosis factor-α 204–5 bovine insulin exposure, and type 1 diabetes 133–38, 182 brain, insulin signalling 225 breast feeding, and gestational diabetes 39 Bypass Angioplasty Revascularisation Investigation (BARI) 127, 147–48 C C-reactive protein 236 association with body mass index and diabetes 196–7

253

association with mortality 198–9 Ca21 signalling and insulin gene transcription 290–1 CABG see coronary artery bypass grafting Caesarian section, and gestational diabetes 36, 39 calcium channel blockers, renal effects 67 calcium signalling and insulin gene transcription 290–1 calpain-10 284–5, 296 Candesartan and Lisinopril Microalbuminuria Study 122 capillary blood glucose, use in screening 6 see also blood glucose meters captopril, renoprotective effect 65, 152 see also ACE inhibitors carbohydrate intake 14 cardiovascular disease risk 53 apolipoprotein E polymorphisms 287 association of hyperinsulinaemia with impaired fibrinolysis 194–5, 236 and C-reactive protein 197, 198–9, 236 anddiet 13–14 evaluation of 18 effect of exercise 21 hyperinsulinaemia cluster 200–1 effect of orlistat 214–5 in pre-diabetic state 201–2 effect of ramipril 92–3 in type 2 diabetes 189–190 and Von Willebrand factor 198–200 effect of weight loss 233–4 central obesity see abdominal obesity cerebral insulin signalling 225 cerebrovascular disease, progression after transplant surgery 156–7, 184 chemical-induced diabetes 56 childhood growth rate and risk of type 2 diabetes 260, 261 childhood onset diabetes immunology 135–6, 182 incidence 131–3 children, night-time insulin pump therapy 99–100 cholesterol intake 13–14 cholesterol levels and fat intake 13 effect of metformin-rosiglitazone combination 81 effect of niacin (ADMIT study) 104–5 as risk factor 5 see also dyslipidaemia; hyperlipidaemia; LDL cholesterol chromium deficiency 17 classification of diabetes 54–7

254

GENERAL INDEX

type 1 diabetes 129–131 White’s classification 254 combination therapy in type 2 diabetes 120 metformin and nateglinide 82–4 metformin and rosiglitazone 78–82 complications of diabetes acute 9–10, 42 association with blood pressure 151–2 asymptomatic bacteriuria 159–61 risk factors 119–21 for micro-angiopathy 153–4 risk of hyperglycaemia 157–59 social impact 3 see also autonomic neuropathy; nephropathy; neuropathy; peripheral neuropathy; peripheral vascular disease; retinopathy congenital anomalies in diabetic pregnancies 253–56 continuing care visits 8–9 continuous glucose monitoring 170, 184 continuous subcutaneous insulin infusion (CSII) 47–48, 120 comparison with MDI 92–4 use of insulin aspart 116–17 use in pregnancy 262–3, 264 see also insulin pumps corn syrup 14–15 coronary artery bypass grafting 127 BARI trial 147–48 coronary heart disease, progression after transplant surgery 156–7, 184 cows’ milk exposure, and risk of type 1 diabetes 137–38, 182 CSII see continuous subcutaneous insulin infusion cytokines 195–6 D Da Qing trial 63, 73 daclizumab, use in islet transplantation 271 DCCT see Diabetes Control and Complications Trial DECODE study, diagnostic criteria 53 dextrose 14–15 diabesity 227 Diabetes Care 3 Diabetes Control and Complications Trial (DCCT) 92, 127, 145–7, 182 effect of pregnancy on retinopathy 243–4, 264 Diabetes Prevention Program (DPP) 69–70

Diabetes Prevention Study (DPS) 72–73 Diabetes Prevention Trial of Type 1 Diabetes (DPT-1) 139–40 DIABHYCAR study 67–68 diagnosis of diabetes 51–59, 209–9 ADA criteria 246–7, 265 role of HbA1c 171–3 WHO criteria 246–7, 265 in young adults 136–7 see also fasting plasma glucose; oral glucose tolerance test DiaMond project 131–3 diet 10–17 fat substitutes 48–49 fibre intake 15, 166–7, 184 role in prevention of type 2 diabetes 63, 72–3 very low-calorie 228, 229 see also lifestyle modification; medical nutrition therapy drug-induced diabetes 56 dyslipidaemia benefits of Mediterranean-type diet 178–80 and fructose 14 management 25–7 see also hyperlipidaemia; hypertriglyceridaemia E economic aspects of glycaemic control 173–4 educational level, and risk of metabolic syndrome 174–7 elderly people, and exercise 23 endogenous glucose production in type 2 diabetes 210–11 endothelial dysfunction 190 Epidemiology of Diabetes Complications (EDC) Study 141 Epidemiology of Diabetes Interventions and Complications (EDIC) Study 145–7, 182–3 erectile dysfunction, use of sildenafil 110–11 ethnic risk factors 5 for gestational diabetes 37 EURODIAB IDDM Complications Study 153–4, 183 exercise 18–23 classification of intensity 19 role in gestational diabetes 39 effect on insulin absorption 47 patient evaluation 18–21 role in peripheral vascular disease 25 role in prevention of type 2 diabetes 63, 73, 167–9 see also lifestyle modification

GENERAL INDEX

F family history, as risk factor 7 Fasting Hyperglycaemia Study (Oxford) 73 fasting plasma glucose (FPG) role in diagnosis 51–3, 58, 59, 208–9 role in screening 5–6, 246–7, 264–5 fat intake 13–14 fat substitutes 48–49 fibrates 26–7 fibre intake 15 benefits 166–7, 184 fibrinolysis effect of exercise 22 and hyperinsulinaemia 194–5, 236 Finnish Diabetes Prevention Study 119 Food and Drug Administration (FDA) 15 foot care 23–5 foot ulceration, risk factors 155–6 FPG see fasting plasma glucose Framingham Offspring Study 194–5, 236, 286–7 frequency of clinic visits 8 fructosamine analysis 41 fructose 14 fruit juice, use as sweetener 14–15 G gabapentin, use in neuropathy 123 GAD see glutamic acid decarboxylase gastric reduction surgery 12 gene therapy in type 1 diabetes 282 genetic causes of diabetes 57 genetic factors in age of onset of type 1 diabetes 135–6 genetic studies 296 apolipoprotein E polymorphisms 286–7 calpain-10 284–5 islet-1 gene mutation 288–9 MAPK8IP1 gene 289–90 mitochondrial DNA mutation 287–8 PPAR-γ polymorphism 282–4 SHIP2 285–6 gestational diabetes 36–39, 120 comparison of glyburide with insulin 111–13 and congenital anomalies 255–58 and glucokinase mutations 247–49 use of insulin lispro 96–7 post-partum reclassification 246–7, 264 risk of type 2 diabetes 5, 202 see also pregnancy and diabetes glitazones see pioglitazone;

255

rosiglitazone; troglitazone glucagon levels, in LADA-type diabetes 134 glucokinase mutations 247–9, 265 glucose intolerance association of hyperinsulinaemia with impaired fibrinolysis 194–5 see also glucose tolerance; impaired glucose tolerance; oral glucose tolerance test glucose metabolism, intracellular signalling 290–1 glucose meters 184 accuracy 169 use in screening 6 glucose tolerance effect of dietary interventions 232 effect of orlistat 213–14 see also glucose intolerance; impaired glucose tolerance; oral glucose tolerance test glucose tolerance test see oral glucose tolerance test α-glucosidase inhibitors, STOP-NIDDM trial 70–1 glutamate, role in insulin secretion 274–6 glutamic acid decarboxylase (GAD) 181, 182 use in classification of type 1 diabetes 129–31 glutamic acid decarboxylase antibodies, and prediction of need for insulin 136–7 glyburide, use in gestational diabetes 111–12 glycaemic control blood glucose monitoring 39–41 continuous 170, 184 economic considerations 173–4 effect of exercise 21 and medical nutrition therapy 11 and nephropathy 34 pre-conception care 30, 31 and pre-eclampsia 249–51, 264 and risk of complications 157–58, 162, 182–3 see also poor control; postprandial glycaemic control glycaemic targets 6, 7 glycosylated haemoglobin see HBA1c glycoslyated serum proteins 41 growth hormone, and diabetic retinopathy 114 growth hormone-binding protein 205–208 guidelines 3, 5–49 diagnostic see diagnosis of diabetes H

256

GENERAL INDEX

haemostasis, and hyperinsulinaemia 194–5 HBA1c 41 effect of postprandial glycaemic control 85–7 role in diagnosis 171–2 health care expenses, and glycaemic control 173–4 hepatitis C and prevalence of type 2 diabetes 197–199 hepatocyte nuclear factor 1-α see HNF l α gene HLA type and diabetes 135–6, 181 HNF-l α gene, and MODY 273–4, 295–6 homocysteine, link with vascular disease 193–4, 236 honey 14–15 Hoorn study 190, 198–199, 236 diagnostic criteria 52–3 HOPE study 94–5, 121 hospital admission, guidelines 41–3 human islets, in vitro cultivation 277–9 see also islet transplantation hyperglycaemia and risk of complications 157–9 and risk of congenital anomalies in diabetic pregnancies 255–8 see also glycaemic control hyperglycaemia, non-ketotic hyperosmolar 42 hyperhomocysteinaemia 193–4, 236 hyperinsulinaemia association with impaired fibrinolysis 194–5, 236 and polycystic ovary syndrome 217 hyperinsulinaemia cluster and cardiovascular disease risk 200–1 hyperkalaemia 17 hyperleptinaemia, adenovirus-induced 224 hyperlipidaemia effect of exercise 21 and interleukin 6 gene polymorphism 195–6 see also cholesterol; dyslipidaemia; hypertriglyceridaemia hyperosmolar hyperglycaemia, non- ketotic 42 hypertension 10, 127–8 effect of exercise 21 and nephropathy 34 in pregnancy 31, 244–6, 264 see also pre-eclampsia; pregnancy- induced hypertension and risk of complications in type 2 diabetes 151–2 as risk factor 3 white coat 148–9 see also blood pressure Hypertension Optimal Therapy Trial 152

hypertriglyceridaemia, management 26–7 see also dyslipidaemia; hyperlipidaemia hypocaloric diet, advantages 12 hypoglycaemia 42, 47 and alcohol consumption 16 I IB-1 (islet-brain-1) 289–90 idiopathic diabetes 54–5, 129–31 IFG see impaired fasting glucose IGT see impaired glucose tolerance illness, intercurrent 9 immunomediated diabetes 54 see also autoantibodies; autoimmune diabetes immunosuppressive regimens 271, 295 impaired fasting glucose (IFG) 6, 57 impaired glucose tolerance (IGT) 6, 57 use of acarbose (STOP-NIDDM trial) 70–1 use in diagnosis 51–3 effect of lifestyle modification 74–5 effect of obesity 221 risks 190–1 see also glucose intolerance; glucose tolerance; oral glucose tolerance test impotence see erectile dysfunction in vitro islet cultivation human 277–8 mouse 280–1 incidence of type 1 diabetes 183 in childhood 131–3 inhaled insulin 105–6, 121 initial visit 7–8 injection sites 46 injection technique 46 inpatient care, guidelines 41–3 insulin use in gestational diabetes 39 oral administration 100–3 production in mouse liver cells 291–3 insulin action, effect of weight fluctuations 220–1, 237 insulin aspart 84–5 comparison with Actrapid 79–80 use in CSII 116–7 insulin autoantibodies 142–3 see also autoantibodies; bovine insulin exposure

GENERAL INDEX

insulin gene transcription 290–1 insulin glargine 87–9 insulin inhalation 105–6, 121 insulin injection technique 46 insulin-like growth factor 1 (IGF-1), and diabetic retinopathy 114, 115, 122 insulin lispro 120 comparison of CSII with MDI 92–4 use in gestational diabetes 96–7 and retinopathy in pregnancy 259–60 trial of multiple injection regimen using lispro HM 97– 9 insulin mixtures 45 insulin mRNA, and PDX-1 290–1 insulin pens 45–6 insulin preparations 44 insulin promoter factor 1 (PDX-1) 290–3 insulin pump therapy use in children 99–100 use in pregnancy 262–3, 264 see also continuous subcutaneous insulin infusion insulin regimens, study in type 2 diabetes 112–13 insulin resistance 44–5, 69 and apolipoprotein E polymorphisms 286–7 estimation in type 1 diabetics 141 effect of exercise 21 in LADA-type diabetes 134, 182 and lipodystrophy 294 in muscle tissue 235 and obesity 237 in pathogenesis of type 2 diabetes 210–11 in pre-diabetic state 201–2 effect of statins 107–10 effect of troglitazone 202–4 role of tumour necrosis factor-oc 204–5 insulin secretion effect of weight fluctuations 220–1, 239 role of mitochondrial glutamate 274–6 insulin secretory dysfunction, in pathogenesis of type 2 diabetes 210–11 insulin sensitivity, and SHIP2 285–6 insulin signalling, role in central nervous system 225 insulin storage 45 insulin syringes 45 insulin upstream factor 1 (PDX-1) 290–3 intensive insulin therapy 11 comparison of CSII with MDI 92–4 and risk of microvascular complications 145–7 see also continuous subcutaneous insulin infusion;

257

insulin pump therapy intercurrent illness, management 9 interleukin 6 197 gene polymorphism 195–6 irbesartan Irbesartan Diabetic Nephropathy Trial (IDNT) 121–2 Irbesartan Microalbuminuria Intervention trial 122 Irbesartan Type II Diabetic Nephropathy Trial 65–7 islet cells antibodies 181–2 use in screening 139 see also autoantibodies differentiation of 278–9 see also β cells islet transplantation 44, 271–2, 292, 295 in vitro human islet cultivation 277–8 in vitro mouse islet cultivation 280–1 islet-1 gene mutation 278–9 islet-brain-1 (IB-1) 289–90 islets, in vitro cultivation 277–8, 280–1 isoprostane production 158–9 K ketoacidosis 42 riskinCSII 262–3, 264 ketones, urinary 40–1 kidney transplantation 43, 183–4 and progression of macrovascular disease 156–7 L laboratory evaluation 8, 9 large babies 36, 39 as risk factor for type 2 diabetes 5 laser treatment of retinopathy 36 latent autoimmune diabetes of adults (LADA) 134, 183 LDL (low density lipoprotein) cholesterol 25 and fat intake 13 see also cholesterol 191, 205–208, 225 leptin effect of hyperleptinaemia on adipocytes 224 and tumour necrosis factor-α 204–5 life style modification 10 Diabetes Prevention Program (DPP) 69–70 Diabetes Prevention Study (DPS) 72–3 effect of increased dietary fibre intake 166–7, 184 in management of type 2 diabetes 227–9 in prevention of type 2 diabetes 119 smoking cessation 165–6, 183

258

GENERAL INDEX

see also diet; exercise lipid abnormalities interleukin 6 gene polymorphism 195–6 see also cholesterol; dyslipidaemia; hyperlipidaemia; hypertriglyceridaemia lipid levels dietary manipulation 230–2 effect of niacin (ADMIT study) 104–5 lipoatrophy and surgical implantation of adipose tissue 294 and thiazolidinediones 293–4 lipodystrophic diabetes 294 lipohypertrophy, effect on insulin absorption 47 lisinopril, Candesartan and Lisinopril Microalbuminuria Study 122 lispro insulin see insulin lispro liver cells, effect of PDX-1 291–3 losartan (RENALL study) 122 low birth weight, health risks 260–1 M macrosomia, fetal 5, 36, 39 macrovascular complications effect of transplant surgery 184 and glycaemic control 157–8 progression after transplant surgery 156–7, 184 macular oedema 36 magnesium deficiency 17 Malmo study 63, 73 Malmohus study 63, 73 maltose 15 management of diabetes 1, 5–49 mannitol 15 MAPK8IP1 gene 289–90, 296 maternally inherited diabetes 287–8 maturity onset diabetes of the young (MODY) 247, 265 prevalence of MODY-3 273–4 study of Spanish families 272–3, 295 medical history 7, 8 medical nutrition therapy (MNT) 6, 10–17 Mediterranean -type diet, benefits 178–80 metabolic syndrome, relationship to educational level 174– 7 metformin combination with nateglinide 83, 84 combination with rosiglitazone 78–82

comparison with acarbose 75–6 Diabetes Prevention Program (DPP) 69–70 mechanism ofaction 78 use in polycystic ovary syndrome 216–17 microalbuminuria 10, 32–4 in adolescent type 1 diabetics 161–3 effect of pregnancy 243–4 see also nephropathy microangiopathy, and C-reactive protein 197 MICRO-HOPE substudy 94–5, 121 micronutrients 17 microvascular complications and glycaemic control 157–8, 182–3 effect of intensive therapy 145–7 effect of pregnancy 243–4, 264 effect of ramipril 94–5 risk factors 153–4 see also autonomic neuropathy; nephropathy; neuropathy; peripheral neuropathy; retinopathy minerals 17 MIRKO mice 235 mitochondrial DNA mutations 287–8 mitochondrial glutamate, role in insulin secretion 274–6 mitochondrial uncoupling proteins 226–7 MNT see medical nutrition therapy Modified Diet in Renal Disease Study 12 MODY see maturity onset diabetes of the young mortality, effect of weight loss 232–5 mouse islets, in vitro cultivation 280–1 multiple daily injection (MDI) comparison with CSII 92–4 trial of insulin lispro HM 97–9 muscle tissue, insulin resistance 235 myocardial infarction, Bypass Angioplasty Revascularisation Investigation 147–8 N nateglinide 120 clinical trial 82–4 National Cholesterol Education Program (NCEP) 13 NAVIGATOR trial 120 nephropathy 10, 128 and angiotensin II receptor blockers 121–2 association with pregnancy-induced hypertension and pre-eclampsia 249, 250, 264 and exercise 20 effect of intensive therapy 145–7

GENERAL INDEX

Irbesartan Type II Diabetic Nephropathy Trial (IDNT) 65–7 management 32–4 and pregnancy 32 and protein intake 12–13 effect of ramipril 94 renoprotective effect of ACE inhibitors 65–7, 68, 121, 152 role of transforming growth factor-β (TGF-β) 154–5 see also microalbuminuria; microangiopathy; proteinuria nerve growth factor (NGF) 106–7 NES2Y cells 290–1 neurogenin-3 278–9 neuropathy 123 andexercise 20 andpregnancy 32 use of recombinant nerve growth factor 106–7 see also autonomic neuropathy; peripheral neuropathy niacin, effect on lipid levels (ADMIT study) 104–5 nicotine dependency see smoking; smoking cessation NIDDM-1 284–5, 296 nifedipine, renal effects 67 night-time insulin pump therapy, use in children 99–100 NIRKOmice 225 nitric oxide production 158–9 non-insulin dependant diabetes see type 2 diabetes non-ketotic hyperosmolar hyperglycaemia 42 NPH insulin, comparison with insulin glargine 87–9 nurse-led counselling, role in smoking cessation 165, 166, 183 nutrition see diet; medical nutrition therapy nutritive sweeteners 14–15 O obesity 11, 221 effect of exercise 22 and fat intake 14 and growth hormone secretion 207–8 effect of hyperleptinaemia on adipocytes 224 and insulin resistance in muscle 235 optimal diet in type 2 diabetes 230–2 refractory 12 and resistin 222 as risk factor 5 and type 2 diabetes 191, 237 see also abdominal obesity; weight reduction

259

obesogenic environment 227 octreotide, use in diabetic retinopathy 114–15, 122–3 OGTT see oral glucose tolerance test oleic acid diet, benefits 178–80 Olestra 49 oral glucose tolerance test (OGTT) use in diagnosis 51–3, 58, 59, 139–40, 208–9 of gestational diabetes 38 use in identifying MODY genotypes 273 use in screening 5–6, 246–7 oral hypoglycaemics and pregnancy 30 risk of hypoglycaemia 116–16 see also acarbose; metformin; phenformin; repaglinide; tolbutamide oral insulin administration 100–3 orlistat 191, 237 effect on cardiovascular disease risk 214–15 effect on glucose tolerance 213–14 oxidative stress 193 P pancreatic and duodenal homeobox factor 1 (PDX-1) 290– 3 pancreatic β cells see β cells; islet cells pancreatic transplantation 43–4, 183–4 and progression of macrovascular disease 156–7 effect on retinopathy 149–51 see also islet transplantation pancreatitis risk, role of fat intake 13 pathogenesis of type 1 diabetes 139, 140 of type 2 diabetes 210–11 patient self-monitoring see self-monitoring of blood glucose PDX-1 (pancreatic and duodenal homeobox factor 1) 290– 3 percutaneous transluminal coronary angioplasty (PCTA) 147–8 perinatal morbidity and mortality 251–5 peripheral neuropathy 20, 24 see also neuropathy peripheral vascular disease (PVD) evaluation 18, 24 management 25 progression after transplant surgery 156–7, 184

260

GENERAL INDEX

peroxisomeproliferator-activated receptors (PPARs) 293, 296 polymorphism 282–4 phenformin, use in impaired glucose tolerance 63 phenofibrate 26–7 photocoagulation 36 physical activity see exercise physical examination at initial visit 7–8 at continuing care visits 9–10 offeet 23–4 Pima Indians effects of weight fluctuation 220–1, 237 study of diagnostic criteria 51–3 pioglitazone 204, 117–8 plasma lipids see lipid levels polycystic ovary syndrome 37 use of metformin 216–17 polyneuropathy 123 andexercise 20 use of recombinant nerve growth factor 106–7 see also neuropathy polyols 15 polyunsaturated fat intake 13 poor control use of continuous subcutaneous insulin infusion 48 indications for hospital admission 42 see also glycaemic control post-prandial glycaemic control 63–4, 77–8, 120 and HbA1c 85–7 use of nateglinide 82–4 potassium intake 17 PPARs (peroxisome proliferator-activated receptors) 293, 296 polymorphism 282–4 pre-conception care 29–32 see also pregnancy pre-diabetes and cardiovascular disease risk 201–3 risk of stillbirth and perinatal death 251–3 see also impaired glucose tolerance pre-eclampsia association with severity of diabetes 253–5, 263–4 and glycaemic control 249–51, 264 risk in gestational diabetes 36 screening 244–6, 264 pre-gestational diabetes, risks of adverse neonatal outcome and pre-eclampsia 253–5 pregnancy 3, 55, 56, 120

ambulatory blood pressure monitoring 244–6, 264 congenital anomalies 255–8 continuous subcutaneous insulin infusion 48, 262–3, 264 and insulin lispro 259–60 medical nutrition therapy 17 effect on microvascular complications 243–4, 264 pre-eclampsia risk and glycaemic control 249–51 preparation for 29–32 risk of pre-diabetes 251–3 risk of pre-gestational diabetes 253–5 screening for retinopathy 36 see also gestational diabetes pregnancy-induced hypertension and glycaemic control 249–51 screening for 244–6, 264 prevention of type 2 diabetes 119 Diabetes Prevention Study (DPS) 72–3 Diabetes Prevention Program (DPP) 69–70 role of exercise 167–8 role of orlistat 213–14 STOP-NIDDM trial 70–1 PRIME study 121 protective mechanism loss 20 protein intake 12–13 restriction in nephropathy 10 proteinuria 33 in pregnancy, neonatal outcome 254, 255, 263 see also microalbuminuria; nephropathy Q Q310X mutation 288–9, 296 questionnaires, role in screening for diabetes 6 R racial risk factors 5 for gestational diabetes 37 ramipril 121 DIABHYCAR study 67–8 HOPE and MICRO-HOPE studies 94–5 see also ACE inhibitors recombinant adenoassociated virus (rAAV), use in gene therapy 282 recombinant human nerve growth factor 106–7, 123 refractory obesity 12 see also abdominal obesity; obesity; weight reduction renal transplantation 43, 183–4 and progression of macrovascular disease 156–7

GENERAL INDEX

RENALL study 122 repaglinide 89–92, 115–16, 120 resistin 191, 222, 225 retinal examination 10 retinopathy association with pregnancy-induced hypertension and pre-eclampsia 249, 250, 264 and glycaemic control 183 and insulin lispro in pregnancy 259–60 effect of intensive therapy 145–7 use of octreotide 114–15, 122–3 effect of pancreas and kidney transplantation 149–51 effect of pregnancy 243–4, 264 risks of exercise 18, 19 screening 35–6 effect of transplant surgery 183–4 risk factors for asymptomatic bacteriuria in women 160, 161 C-reactive protein 197, 198–9, 236 for complications of diabetes 119–20 for foot ulceration 155–6 for gestational diabetes 37 hyperhomocysteinaemia 193–4, 236 hyperinsulinaemia cluster 200–1 low cardio respiratory fitness 167–8 for microvascular complications 153–4 for type 2 diabetes 5, 6, 58, 72 Von Willebrand factor 198–9 rosiglitazone 204 combination with metformin 78–82 mechanism of action 78 effect on resistin levels 222 side effects 81 S S6 kinase 1 (S6K1) 276–7 saccharin 15 San Antonio Heart Study 190–1 saturated fat intake 13–14 screening for albuminuria 33–4 for diabetes 58, 59 type 2 5–6 role of fasting blood glucose 208–9 for gestational diabetes 37–8 role of glucose tolerance test 208–9 use of islet cell antibodies 139 for pregnancy induced hypertension 244–6, 264 for retinopathy 35–6 for risk of foot ulceration 155–6

261

see also diagnostic criteria self-monitoring of blood glucose (SMBG) 6, 40 accuracy of glucose meters 169 SHIP2 (SH2 domain-containing inositol 5- phosphatase) and insulin sensitivity 285–6 SIA (single-chain insulin analogue), use in gene therapy 282 sibutramine 191, 217–20, 238 sildenafil 110–11 simvastatin 107–10 single-chain insulin analogue (SIA), use in gene therapy 282 sirolimus, use in islet transplantation 271 SMBG see self-monitoring of blood glucose smoking 28– 9 smoking cessation 165–6, 183 socio-economic status, and risk of metabolic syndrome 174–7 sodium intake 15–16 somatostatin, use in diabetic retinopathy 114, 115 sorbitol 15 standards of care 6–10 statins use in hypertriglyceridaemia 27 use in type 2 diabetics 107–10 stem cells 279, 292 use in in vitro islet cultivation 280–1 stillbirth risk and pre-diabetes 251–3 Stockholm Diabetes Intervention Study 146 STOP-NIDDM trial 70–1 sucralose 15 sucrose 14 sugar alcohols 15 sugar intake 14 sulphonylureas, risk of hypoglycaemia 115–16 surgical treatment of obesity 12 Swedish Multimorbidity Study 214–15 sweeteners 14–15 syndrome X 197 T tacrolimus, use in islet transplantation 271 âTC3 cells 288, 289 TGF-β (transforming growth factor-β1) 152, 154–5 thiazide diuretics and type 2 diabetes risk 199–200 thiazolidinediones 69–70, 202–4 actions in mice with lipoatrophy 293–4 and resistin 222 see also pioglitazone

262

GENERAL INDEX

thymus, antigen-presenting cells 140–1 TNF-α see tumour necrosis factor-α tobacco addiction see smoking; smoking cessation tolbutamide, use in impaired glucose tolerance 63, 73 transforming growth factor-β1 (TGF-β1) 152, 154–5 transplant surgery 43–4, 183–4 adipose tissue transplantation in lipodystrophic diabetes 294 islet transplantation 271–2 and progression of macrovascular disease 156–7 effect on retinopathy 149–51 treatment aims 6, 7 tricyclic antidepressants, use in neuropathy 123 triglyceride levels and fat intake 13 effect of niacin (ADMIT study) 104–5 as risk factor 5 see also hypertriglyceridaemia troglitazone 69–70, 202–4 tumour necrosis factor 197 tumour necrosis factor-oc receptor 2 gene polymorphism 204–5 24 hour blood pressure measurement see ambulatory blood pressure monitoring type 1 diabetes in adolescents 161–2 aetiology 181–2 and age of onset 135–6 asymptomatic 139–40 autoantibody negative 129–31, 273–4, 295 differences between adult and childhood onset 135–6 andexercise 22 gene therapy 282 incidence 181 inchildhood 131–3 and insulin resistance 141 and medical nutrition therapy 11 pathogenesis 139, 140 effects of pregnancy 243–4 prevalence of MODY-3 273–4, 295 prevalence of white coat hypertension 148–9 risk factors for micro-angiopathy 153–4 screening for retinopathy 35 urine ketone determination 40–1 type 1B diabetes 129–31 type 2 diabetes 55 aetiology 189 and antihypertensives 199–200 association with hepatitis C 197–8

association with weight at birth 260–1 benefits of exercise 167–9 benefits of Mediterranean-type diet 178–80 blood pressure and risk of vascular complications 151– 3 and calpain-10 284–5 cardiovascular disease risk 189–90, 200–1, 236 classification 189 and congenital anomalies 255–8 and diet 166–7, 184, 230–2 and exercise 21–3 and hyperhomocysteinaemia 193–4, 236 life style modification 227–9 and medical nutrition therapy 12 morbidity and mortality 119 and obesity 222–3, 237 see also abdominal obesity pathogenesis 210–11 and PPAR-γ polymorphism 282–4 prevention see prevention of type 2 diabetes risk factors 5, 6, 58, 72 screening for 5–6 screening for retinopathy 35 U ultralente insulin, use in type 2 diabetes 112–13 uncoupling proteins (UCPs) 226–7 United Kingdom Prospective Diabetic Study (UKPDS) 127, 128, 151–2 urinalysis 33–4 role in glycaemic control 40–1 urinary albumin excretion levels, and white coat hypertension 148, 149 urine ketone determination 40–1 V vascular disease role of hyperhomocysteinaemia 193–4, 236 see also cardiovascular disease risk; peripheral vascular disease very low-calorie diets 228, 229 Viagra (sildenafil) 110–11 viruses, role in aetiology of type 1 diabetes 182 visceral adiposity see abdominal obesity vitamins 17 vitreoretinal surgery 36 VLDL (very low-density lipoprotein) cholesterol, and fat intake 13

GENERAL INDEX

Von Willebrand factor, association with mortality 198–9, 236 W weight fluctuations, effects on insulin action and secretion 220–1, 237 weight reduction 221 advantages 12 fat substitutes 48–9 in gestational diabetes 39 effect on mortality 232–5 use of orlistat 191, 213–15, 237 use of sibutramine 217–20, 238 role of uncoupling proteins 226–7 see also abdominal obesity; medical nutrition therapy; obesity white coat hypertension, prevalence 148–9 Whitehall study 63, 72 World Health Organization (WHO) criteria for diagnosis 51–3, 208–9, 246–7, 265 White’s classification of diabetes 256 X xylitol 15

263