Insulin Resistance - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References

INSULIN RESISTANCE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES ...

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INSULIN

RESISTANCE A M EDICAL D ICTIONARY , B IBLIOGRAPHY , AND A NNOTATED R ESEARCH G UIDE TO I NTERNET R E FERENCES

J AMES N. P ARKER , M.D. AND P HILIP M. P ARKER , P H .D., E DITORS

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ICON Health Publications ICON Group International, Inc. 4370 La Jolla Village Drive, 4th Floor San Diego, CA 92122 USA Copyright 2004 by ICON Group International, Inc. Copyright 2004 by ICON Group International, Inc. All rights reserved. This book is protected by copyright. No part of it may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, recording, or otherwise, without written permission from the publisher. Printed in the United States of America. Last digit indicates print number: 10 9 8 7 6 4 5 3 2 1

Publisher, Health Care: Philip Parker, Ph.D. Editor(s): James Parker, M.D., Philip Parker, Ph.D. Publisher's note: The ideas, procedures, and suggestions contained in this book are not intended for the diagnosis or treatment of a health problem. As new medical or scientific information becomes available from academic and clinical research, recommended treatments and drug therapies may undergo changes. The authors, editors, and publisher have attempted to make the information in this book up to date and accurate in accord with accepted standards at the time of publication. The authors, editors, and publisher are not responsible for errors or omissions or for consequences from application of the book, and make no warranty, expressed or implied, in regard to the contents of this book. Any practice described in this book should be applied by the reader in accordance with professional standards of care used in regard to the unique circumstances that may apply in each situation. The reader is advised to always check product information (package inserts) for changes and new information regarding dosage and contraindications before prescribing any drug or pharmacological product. Caution is especially urged when using new or infrequently ordered drugs, herbal remedies, vitamins and supplements, alternative therapies, complementary therapies and medicines, and integrative medical treatments. Cataloging-in-Publication Data Parker, James N., 1961Parker, Philip M., 1960Insulin Resistance: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References / James N. Parker and Philip M. Parker, editors p. cm. Includes bibliographical references, glossary, and index. ISBN: 0-597-84468-2 1. Insulin Resistance-Popular works. I. Title.

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Disclaimer This publication is not intended to be used for the diagnosis or treatment of a health problem. It is sold with the understanding that the publisher, editors, and authors are not engaging in the rendering of medical, psychological, financial, legal, or other professional services. References to any entity, product, service, or source of information that may be contained in this publication should not be considered an endorsement, either direct or implied, by the publisher, editors, or authors. ICON Group International, Inc., the editors, and the authors are not responsible for the content of any Web pages or publications referenced in this publication.

Copyright Notice If a physician wishes to copy limited passages from this book for patient use, this right is automatically granted without written permission from ICON Group International, Inc. (ICON Group). However, all of ICON Group publications have copyrights. With exception to the above, copying our publications in whole or in part, for whatever reason, is a violation of copyright laws and can lead to penalties and fines. Should you want to copy tables, graphs, or other materials, please contact us to request permission (E-mail: [email protected]). ICON Group often grants permission for very limited reproduction of our publications for internal use, press releases, and academic research. Such reproduction requires confirmed permission from ICON Group International, Inc. The disclaimer above must accompany all reproductions, in whole or in part, of this book.

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Acknowledgements The collective knowledge generated from academic and applied research summarized in various references has been critical in the creation of this book which is best viewed as a comprehensive compilation and collection of information prepared by various official agencies which produce publications on insulin resistance. Books in this series draw from various agencies and institutions associated with the United States Department of Health and Human Services, and in particular, the Office of the Secretary of Health and Human Services (OS), the Administration for Children and Families (ACF), the Administration on Aging (AOA), the Agency for Healthcare Research and Quality (AHRQ), the Agency for Toxic Substances and Disease Registry (ATSDR), the Centers for Disease Control and Prevention (CDC), the Food and Drug Administration (FDA), the Healthcare Financing Administration (HCFA), the Health Resources and Services Administration (HRSA), the Indian Health Service (IHS), the institutions of the National Institutes of Health (NIH), the Program Support Center (PSC), and the Substance Abuse and Mental Health Services Administration (SAMHSA). In addition to these sources, information gathered from the National Library of Medicine, the United States Patent Office, the European Union, and their related organizations has been invaluable in the creation of this book. Some of the work represented was financially supported by the Research and Development Committee at INSEAD. This support is gratefully acknowledged. Finally, special thanks are owed to Tiffany Freeman for her excellent editorial support.

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About the Editors James N. Parker, M.D. Dr. James N. Parker received his Bachelor of Science degree in Psychobiology from the University of California, Riverside and his M.D. from the University of California, San Diego. In addition to authoring numerous research publications, he has lectured at various academic institutions. Dr. Parker is the medical editor for health books by ICON Health Publications. Philip M. Parker, Ph.D. Philip M. Parker is the Eli Lilly Chair Professor of Innovation, Business and Society at INSEAD (Fontainebleau, France and Singapore). Dr. Parker has also been Professor at the University of California, San Diego and has taught courses at Harvard University, the Hong Kong University of Science and Technology, the Massachusetts Institute of Technology, Stanford University, and UCLA. Dr. Parker is the associate editor for ICON Health Publications.

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About ICON Health Publications To discover more about ICON Health Publications, simply check with your preferred online booksellers, including Barnes&Noble.com and Amazon.com which currently carry all of our titles. Or, feel free to contact us directly for bulk purchases or institutional discounts: ICON Group International, Inc. 4370 La Jolla Village Drive, Fourth Floor San Diego, CA 92122 USA Fax: 858-546-4341 Web site: www.icongrouponline.com/health

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Table of Contents FORWARD .......................................................................................................................................... 1 CHAPTER 1. STUDIES ON INSULIN RESISTANCE ................................................................................ 3 Overview........................................................................................................................................ 3 The Combined Health Information Database................................................................................. 3 Federally Funded Research on Insulin Resistance ....................................................................... 16 E-Journals: PubMed Central ....................................................................................................... 76 The National Library of Medicine: PubMed ................................................................................ 79 CHAPTER 2. NUTRITION AND INSULIN RESISTANCE .................................................................... 129 Overview.................................................................................................................................... 129 Finding Nutrition Studies on Insulin Resistance...................................................................... 129 Federal Resources on Nutrition ................................................................................................. 135 Additional Web Resources ......................................................................................................... 135 CHAPTER 3. DISSERTATIONS ON INSULIN RESISTANCE................................................................ 137 Overview.................................................................................................................................... 137 Dissertations on Insulin Resistance........................................................................................... 137 Keeping Current ........................................................................................................................ 138 CHAPTER 4. CLINICAL TRIALS AND INSULIN RESISTANCE .......................................................... 139 Overview.................................................................................................................................... 139 Recent Trials on Insulin Resistance........................................................................................... 139 Keeping Current on Clinical Trials ........................................................................................... 150 CHAPTER 5. PATENTS ON INSULIN RESISTANCE .......................................................................... 153 Overview.................................................................................................................................... 153 Patents on Insulin Resistance .................................................................................................... 153 Patent Applications on Insulin Resistance ................................................................................ 169 Keeping Current ........................................................................................................................ 200 CHAPTER 6. BOOKS ON INSULIN RESISTANCE .............................................................................. 201 Overview.................................................................................................................................... 201 Book Summaries: Federal Agencies............................................................................................ 201 Book Summaries: Online Booksellers......................................................................................... 202 Chapters on Insulin Resistance.................................................................................................. 204 CHAPTER 7. MULTIMEDIA ON INSULIN RESISTANCE ................................................................... 207 Overview.................................................................................................................................... 207 Video Recordings ....................................................................................................................... 207 Audio Recordings....................................................................................................................... 210 CHAPTER 8. PERIODICALS AND NEWS ON INSULIN RESISTANCE ................................................ 211 Overview.................................................................................................................................... 211 News Services and Press Releases.............................................................................................. 211 Newsletter Articles .................................................................................................................... 215 Academic Periodicals covering Insulin Resistance .................................................................... 217 APPENDIX A. PHYSICIAN RESOURCES .......................................................................................... 221 Overview.................................................................................................................................... 221 NIH Guidelines.......................................................................................................................... 221 NIH Databases........................................................................................................................... 223 Other Commercial Databases..................................................................................................... 225 The Genome Project and Insulin Resistance.............................................................................. 225 APPENDIX B. PATIENT RESOURCES ............................................................................................... 229 Overview.................................................................................................................................... 229 Patient Guideline Sources.......................................................................................................... 229 Finding Associations.................................................................................................................. 233 APPENDIX C. FINDING MEDICAL LIBRARIES ................................................................................ 237 Overview.................................................................................................................................... 237

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Preparation................................................................................................................................. 237 Finding a Local Medical Library................................................................................................ 237 Medical Libraries in the U.S. and Canada ................................................................................. 237 ONLINE GLOSSARIES................................................................................................................ 243 Online Dictionary Directories ................................................................................................... 243 INSULIN RESISTANCE DICTIONARY................................................................................... 245 INDEX .............................................................................................................................................. 319

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FORWARD In March 2001, the National Institutes of Health issued the following warning: "The number of Web sites offering health-related resources grows every day. Many sites provide valuable information, while others may have information that is unreliable or misleading."1 Furthermore, because of the rapid increase in Internet-based information, many hours can be wasted searching, selecting, and printing. Since only the smallest fraction of information dealing with insulin resistance is indexed in search engines, such as www.google.com or others, a non-systematic approach to Internet research can be not only time consuming, but also incomplete. This book was created for medical professionals, students, and members of the general public who want to know as much as possible about insulin resistance, using the most advanced research tools available and spending the least amount of time doing so. In addition to offering a structured and comprehensive bibliography, the pages that follow will tell you where and how to find reliable information covering virtually all topics related to insulin resistance, from the essentials to the most advanced areas of research. Public, academic, government, and peer-reviewed research studies are emphasized. Various abstracts are reproduced to give you some of the latest official information available to date on insulin resistance. Abundant guidance is given on how to obtain free-of-charge primary research results via the Internet. While this book focuses on the field of medicine, when some sources provide access to non-medical information relating to insulin resistance, these are noted in the text. E-book and electronic versions of this book are fully interactive with each of the Internet sites mentioned (clicking on a hyperlink automatically opens your browser to the site indicated). If you are using the hard copy version of this book, you can access a cited Web site by typing the provided Web address directly into your Internet browser. You may find it useful to refer to synonyms or related terms when accessing these Internet databases. NOTE: At the time of publication, the Web addresses were functional. However, some links may fail due to URL address changes, which is a common occurrence on the Internet. For readers unfamiliar with the Internet, detailed instructions are offered on how to access electronic resources. For readers unfamiliar with medical terminology, a comprehensive glossary is provided. For readers without access to Internet resources, a directory of medical libraries, that have or can locate references cited here, is given. We hope these resources will prove useful to the widest possible audience seeking information on insulin resistance. The Editors

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From the NIH, National Cancer Institute (NCI): http://www.cancer.gov/cancerinfo/ten-things-to-know.

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CHAPTER 1. STUDIES ON INSULIN RESISTANCE Overview In this chapter, we will show you how to locate peer-reviewed references and studies on insulin resistance.

The Combined Health Information Database The Combined Health Information Database summarizes studies across numerous federal agencies. To limit your investigation to research studies and insulin resistance, you will need to use the advanced search options. First, go to http://chid.nih.gov/index.html. From there, select the “Detailed Search” option (or go directly to that page with the following hyperlink: http://chid.nih.gov/detail/detail.html). The trick in extracting studies is found in the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Journal Article.” At the top of the search form, select the number of records you would like to see (we recommend 100) and check the box to display “whole records.” We recommend that you type “insulin resistance” (or synonyms) into the “For these words:” box. Consider using the option “anywhere in record” to make your search as broad as possible. If you want to limit the search to only a particular field, such as the title of the journal, then select this option in the “Search in these fields” drop box. The following is what you can expect from this type of search: •

Is Insulin Sensitivity a Causal Intermediate in the Relationship Between Alcohol Consumption and carotid Atherosclerosis?: The Insulin Resistance and Atherosclerosis Study Source: Diabetes Care. 25(8): 1425=1431. August 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: An association has been demonstrated between alcohol consumption and atherosclerosis. Insulin resistance, also a risk factor for atherosclerosis, has been shown to have a similar association with alcohol intake. This raises the question of whether insulin sensitivity is a causal intermediate in the alcohol-atherosclerosis relationship. This article reports on the Insulin Resistance Atherosclerosis Study, a multicenter

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cohort study designed to investigate relationships among insulin sensitivity, risk factors for cardiovascular disease, and carotid artery atherosclerosis. A J-shaped association was observed between alcohol consumption and common carotid artery intimal medial thickness. The protective aspect of the alcohol-atherosclerosis relationship was attenuated by 25 percent after the adjustment for insulin sensitivity. However, an interaction was observed between alcohol consumption and glucose tolerance (GT) status. In comparison with never-drinkers, all levels of alcohol consumption were associated with less atherosclerosis in participants with normal GT status. Participants with impaired GT status (but not diabetes) demonstrated a J-shaped alcoholatherosclerosis association. All levels of alcohol consumption were association with more atherosclerosis in participants with diabetes. These findings contrast with previous reports and do not support current recommendations regarding moderate alcohol consumption in people with diabetes. The authors call for more research to clarify this issue. 2 figures. 1 table. 43 references. •

Factor Analysis of Metabolic Syndrome Using Directly Measured Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study Source: Diabetes. 51(7): 2642-2647. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Factor analysis, a multivariate correlation technique, has been used to provide insight into the underlying structure of metabolic syndrome, which is characterized by physiological complexity and strong statistically intercorrelation among its key variables. This article reports on a study that investigated, using factor analysis, the clustering of physiologic variables using data from 1,087 nondiabetic participants in the Insulin Resistance Atherosclerosis Study (IRAS). This study includes information on the directly measured insulin sensitivity index from intravenous glucose tolerance testing among African-American, Hispanic, and non-Hispanic white subjects aged 40 to 69 years at various stages of glucose tolerance. Factor analysis identified two underlying factors among a group of metabolic syndrome variables in this dataset. Analyses using surrogate measures of insulin resistance suggested that these variables provide adequate information to explore the underlying intercorrelational structure of metabolic syndrome. Additional clarification of the physiologic characteristics of metabolic syndrome is required as individuals with this condition are increasingly being considered candidates for behavioral and pharmacologic (drug) intervention. 6 tables. 38 references.

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Glucose Intolerance and Insulin Resistance in Aging is Related to Abdominal Obesity Source: Diabetes Spectrum. 6(4): 262-263. July-August 1993. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: In this article, the author considers recent findings that glucose intolerance and insulin resistance in aging are related to abdominal obesity. She stresses that some conditions often thought of as inevitable results of aging may instead be avoidable effects of fat accumulation. Topics include abdominal fat as a risk factor for developing glucose intolerance, insulin resistance, dyslipidemia, and hypertension; the link between abdominal obesity and the development of NIDDM and cardiovascular disease (CVD); sex and age factors; modest changes in body composition and their effects on

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glucose metabolism; the relationship between deteriorations in glucose tolerance and insulin resistance; and the possibility that monitoring a simple measure, such as waist size, may lead to early recognition of risk for NIDDM and CVD. 10 references. •

Insulin Resistance: An often Unrecognized Problem Accompanying Chronic Medical Disorders Source: Postgraduate Medicine. 93(7): 99-107. May 15, 1993. Summary: In this article, the author examines the implications of lifestyle factors in planning treatment regimens for patients with one or more chronic disorders associated with insulin resistance, such as hypertension and noninsulin-dependent diabetes (NIDDM). Lifestyle factors considered include obesity, inactivity, smoking, hyperglycemia, and use of certain antihypertensive drugs. The author also discusses the association of insulin resistance with a number of risk factors for atherosclerosis, including glucose intolerance, hypertension, and dyslipidemia. One sidebar discusses a cutaneous marker of insulin resistance, acanthosis nigricans. 57 references. (AA-M).

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Psychological Insulin Resistance: A Challenge for Diabetes Patients and Health Professionals Source: Today's Therapeutic Trends: Journal of New Developments in Clinical Medicine. 13(1): 21-27. 1995. Contact: Available from Communications Media for Education, Inc. P.O. Box 712, Princeton Junction, NJ 08550. Summary: In this article, the authors explore the phenomenon of psychological insulin resistance (PIR), the occurrence of patient resistance to the initiation of insulin therapy as part of the management of noninsulin dependent diabetes mellitus (NIDDM). The authors note that PIR on the part of the diabetes patient may be unconsciously shared as well by members of the diabetes health care team (DHC). The authors discuss identifying PIR and its causes; overcoming PIR, with confrontation, persistence, and reality checks; concerns and fears regarding insulin therapy; the role of appropriate dietary strategies; and the importance of considering insulin therapy not as a strategy of last resort, but rather as a frequent consequence of the natural history of NIDDM. 2 references.

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Insulin Resistance or Insulin Deficiency: Which is the Primary Cause of NIDDM? Source: Diabetes. 43(6): 735-740. June 1994. Summary: In this article, the authors review the evidence supporting the balanced theory that both insulin resistance and insulin deficiency contribute to the pathogenesis of NIDDM, but that the relative importance of each factor may vary from patient to patient. After a brief discussion of the controversies in this area, the authors discuss insulin resistance and insulin deficiency in patients with established hyperglycemia and the areas of controversy, including identifying prediabetic individuals, the vicious cycle of insulin resistance and insulin deficiency, the difficulty in designing relevant tests of physiological function, and NIDDM as a syndrome of multiple diseases with different causes. The last section of the article describes the lessons that can be gleaned from molecular genetics and applied to this controversy. 1 figure. 1 table. 38 references.

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Insulin Resistance, the Metabolic Syndrome, and Risk of Incident Cardiovascular Disease in Nondiabetic American Indians Source: Diabetes Care. 26(3): 861-867. March 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Insulin resistance (IR) and the metabolic syndrome (MS) are associated with type 2 diabetes and adverse cardiovascular disease (CVD) risk factor profiles. Whether IR and MS predict CVD independently of diabetes and other CVD risk factors is not known. This article reports on a study that examines whether IR or presence of MR are independently associated with CVD in nondiabetic American Indians (AI). The authors examined 2,283 nondiabetic AI who were free of CVD at the baseline examination of the Strong Heart Study (SHS). CVD risk factors were measured, IR was quantified using the homeostasis model assessment (HOMA), and MS was assessed for each participant. Incident (new) CVD and diabetes were ascertained during follow up. MS was present in 798 individuals (35 percent), and 181 participants (7.9 percent) developed CVD over 7.6 years (plus or minus 1.8 years) of follow up. Age, body mass index (BMI), waist circumference, and triglyceride levels increased and HDL cholesterol decreased across tertiles of HOMA-IR. Risk of diabetes increased as a function of baseline HOMA-IR and MS. In analyses adjusted for CVD risk factors, risk of CVD did not increase either as a function of baseline HOMA-IR or MS, but individual CVD risk factors predicted subsequent CVD. 2 figures. 4 tables. 35 references.

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Deadly Quartet: The Insulin Resistance Syndrome Source: Southern Medical Journal. 90(12): 1162-1168. December 1997. Contact: Available from Southern Medical Association. 35 Lakeshore Drive, Birmingham, AL 35209. (205) 945-1840. Summary: Obesity, type 2 diabetes, hypertension, and dyslipidemia ('the deadly quartet' or syndrome X) are common metabolic disorders that predispose individuals to early cardiovascular disease. In this review article, the authors examine the relationship between insulin resistance and 'the deadly quartet', review the literature, and address therapeutic implications. The article notes that coronary atherosclerosis accounts for 77 percent of hospitalizations due to diabetic complications. Options for preventing and treating 'the deadly quartet' include diet modification, weight loss, exercise, and oral agents such as sulfonylurea, metformin, acarbose, and troglitazone. The authors conclude that increased understanding and more effective prevention and treatment of obesity should have a major impact on reducing the development of 'the deadly quartet.' 5 figures. 50 references. (AA-M).

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Longitudinal study on Pubertal Insulin Resistance Source: Diabetes. 50(11): 2444-2450. November 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Previous cross-sectional studies show that puberty is associated with a reduction in insulin sensitivity (Si), but no longitudinal studies have examined this change in detail. This article reports on a longitudinal study in 60 children (33 male and 27 female subjects; 32 Caucasian and 28 African American) examined at Tanner stage I (age 9.2 years, plus or minus 1.4 years) and after 2.0 years (plus or minus 0.6 years) of

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follow up. At follow up, 29 children remained at Tanner stage I and 31 had progressed to Tanner stage III or IV. Tanner stage was assessed by physical examined. Si, the acute insulin response (AIR), and the disposition index (DI) were determined by the tolbutamide modified intravenous glucose tolerance test and minimal modeling, body fat mass and visceral fat were assessed, and fasting blood was analyzed for hormone levels. In children progressing to Tanner stage III, Si fell significantly by 32 percent, AID increased by 30 percent, DI fell by 27 percent, and there was a significant increase in fasting glucose and insulin. In children remaining at Tanner stage I, there was a slight increase in Si with no significant change in AIR or fasting glucose and insulin. The pubertal fall in Si was more consistent in African Americans; remained significant after controlling for age, sex, and change in fat mass, visceral fat, and fat free mass; and was similar in children at low, medium, and high body fat. The significant fall in DI suggests conservation in beta cell function or an inadequate beta cell response to the fall in Si. The fall in Si was not associated with changes in body fat, visceral fat, IGF I, androgens, or estradiol. 1 figure. 3 tables. 33 references. •

Homeostasis Model Assessment of Insulin Resistance in Relation to the Incidence of Cardiovascular Disease: The San Antonia Heart Study Source: Diabetes Care. 25(7): 1177-1184. July 2002. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: The prospective association between insulin levels and risk of cardiovascular disease (CVD) is controversial. The objective of the study reported in this article was to investigate the relationship of the homeostasis model assessment of insulin resistance (HOMA-IR), as well as insulin levels, with risk of nonfatal and fatal CVD over the 8 year follow-up of the San Antonio Heart Study. Between 1984 and 1988, randomly selected Mexican-American and nonHispanic white residents of San Antonio participated in baseline examinations that included fasting blood samples for glucose, insulin, and lipids, a glucose tolerance test, anthropometric measurements, and a lifestyle questionnaire. Between 1991 and 1996, 2,569 subjects who were free of diabetes at baseline were reexamined using the same protocol. Over the follow up period, 187 subjects experienced an incident cardiovascular event (heart attack, heart surgery, angina, or CVD death). The authors found a significant association between HOMA-IR and risk of CVD, after adjustment for multiple covariates. The topic remains controversial, however, and additional studies are required, particularly among women and minority populations. 3 figures. 3 tables. 41 references.

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Reducing Insulin Resistance (debate) Source: Practical Diabetology. 17(1): 14-16, 19-22. March 1998. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923. Summary: The question of insulin resistance, hyperinsulinemia, and their roles in macrovascular disease is one that has puzzled diabetes researchers for decades. These paired articles present opposing viewpoints regarding the reduction of insulin resistance. A brief introduction to the articles poses two central questions: Does insulin resistance cause vascular disease, or is it the result of hyperinsulinemia? If hyperinsulinemia is a causative agent, is it only endogenous hyperinsulinemia, or does exogenous insulin have the same effect? The authors of the first article conclude that insulin sensitizers that reduce insulin resistance do not provide superior glycemic

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control. In addition, they argue that these insulin sensitizers have not been proven to reduce cardiovascular risk in people with type 2 diabetes. They instead advocate the use of established, less expensive methods to control glucose levels and reduce cardiovascular risk. The author of the second article argues the opposite: insulin sensitizers, rather than insulin, provide adequate glycemic control and reduce cardiovascular risk in people with type 2 diabetes. The editor does not resolve the debate, choosing instead to let readers decided. 1 figure. 48 references. •

Insulin Resistance and Insulin Secretory Dysfunction as Precursors of Non-InsulinDependent Diabetes Mellitus: Prospective Studies of Pima Indians Source: New England Journal of Medicine. 329(27): 1988-1992. December 30, 1993. Summary: The relative roles of obesity, insulin resistance, insulin secretory dysfunction, and excess hepatic glucose production in the development of noninsulindependent diabetes mellitus (NIDDM) are controversial. In this article, the authors report on a prospective study conducted to determine which of these factors predicted the development of NIDDM in a group of Pima Indians. A body-composition assessment, oral and intravenous glucose-tolerance tests, and a hyperinsulinemiceuglycemic clamp study were performed in 100 non-diabetic Pima Indians (87 women and 113 men; mean age 26 plus or minus 6 years); the subjects were followed yearly thereafter for an average of 5.3 years. Results showed that diabetes developed in 38 subjects during follow-up. The authors conclude that insulin resistance is a major risk factor for the development of NIDDM and a low acute insulin response to glucose is an additional but weaker risk factor. 2 figures. 1 table. 32 references. (AA-M).

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Counseling Patients With Type 2 Diabetes and Insulin Resistance in the Outpatient Setting Source: Diabetes Educator. 28(6): 938,940-943,947-950,952-954,956-957. NovemberDecember 2002. Contact: Available from American Association of Diabetes Educators (AADE). 100 West Monroe Street, 4th Floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: The task of self management of diabetes can be daunting for patients because it requires making significant lifestyle and behavioral changes and involves frequent visits to health care professionals, regular blood glucose monitoring, complex drug regimens, and vigilant treatment of complications. This article describes the role of counseling for patients with type 2 diabetes and insulin resistance, to provide the essential support and encouragement for patients to successfully manage their disease. The article focuses on insulin resistance which, besides being a leading risk factor for type 2 diabetes, is also associated with hypertension, dyslipidemia, obesity, and cardiovascular disease. Making lifestyle changes can reduce insulin resistance and help prevent the onset of diabetes. For those with type 2 diabetes, treatment with insulinsensitizing drugs, such as the TZDs and biguanides, can improve glycemic control and prevent some of the adverse consequences of the disease. Adherence to both lifestyle and medication regimens is very important and should be actively supported by all members of the health care team. 2 figures. 8 tables. 52 references.

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Birth Weight, Type 2 Diabetes, and Insulin Resistance in Pima Indian Children and Young Adults Source: Diabetes Care. 22(6): 944-950. June 1999.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a population-based study that investigated the mechanisms underlying the association between birth weight and type 2 diabetes in 3,061 Pima Indians age 5 to 29 years. Glucose and insulin concentrations were measured during a 75-gram oral glucose tolerance test, and insulin resistance was estimated according to the homeostatic model. Relationships between birth weight, height, weight, fasting and postload concentrations of glucose and insulin, and homeostasis model assessment-insulin resistance (HOMA-IR) were examined with multiple regression analyses. The study found that birth weight was positively related to current weight and height. The 2-hour glucose concentrations showed a U-shaped relationship with birth weight in subjects older than 10 years, and this relation was independent of current body size. The highest mean insulin levels were observed in subjects who were lightest at birth but who had the greatest weight for height in childhood, adolescence, or adulthood. In 2,272 nondiabetic subjects, after adjustment for weight and height, fasting and 2-hour insulin concentrations and HOMA-IR were negatively correlated with birth weight. The article concludes that low birth weight Pimas are thinner at ages 5 to 29, yet they are more insulin resistant relative to their body size than those of normal birth weight. By contrast, those with high birth weight are more obese but less insulin resistant relative to their body size. The insulin resistance of low birth weight Pima Indians may explain their increased risk for type 2 diabetes. 5 figures. 2 tables. 27 references. (AA-M). •

Insulin Resistance and Insulin Secretory Dysfunction Are Independent Predictors of Worsening of Glucose Tolerance During Each Stage of Type 2 Diabetes Development Source: Diabetes Care. 24(1): 89-94. January 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article describes a study that assessed the predictive effect of insulin resistance and insulin secretory dysfunction separately for the progression from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and from IGT to diabetes. Insulin-stimulated glucose disposal (M), acute insulin secretory response (AIR), and body composition were measured in 254 Pima Indians with NGT and in 145 Pima Indians with IGT, who were then followed for 0.5 to 13 years. The study found that, after followups of 4.4 plus or minus 3.1 and 5.5 plus or minus 3.4 years, 79 of the subjects with initial NGT had developed IGT, and 64 of the subjects with initial IGT had developed diabetes. In proportional hazards analyses with adjustment for age, gender, and percent body fat, low M and low AIR were independent predictors of both the progression from NGT to IGT and from IGT to diabetes. The article concludes that, during each stage of the development of type 2 diabetes, insulin resistance and insulin secretory dysfunction are independent predictors of worsening glucose tolerance and are, therefore, both targets for the primary prevention of the disease. 1 figure. 2 tables. 20 references. (AA-M).

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Insulin Resistance: A Model for Patient Education Source: Practical Diabetology. 19(4): 37-41. December 2000. Contact: Available from R.A. Rapaport Publishing, Inc. 150 West 22nd Street, New York, NY 10011. (800) 234-0923.

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Summary: This article describes various teaching tools that health professionals can use to educate patients who have type 2 diabetes about their disease. One tool is a diagram that graphically illustrates that managing diabetes involves more than just blood glucose control. Diabetes management also includes managing weight and reaching target goals for both blood pressure and blood lipids. Some people who are insulin resistant cannot see the scope of their problem when every measured blood glucose value is within range, so another tool is an illustration that can help the patient recognize that blood glucose is maintained within range at the expense of overworked beta cells. Another illustration can be used to help educators focus their discussion on what strategies the patient can use to reduce insulin resistance and the burden on the overworked beta cells. Other illustrations can be used to depict what happens when the beta cells cannot produce enough insulin to meet the demands of the insulin resistant patient's body and to help the patient understand that the treatment of type 2 diabetes may require drugs that either increase inulin or provide more insulin. A final illustration can be used to initiate discussion about the nonpharmacologic strategies used to treat diabetes and help the patient identify members of his support system. 7 figures. 7 references. •

Syndrome X: Syndrome X Insulin Resistance May Lead to Type 2 Diabetes Source: Dietitian's Edge. 2(1): 44, 45. January-February 2001. Contact: Available from Dietitian's Edge. 70 Hilltop Road, 3rd Floor, Ramsey, NJ 07446. (201) 825-2552. Fax (201) 825-0553. E-mail: [email protected]. Summary: This article discusses the causes and treatment of Syndrome X. This complex condition, which is often referred to as metabolic syndrome or insulin resistance syndrome, involves a clustering of heart disease risk factors such as insulin resistance, hyperinsulinemia, hypertension, and obesity. The doctor, Gerald Reaven, who first defined this cluster of risk factors as Syndrome X in 1988 has written a book about the disease. Syndrome X results from a series of metabolic changes that occur over time. Although genetics may play a role in the syndrome, factors such as poor diet, obesity, inactivity, and smoking increase the risk of developing Syndrome X. Treatment involves losing weight, making dietary changes, increasing physical activity, and quitting smoking. Although there are no official dietary recommendations for people who have Syndrome X, the book written by Dr. Reaven recommends a specific macronutrient intake where 45 percent of calories are from carbohydrates, 40 percent are from fat, and 15 percent are from protein. This diet is controversial because major health associations recommend a low fat, high carbohydrate diet. In addition to weight loss and improved diet, physical activity can help protect against Syndrome X by lowering blood pressure, improving high density lipoprotein levels, promoting weight loss, and improving insulin resistance and glucose tolerance. The article concludes with recommendations that dietitians can give patients with Syndrome X. 1 table. 14 references.

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Natural History of Macrovascular Disease in Type 2 Diabetes: Role of Insulin Resistance Source: Diabetes Care. 22(Supplement 3): C2-C5. April 1999. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article provides a theoretical framework for understanding the relationship between type 2 diabetes and macrovascular disease. It has been hypothesized that diabetes and atherosclerosis have common antecedents, that fetal and

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early life nutritional deficiencies produce insulin resistance syndrome (IRS) and that IRS constitutes the common ground that leads to both type 2 diabetes and cardiovascular disease. The article reviews data supporting this concept and highlights classic, neoclassic, and postmodern studies that show insulin to be a cardiovascular risk factor. Classic studies, published in 1979 and 1980, all showed that hyperinsulinemia was predictive of the future development of cardiovascular disease in men, while the neoclassic studies produced largely negative evidence. Two postmodern studies showed that specific insulin levels conferred an increase in cardiovascular risk. However, data from the Diabetes Control and Complications Trial support the concept that insulin has beneficial effects on lipid profiles. The article also examines glycemia as a cardiovascular risk factor. Although the role of glycemia was controversial for many years, several studies have shown that glycemia is a cardiovascular risk factor. The article presents theoretical mechanisms that could explain how glycemia could produce atherosclerosis. The article concludes that adequate clinical trials on the atherogenic potential of insulin need to be conducted to resolve the controversy on the benefits or risks of exogenous insulin therapy on macrovascular disease. 1 figure. 19 references. •

Focus on Insulin Resistance in Type 2 Diabetes: Therapeutic Implications Source: Diabetes Educator. 24(2): 188-193. March-April 1998. Contact: Available from American Association of Diabetes Educators. 100 West Monroe, 4th floor, Chicago, IL 60603-1901. (312) 424-2426. Summary: This article provides information about the therapeutic implications of insulin resistance in type 2 diabetes. According to the article, insulin resistance is defined as a blunted response of the body to normal or supranormal insulin concentrations. Until the last few years, tools for managing type 2 diabetes were limited to diet, exercise, and insulin or sulfonylureas. Drugs that are capable of lowering hepatic glucose output (metformin), slowing postprandial glucose absorption (acarbose), and improving peripheral insulin sensitivity (troglitazone) are now available. Topics include insulin actions; insulin resistance and its measurement; the relationship between insulin resistance and type 2 diabetes; risk factors for insulin resistance and type 2 diabetes; beta cell dysfunction and the development of type 2 diabetes; type 2 diabetes therapies and their effects on insulin resistance; and implications for practice. The authors conclude that the knowledge that obesity and inactivity contribute to insulin resistance is of central importance. Diabetes educators should use all available means of education, persuasion, and behavior modification to get patients to adhere to an appropriate diet, an exercise program, and a drug regimen. 2 figures. 2 tables. 35 references. (AA-M).

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Intensity and Amount of Physical Activity in Relation to Insulin Sensitivity: The Insulin Resistance Atherosclerosis Study Source: JAMA. Journal of American Medical Association. 279(9): 669-674. March 4, 1998. Summary: This article reports on a study designed to determine whether habitual, nonvigorous physical activity, as well as vigorous and overall activity, is associated with increased insulin sensitivity. The authors note that exercise training is associated with improved insulin sensitivity, but that the potential impact of habitual, nonvigorous activity is uncertain. Participants in this study included 1,467 men and women of African American, Hispanic, and non-Hispanic white ethnicity between the ages of 40 and 69. According to the results of the study, the correlation coefficient between insulin sensitivity and total estimated energy expenditure (EEE) was 0.14 when habitual

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physical activity was assessed by 1-year recall of activities. The association between vigorous and nonvigorous levels of EEE and insulin sensitivity was weakened after adjustment for the potential mediators, body mass index, and waist-to-hip ratio. Results were similar for subgroups of sex, ethnicity, and diabetes. The results of the study indicate that increased participation in nonvigorous, as well as overall and vigorous physical activity, was associated with significantly higher insulin sensitivity. These findings lend further support to current public health recommendations for increased moderate-intensity physical activity on most days. 6 tables. 40 references. (AA-M). •

Metformin as an Adjunct Therapy in Adolescents with Type 1 Diabetes and Insulin Resistance Source: Diabetes Care. 26(1): 138-143. January 2003. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study that evaluated whether, in adolescents with type 1 diabetes, the addition of metformin to insulin and standard diabetes management results in higher insulin sensitivity and lower HbA1c (glycosylated hemoglobin, a measure of blood glucose levels over time), fasting glucose, insulin dosage, and body mass index (BMI). This randomized, placebo-controlled 3 month trial of metformin therapy included 27 adolescents with type 1 diabetes, high insulin dosage, and HbA1c greater than 8 percent. Results showed that metformin treatment lowered HbA1c and decreased insulin dosage with no weight gain in teens with type 1 diabetes in poor metabolic control. Changes in insulin sensitivity were not documented in this study. 1 figure. 2 tables. 32 references.

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Increased Insulin Resistance and Insulin Secretion in Nondiabetic African-Americans and Hispanics Compared With Non-Hispanic Whites: The Insulin Resistance Atherosclerosis Study Source: Diabetes. 45(6): 742-748. June 1996. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 342-2383. Summary: This article reports on a study to compare increased insulin resistance and insulin secretion rates in nondiabetic African Americans and Hispanics compared with nondiabetic non-Hispanic whites. Fasting and 2-hour postglucose load glucose and insulin levels, insulin-mediated glucose disposal (insulin sensitivity index), glucose effectiveness, and first-phase insulin response were determined in nondiabetic African Americans 9n=288), Hispanics (n=363) and non-Hispanic whites (n=435). African Americans and Hispanics were more obese than non-Hispanic whites. Both African Americans and Hispanics had higher fasting and 2 hour insulin concentrations and insulin response, but lower insulin mediated glucose disposal, than non-Hispanic whites. These results suggest that greater insulin resistance may be in large part responsible for the higher prevalence of noninsulin-dependent diabetes mellitus (NIDDM) in these minority groups. However, in Hispanics, the greater insulin resistance may be due to greater adiposity and other behavioral factors. 4 tables. 50 references. (AA-M).

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Prediction of Type 2 Diabetes Using Simple Measures of Insulin Resistance Source: Diabetes. 52(2): 463-469. February 2003.

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Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reports on a study undertaken to determine and formally compare the ability of simple indices of insulin resistance (IR) to predict type 2 diabetes. The authors used combined prospective data that included well-characterized cohorts of non-Hispanic white, African-American, Hispanic American, and Mexican subjects with 5 to 8 years of follow up. Poisson regression was used to assess the ability of each candidate index to predict incident diabetes at the follow up examination (343 of 3,574 subjects developed diabetes). The authors found substantial differences between published IR indexes in the prediction of diabetes, with ISI 0,120 consistently showing the strongest prediction. This index may reflect other aspects of diabetes pathogenesis in addition to IR, which might explain its strong predictive abilities despite its moderate correlation with direct measures of IR. 6 tables. 28 references. •

Understanding Insulin Resistance and Syndrome X Source: Patient Care. 30(11): 198-202, 205-208, 211. June 15, 1996. Contact: Available from Medical Economics. 5 Paragon Drive, Montvale, NJ 07645. (800) 432-4570. Fax (201) 573-4956. Summary: This article reviews insulin resistance and syndrome X; the latter is a syndrome in which insulin resistance is associated with obesity, glucose intolerance, hypertension, dyslipidemia, and atherosclerosis, especially coronary artery disease. Topics include risk factors for insulin resistance syndromes; the role of genetics; impaired glucose tolerance; problems with dyslipidemia and hyperinsulinemia; the role of obesity; recognizing insulin resistance syndromes; approaches to treatment; drug therapy, including the use of metformin, acarbose, thiazolidinediones, gemfibrozil, and ACE inhibitors; the consequences and complications of insulin resistance syndromes; and rare, severe forms of insulin resistance. One chart outlines the recommended patient management algorithm for insulin resistance syndromes. One sidebar describes the Diabetes Prevention Program, a current research effort seeking volunteers; another sidebar describes insulin resistance in patients with insulin-dependent diabetes mellitus. 2 figures. 24 references.

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Recent Advances in Our Understanding of Insulin Action and Insulin Resistance Source: Diabetes Care. 24(3): 588-597. March 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This article reviews recent advances in the understanding of insulin action and insulin resistance. The article begins by summarizing insulin action at the cellular level, focusing on current knowledge of this action and the importance of nuclear transport of signaling molecules. This is followed by a discussion on the discovery of evoluntionarily conserved molecules of the insulin signaling pathways. The article then examines the role of insulin signaling systems in insulin resistance, focusing on Ser/Thr phosphorylation of IR substrate (IRS) proteins and insulin resistance, tumor necrosis factor alpha as an inducer of insulin resistance, the role of peroxisome proliferator activated receptor gamma in insulin action and insulin resistance, fatty acids and insulin resistance, and feedback regulation of insulin signaling cascades. In addition, the article provides a summary of a few in vitro and cellular models of insulin resistance. Findings from these studies indicate that Ser/Thr phosphorylation of the IRS

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protein after insulin stimulation either enhances or terminates the insulin signal. The article concludes that, although the understanding of insulin resistance has evolved rapidly over the past few years, further studies are needed to determine the mechanisms controlling the intricate regulatory processes that presumably mediate, at least in part, the insulin resistance associated with obesity and hyperinsulinemia. 3 figures. 110 references. •

Insulin Resistance and Hyperinsulinemia: Recognizing the Risk and Reversing the Process Source: Physician Assistant. 24(9): 23-24, 26, 29-30, 33-36, 38-39. September 2000. Contact: Available from Springhouse Corporation. Physician Assistant, P.O. Box 908, Springhouse, PA 19477. (215) 646-8700. Fax (215) 646-4399. Summary: This article reviews the pathophysiology, risk factors, and dietary therapy for hyperinsulinemia (HI) and discusses the link between HI and vascular disease. Insulin resistance (IR) with concomitant HI is a significant risk factor for the development of type 2 diabetes and coronary heart disease. A person develops IR/HI when the insulin response to nutrients becomes chronically elevated. IR/HI is caused by a complexity of genetic and environmental influences. Early identification is important because of the microvascular and macrovascular damage the body experiences prior to the onset of hyperglycemia. Understanding the pathophysiology of IR/HI, the metabolism of nutrients, and the optimal therapeutic diet can help clinicians reverse the primary metabolic disturbance and prevent progression to diabetes, heart disease, and end organ damage. Nutritional therapy should be initiated prior to or in conjunction with pharmacotherapy. Based on physiologic, epidemiologic, and clinical evidence, the low fat, high carbohydrate diet is not appropriate for the IR/HI patient. The most appropriate diet for people who have IR/HI is adequate protein, moderate complex carbohydrate, minimal refined carbohydrate, and healthy fats. Micronutrients are also important in optimizing the health of a patient who has IR/HI. Exercise is also an important key to insulin sensitivity; therefore, exercise, together with a low to no starch diet will cause a dramatic increase in fat utilization for energy. Although diet therapy is needed to reverse the metabolic disturbance associated with IR/HI, pharmacotherapies may be needed to treat the associated risk factors that often accompany IR/HI. 2 figures. 6 tables. 60 references. (AA-M).

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Evaluation of the Insulin Resistance Syndrome in 5-to 10-Year-Old OverweightObese African-American Children Source: Diabetes Care. 24(8): 1359-1364. August 2001. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article describes a study that characterized the insulin sensitivity of overweight and obese 5 to 10 year old African American children screened for participation in a diabetes prevention study and identified the association of insulin sensitivity with obesity, hyperlipidemia, and hypertension. Measures of insulin resistance and insulin sensitivity were calculated from a 2 hour oral glucose tolerance test in 137 African American children. Measures of low density lipoprotein (LDL), high density lipoprotein (HDL), total cholesterol, triglycerides, blood pressure, and body composition were obtained for a subset of the children. The study found that, in response to a glucose challenge, girls and older and heavier children produced significantly more insulin. As body mass index increased, there was a statistically

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significant decrease in insulin sensitivity, particularly in girls. Insulin sensitivity was inversely correlated with increases in blood pressure, triglycerides, subcutaneous fat, the percentage of total body fat, and Tanner stage, but it was not correlated with LDL and HDL. Total cholesterol was inversely related to whole body insulin sensitivity. These associations suggest that a clustering of risk factors is present in these children. Results provide evidence that overweight African American children should be monitored for insulin resistance and cardiovascular risk factors early in life and that this monitoring should occur as part of their ongoing medical care. 2 figures. 1 table. 32 references. (AA-M). •

Insulin Resistance and Atherosclerosis Source: Diabetes Reviews. 5(4): 331-342. 1997. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This review article evaluates the relationship between insulin resistance and atherosclerosis in people who do not have diabetes. The main goal of the article is to review the risk factors for coronary heart disease (CHD) that occur with increased frequency in insulin resistant people, and to offer pathophysiological explanations for these relationships. The authors point out that CHD is the major cause of morbidity and mortality in people with type 2 diabetes, and that insulin resistance is present in most people who have type 2. Because insulin resistance is so common in people with type 2 diabetes, it is difficult to assess its role in CHD development. Topics include insulin resistance versus hyperinsulinemia; insulin resistance, compensatory hyperinsulinemia, dyslipidemia, and CHD; the relationship between hypertriglyceridemia and other risk factors for CHD; and insulin resistance and/or compensatory hyperinsulinemia, hypertension, and CHD. The article notes that the ability of insulin to stimulate glucose uptake varies significantly from person to person. The authors conclude that, at the present time, it is difficult to know if insulin resistance is primarily responsible for accelerating the process of atherogenesis. They also conclude that resistance to insulin-mediated glucose disposal and its consequences play a key role in the pathogenesis and clinical course of type 2 diabetes, hypertension, and CHD. 4 figures. 1 table. 90 references. (AA-M).

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Insulin Resistance and Associated Compensatory Responses in African-American and Hispanic Children Source: Diabetes Care. 25(12): 2184-2190. December 2002. Contact: Available from American Diabetes Association (ADA). 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: This study was undertaken to compare insulin resistance relative to body fat and the associated compensatory responses in 57 healthy children living in Los Angeles, California (14 Caucasians, 15 African-Americans, and 28 Hispanics). Insulin sensitivity and acute insulin response were determined by intravenous glucose tolerance test. Insulin secretion, hepatic insulin extraction, and insulin clearance were estimated by Cpeptide and insulin modeling. Results showed that insulin sensitivity was significantly lower in Hispanics and African-Americans compared with Caucasian children, and acute insulin response was significantly higher in African-American children. No ethnic differences were noted in the first-phase secretion, but second phase insulin secretion was significantly higher in Hispanic children than in African-American children. The greater acute insulin response in African-Americans, despite lower secretion, was

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explained by a lower hepatic insulin extraction in African-Americans compared with Hispanics. The authors conclude that Hispanic and African-American children are more insulin resistant than Caucasian children, but the associated compensatory response are different across ethnic groups. 1 figure. 2 tables. 25 references. •

Troglitazone: A New and Unique Oral Anti-Diabetic Agent for the Treatment of Type II Diabetes and the Insulin Resistance Syndrome Source: Clinical Diabetes. 15(2): 60-65. March-April 1997. Contact: Available from American Diabetes Association. 1701 North Beauregard Street, Alexandria, VA 22311. (800) 232-3472. Website: www.diabetes.org. Summary: Troglitazone is the fourth in the newest class of oral anti diabetes agents, thiazolidinedione, to be approved in the United States. Troglitazone works mainly by improving insulin resistance without stimulating insulin secretion. This article helps primary caregivers understand the clinical usefulness of troglitazone. The indication for troglitazone is for insulin-requiring patients with Type II diabetes (noninsulindependent diabetes, or NIDDM) in poor metabolic control (defined as HbA1c greater than 8.5 percent) despite insulin therapy of greater than 30 U per day given in multiple injections. When prescribing troglitazone to this patient population, no insulin dose reduction is recommended at the outset. If fasting and or pre-meal glucose values consistently drop below 120 to 140 mg per day, the author recommends a 10 to 20 percent reduction in insulin dose in order to reduce the incidence of hypoglycemia. Troglitazone may also prove beneficial in preventing Type II diabetes and treating other conditions associated with the insulin resistance syndrome, such as hypertension, dyslipidemia, and atherosclerosis. 2 figures. 2 tables. 33 references. (AA-M).

Federally Funded Research on Insulin Resistance The U.S. Government supports a variety of research studies relating to insulin resistance. These studies are tracked by the Office of Extramural Research at the National Institutes of Health.2 CRISP (Computerized Retrieval of Information on Scientific Projects) is a searchable database of federally funded biomedical research projects conducted at universities, hospitals, and other institutions. Search the CRISP Web site at http://crisp.cit.nih.gov/crisp/crisp_query.generate_screen. You will have the option to perform targeted searches by various criteria, including geography, date, and topics related to insulin resistance. For most of the studies, the agencies reporting into CRISP provide summaries or abstracts. As opposed to clinical trial research using patients, many federally funded studies use animals or simulated models to explore insulin resistance. The following is typical of the type of information found when searching the CRISP database for insulin resistance:

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Healthcare projects are funded by the National Institutes of Health (NIH), Substance Abuse and Mental Health Services (SAMHSA), Health Resources and Services Administration (HRSA), Food and Drug Administration (FDA), Centers for Disease Control and Prevention (CDCP), Agency for Healthcare Research and Quality (AHRQ), and Office of Assistant Secretary of Health (OASH).

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Project Title: ADIPOSE TISSUE PRODUCTION OF THE NOS INHIBITOR, ADMA Principal Investigator & Institution: Tsao, Philip S.; Assistant Professor of Medicine; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS) and is elevated with several risk factors for cardiovascular disease. We have previously demonstrated a direct relationship between the degree of insulin resistance, a cardinal feature of obesity, and circulating levels of ADMA. Our preliminary data indicate that adipose tissue elaborates significant quantities of ADMA. Moreover, this effect is accentuated in tissue derived from obese animals. We hypothesize that adipose tissue can serve as a major source of ADMA and that insulin resistance has important modulatory functions. Thus we will use our in vitro and in vivo models to elucidate the following specific aims: 1. To identify the cellular source(s) of ADMA elaboration from adipose tissue and potential regulatory mechanisms. We will isolate adipocytes and stromal endothelial cells from fat pads to determine the relative contribution of each to ADMA production. In addition, mechanisms of ADMA metabolism will be elucidated in these cells. 2. To determine the role of insulin resistance in adipose tissue ADMA production. Insulin resistance will be induced both in vivo and in vitro and the resultant effects upon ADMA regulation will be assessed. Dysregulation of candidate signaling molecules upon ADMA will be determined as well as the potential benefits of insulin sensitizing compounds (TZDs). 3. To modulate ADMA metabolism by overexpression of DDAH and determine the effects upon ADMA elaboration and cell function. Adipocytes and endothelial cells stably overexpressing DDAH will be examined for functional consequences. In addition, a transplant model will be used to examine the potential therapeutic benefit of ectopic DDAH expression. 4. To examine the expression profile of cardiovascular tissues derived from animals that have altered ADMA metabolism. We will utilize a comprehensive cDNA microarray to examine the effects of obesity, insulin resistance, and ADMA metabolism in cardiovascular tissues. Expression profiles will also be compared with non-cardiovascular tissues. Understanding the questions underlying these specific aims will add insight into the underlying mechanisms of ADMA regulation and endothelial dysfunction and undoubtedly have important implications for the treatment of obesity-related cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: AGE, EXERCISE, DIET: EFFECTS ON INSULIN RESISTANCE Principal Investigator & Institution: Kirwan, John P.; Associate Professor,; Reproductive Biology; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106 Timing: Fiscal Year 2004; Project Start 15-SEP-1995; Project End 31-DEC-2008 Summary: (provided by applicant): This application is a revised version of the previously reviewed grant, AG12834. Insulin resistance and diabetes are the source of considerable health and financial burden for our elderly population. Recent estimates show that the direct medical costs of diabetes and its related disorders climbed from $44 billion in 1997 to almost $92 billion in 2002. Consequently, the search for effective treatment or prevention modalities is a high priority in public health care policy. Although diet and exercise improve insulin sensitivity, it is still entirely unclear as to what regimen of diet composition and exercise is most effective in reversing insulin resistance in the elderly. The proposed research will involve the prospective study of 80 older (65-85 years), obese (BMI = 30-40 kg/m 2) men and women. The central

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hypothesis is that a low-glycemic diet, combined with aerobic exercise and nutrition counseling reduces insulin resistance in older obese men and women. The specific aims are, I: Identify the effects of high- and low-glycemic diet and exercise interventions on insulin resistance in obese elderly. II: Ascertain which components of body composition are regulated by high- and low-glycemic diet-exercise interventions. III: Establish which insulin signaling proteins in skeletal muscle regulate the change in insulin resistance in response to high- and low-glycemic diet-exercise interventions. The approach includes a 3-week diet/weight stabilization period during which all subjects will be fed a weightmaintenance typical American diet. Subjects will be randomized to receive either a eucaloric high-glycemic diet (approximaely 90 U), or a eucaloric low-glycemic diet (approximately 55 U). All meals will be prepared in the General Clinical Research Center Metabolic Kitchen. Subjects will participate in a 12-week supervised aerobic exercise program and nutrition counseling. Baseline physiological and metabolic testing will include measures of insulin resistance (euglycemic-hyperinsulinemic clamps), substrate oxidation, total and abdominal fat (hydrostatic weighing and computer tomography), lipids, and cytokines. Muscle biopsies will be obtained to measure expression, phosphorylation and activity of proteins in the insulin-signaling pathway. Myocellular lipid content will be determined by proton-nuclear magnetic spectroscopy. Upon treatment completion, all subjects will remain on their respective diet, maintain weight stability and repeat all baseline testing to determine the study outcome effects. It is our expectation that the approach used in this study will identify a more favorable diet-exercise treatment for insulin resistance, as well as the cellular and metabolic mediators that regulate obesity-related insulin resistance in the elderly. These results will be significant, in that they will provide a preventative and therapeutic intervention that will substantially improve the health and quality of life for the growing number of elderly who have developed, or will develop insulin resistance, or diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AGING, CARDIOMYOPATHY

INSULIN

RESISTANCE,

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DILATED

Principal Investigator & Institution: Shannon, Richard P.; Professor of Medicine; Allegheny-Singer Research Institute 320 E North Ave Pittsburgh, Pa 15212 Timing: Fiscal Year 2004; Project Start 15-JAN-2004; Project End 31-DEC-2008 Summary: (provided by applicant): Congestive heart failure is a leading cause of morbidity and mortality in the elderly, although the mechanisms to explain the enhanced proclivity are poorly understood. It remains debatable as to whether the ageassociated propensity to cardiovascular dysfunction is attributable to aging per se or the accumulation of cardiovascular risk factors that accrue over time. In particular, aging has been closely associated with the development of increased visceral adiposity that has been implicated in the pathogenesis of age associated insulin resistance. Whether age associated insulin resistance contributes to the progression of cardiac dysfunction following myocardial injury has not been explored systematically. The altered cellular actions of insulin that underlie physiological insulin resistance may have significant consequences to the failing heart. The injured myocardium develops an evolving dependence on glucose as its preferred metabolic substrate. The preference is dependent upon the efficiencies of oxidation of glucose in the generation of high-energy phosphates. This preference becomes a requirement as the ability to oxidized fat acids is limited through a series of molecular switches in key regulatory components of fatty acid transport and oxidation. We have determined that advanced, decompensated stages of dilated cardiomyopathy are associated with the development of myocardial

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insulin resistance, which limits myocardial glucose uptake and oxidation. These physiological features are associated with cellular insulin signaling abnormalities in the myocardium that are distinct from those observed in skeletal muscle and adipose tissue in other insulin resistant states. Together, aging and heart failure share the common pathophysiological features of insulin resistance. Whether the effects are additive or synergistic in explaining the increased incidence and severity of heart failure in the elderly remains to be determined. We will determine if aging is associated with accelerated progression of heart failure in conscious dogs with pacing induced dilated cardiomyopathy. We will define the physiological and cellular effects of insulin resistance in the senescent myocardium during the evolution of dilated cardiomyopathy. Finally, we will determine if overcoming myocardial insulin resistance in the aging and failing heart will prevent the progression of dilated cardiomyopathy. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: AUTONOMIC FUNCTION/INSULIN RESISTANCE/MULTIETHNIC POP. Principal Investigator & Institution: Grandinetti, Andrew; None; University of Hawaii at Manoa Honolulu, Hi 96822 Timing: Fiscal Year 2003; Project Start 15-SEP-2003; Project End 31-JUL-2008 Summary: (provided by the applicant): Autonomic nervous system regulation of heartbeat variability is often disrupted among patients with diabetes. Moreover, reduced heart rate variability has been associated with increased Cardiovascular Disease (CVD) mortality among diabetic and non-diabetic populations. CVD mortality rates differ greatly among many ethnic groups. In Hawaii, Native Hawaiians have been shown to have disproportionately higher CVD mortality than Asian and Caucasian groups. Preliminary data from the Native Hawaiian Health Research Project suggest that conventional risk factors associated with Atherosclerosis may not fully account for ethnic disparities in heart disease and stroke mortality rates in Hawaii. Insulin resistance has been associated with increased CVD incidence and mortality, and has also been associated with reduced heart rate variability. The proposed study will investigate the relationship between insulin resistance and autonomic regulation of cardiac function in a multi-ethnic population. The proposed research will also provide baseline data for future longitudinal studies that will investigate the extent to which these novel risk factors explain ethnic disparities in CVD mortality in Hawaii. The findings of the proposed study may have important implications with regards to the treatment of insulin resistance as an independent CVD risk factor. Specific Aims: Collaborator component (Aim #1). Establish a collaborative laboratory in Hawaii for the evaluation of autonomic function in a multiethnic population. Principal Investigator component (Aim #2). Investigate the relationship between insulin resistance, body-fat distribution, and autonomic function. (Aim #3) Establish a cohort with baseline measures of autonomic function and insulin resistance that will serve as a study population for R01-supported longitudinal studies. Hypotheses: By fulfilling these specific aims, we propose to test the following specific research hypotheses: (1.) Autonomic function will differ significantly by ethnicity, after adjustment for age, gender, body-mass index, and central obesity. (2.) Insulin resistance is independently associated with autonomic function, after an adjustment for age, gender, body-mass index, and central obesity. Secondary Questions: Does insulin resistance and plasma glucose interact, in their effects on autonomic function? What role do plasma lipids, blood pressure, diet, and physical activity have in explaining any observed ethnic

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disparities in autonomic function? Is the questionnaire-derived Composite Autonomic Symptom Scale (COMPASS) correlated with autonomic function in Hawaii's multiethnic population? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: BIOCHEMICAL MECHANISMS OF IN VIVO INSULIN RESISTANCE Principal Investigator & Institution: Rossetti, Luciano; Professor; Medicine; Yeshiva University 500 W 185Th St New York, Ny 10033 Timing: Fiscal Year 2002; Project Start 01-AUG-1994; Project End 31-JUL-2004 Summary: In this project, we propose to continue our investigation of the biochemical and molecular mechanism(s) by which "insulin resistance" is acquired. Our long-term focus has been on the potential link between nutrient excess and impairment of insulin action. In this regard, we have recently shown that increased nutrient (eg, carbohydrate and lipid) availability results in insulin resistance and in increased leptin gene expression via increased flux of carbons into the hexosamine biosynthetic pathway. We propose herein that a close loop feed-back regulation is normally operating between nutrients and their metabolic outcomes. Thus, nutrient excess is sensed via the hexosamine biosynthetic pathway and generates signals leading to decreased insulin action on glucose uptake and to increased leptin gene expression. They also favor increased storage into lipid via increased tissue levels of Malonyl-CoA and Long ChainCoA and ultimately increased adiposity and weight gain. However, the concomitant induction of leptin expression attempts to counteract this drive by antagonizing the effects of nutrients on Malonyl-CoA and triglyceride storage, on the hexosamine pathway and perhaps via direct effects on insulin signaling. Any disruption of this physiological response (due to either impaired stimulation of leptin expression by nutrients or to decreased effectiveness of leptin action on target tissues) is likely to lead to increased adiposity and more insulin resistance. Based on preliminary results and on this overall hypothesis we wish to pursue the following specific aims: 1. How do nutrients regulate insulin action? We will focus on the interaction between increased lipid availability and skeletal muscle insulin signaling and action. We hypothesize that the susceptibility to develop insulin resistance in response to excessive nutrient exposure is modulated by the skeletal muscle ability to utilize fructose-6-phosphate in the glycolytic pathway. 2. How does leptin modulate hepatic and muscle glucose/lipid metabolism and insulin action? We will examine whether specific hypothalamic targets of leptin play distinct roles in mediating its complex metabolic effects. 3. Is leptin synthesis and/or action modulated following prolonged stimulation? We will generate short-term models of relative hyperleptinemia and will test the hypothesis that the "protective" effect of leptin against nutrient excess wanes if the leptin signal/transduction system is chronically over-stimulated. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: CARDIOVASCULAR DISEASE FOLLOWING HYPERTENSIVE PREGNANCY Principal Investigator & Institution: Wolf, Myles S.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): Candidate: Dr. Myles Wolf received the M.D. degree in 1996 from SUNY-Brooklyn. He completed internal medicine and nephrology training at MGH. In 2002, he received the Master of Medical Sciences degree in clinical

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physiological investigation from Harvard Medical School through its NIH K30supported Scholars in Clinical Science Program. Mentor: David Nathan, M.D., is a world-renowned clinical investigator who has trained numerous investigators in the areas of diabetes and insulin resistance, a field in which he has published extensively. As Director of the MGH GCRC and as a founding member of the Scholars in Clinical Science Program, Dr. Nathan will ensure the success of Dr. Wolf's research training, project and overall career development. Research: cardiovascular disease (CVD) is the leading cause of mortality among women in the U.S. Reducing its burden requires further understanding of its early mechanisms. Women with hypertensive disorders of pregnancy (HDP), including preeclampsia and gestational hypertension, return to their normotensive baseline soon after delivery, yet they are at increased risk for CVD in later years. Therefore, these women represent in-vivo human models of the pre-CVD state in whom its early mechanisms may be studied. In their first study, they will test the hypothesis that otherwise asymptomatic women with prior HDP display evidence of increased CVD risk relative to those with normal pregnancy as early as one year postpartum. In addition to examining traditional CVD risk factors, they will focus on insulin resistance, inflammation and microalbuminuria, factors that are associated with HDP but have been understudied in the postpartum period. In a second physiological study, they will examine vascular reactivity using brachial artery ultrasound, and insulin sensitivity using intravenous glucose tolerance tests. The hypotheses to be tested are that women with HDP display evidence of endothelial dysfunction during the early postpartum period and that this alteration is related to insulin resistance. All subjects will be identified from the MGH Obstetric Maternal Study, the largest pregnancy cohort in Massachusetts, and the source of several important studies during pregnancy. The proposed study is sufficiently powered (>90%), IRB-approved and pilot data support its feasibility. They believe the results will provide critical insight into mechanisms of CVD in women and potentially suggest means to alter their CVD risk. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CAVEOLAE IN INSULIN SIGNALING Principal Investigator & Institution: Mastick, Cynthia C.; Biochemistry; University of Nevada Reno 204 Ross Hall Mailstop 325 Reno, Nv 89557 Timing: Fiscal Year 2004; Project Start 01-SEP-1999; Project End 31-DEC-2007 Summary: (provided by applicant): The long-term objective of this proposal is to increase our knowledge of the cellular mechanisms of insulin action. When insulin binds to its receptor at the cell surface signals are transmitted to the metabolic enzymes and glucose transporters regulated by insulin through signal transduction cascades. However, the molecular details of these pathways remain incompletely understood. Inhibition or disruption of these pathways leads to insulin resistance, and in susceptible individuals the development of diabetes. The focus of this proposal is the characterization of a unique insulin-stimulated signaling pathway that leads to tyrosine phosphorylation of caveolins-1 and -2, structural components of specialized cell surface domains termed caveolae. Tyrosine phosphorylation of the caveolins is both insulinspecific and cell type dependent, occurring only in adipocytes, suggesting that caveolin phosphorylation has an important function in these cells. Tyrosine phosphorylation promotes protein/protein interactions via SH2 domains, and the activation of downstream signaling cascades. Using a novel yeast-based phosphotyrosine dependent protein interaction screen, two proteins that interact with caveolin-1 in a phosphorylation-dependent manner were identified: TNFalpha receptor associated factor 2 (TRAF2) and C-terminal Src kinase (Csk). These findings indicate two important

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Insulin Resistance

roles for caveolae in adipocytes: (1) modulation of TNFalpha signaling and (2) regulation of the actin cytoskeleton through Csk-mediated phosphorylation of the Src family kinases. These interactions implicate caveolae in TNFalpha-induced insulin resistance and in the insulin-induced actin rearrangements required for the stimulation of glucose transport in adipocytes. The specific aims of this proposal are to: 1. Determine the signaling pathways that lead to caveolin phosphorylation on both tyrosine and serine. 2. Determine the signaling pathways that lie downstream of caveolin phosphorylation (specifically TNF induced insulin resistance and regulation of the actin cytoskeleton and GluT4 translocation). 3. Examine the link between caveolin phosphorylation and metabolic regulation in vivo through the creation of fat-specific caveolin-1 and caveolin-1/Y14F knock-in mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: CORTISOL, CENTRAL OBESITY, AND INSULIN RESISTANCE Principal Investigator & Institution: Purnell, Jonathan Q.; Associate Professor; Medicine; Oregon Health & Science University Portland, or 972393098 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2004 Summary: (adapted from the application) Central (visceral) obesity contributes to an excess risk of diabetes, dyslipidemia, hypertension, and premature death from coronary heart disease. A feed-back loop model of weight regulation has emerged from recent studies of animals and humans: afferent hormones signal amount of fat mass to the central nervous system; weight regulation centers in the hypothalamus interpret these signals and control efferent systems including appetite, energy expenditure, and enzymes in the fat cell, such as lipoprotein lipase, that facilitate partitioning of energy into lipid storage. It is proposed in this grant that the hypothalamic-pituitary-adrenal axis is an effector system of hypothalamic weight regulatory centers and that increased cortisol production rates in the obese state directly regulate enzyme transcription in the fat cell to promote lipid uptake and central fat distribution. Cross sectional data from lean and obese humans using stable isotope enrichment determined by mass spectroscopy demonstrate that increases in cortisol production rates across the physiological range are associated with increased adipocyte lipoprotein lipase activity, accumulation of fat mass independent of non-fat mass, increased visceral fat, and increased insulin resistance. These findings, however, do not establish whether increased cortisol production causes, or is simply associated with these variables. To directly test whether cortisol enhances lipid uptake, fat mass accumulation, increased visceral fat mass, and insulin resistance, it is proposed to study the effect of administration of increasing doses of hydrocortisone (including doses within the physiological replacement range) in subjects with complete adrenal failure on these parameters. Finally, leading cellular candidates for the regulation of adipocyte lipoprotein lipase gene expression and fat cell differentiation, including PPAR-gamma and C/EBP, will be measured in adipose samples from the subjects in these studies to provide a mechanistic link between peripheral signaling systems such as cortisol and the adipocyte enzymes involved with fat partitioning. These studies will not only provide insight into the mechanisms of central obesity and its metabolic consequences, they also have great importance to clinicians who care for subjects with adrenal insufficiency as to the consequences of recommended replacement doses of cortisol on risk factors for heart disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: COUPLING OF D-CHIRO-INOSITOL TO INSULIN IN PCOS WOMEN Principal Investigator & Institution: Iuorno, Maria J.; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2003; Project Start 01-AUG-2003; Project End 31-JUL-2005 Summary: (provided by applicant): Polycystic ovary syndrome (PCOS) is characterized by hyperandrogenism and chronic anovulation and it is the most common form of female infertility in the U.S. It has been demonstrated that insulin resistance accompanied by compensatory hyperinsulinemia is, in part, responsible for the hyperandrogenism and anovulation of this disorder. The cellular mechanisms of insulin resistance in PCOS are still largely unknown. D-chiro-inositol phosphoglycan (DCI-IPG) is a nonclassical mediator of insulin action that has been demonstrated to increase glucose utilization. Previous studies have shown that administering a drug similar to the native mediator to women with PCOS increases insulin sensitivity, reduces ovarian androgen production and improves ovulation in these women. Therefore, it seems likely that women with PCOS have a defect in DCI-IPG cellular activity that leads to insulin resistance. The aim of this application is to determine whether a defect in coupling between D-chiro-inositol phosphoglycan and insulin plays a role in the insulin resistance of PCOS. We propose to assess the coupling of the DCI-IPG to insulin in women with PCOS and normal women: 1) by administering diazoxide to these women in order to temporarily suppress their pancreatic insulin secretion and measure a change in activity in DCI-IPG in plasma of these women following suppression of insulin and 2) by restoring insulin following diazoxide administration using an insulin clamp and measuring the degree to which DCI-IPG activity is also restored during the clamp in normal women versus women with PCOS. Hence, both PCOS women and normal control women will be evaluated for this insulin to DCI-IPG activity relationship. It is our hypothesis that at least one mechanism of insulin resistance in PCOS is due to defective coupling between insulin and DCI-IPG activity. The results of these studies will 1) describe the physiologic, in vivo relationship between insulin and DCI-IPG in normal women; 2) provide a mechanism for insulin resistance in PCOS as it relates to the DCI-IPG insulin signaling cascade; 3) provide the groundwork for further clinical studies to explore the role of defective coupling in other insulin resistant human conditions (such obesity or type 2 diabetes); and 4) lead to novel specific therapies for the insulin resistance of PCOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: DGAT OVEREXPRESSION IN MOUSE ADIPOSE TISSUE AND MUSCLE Principal Investigator & Institution: Yu, Yi-Hao; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-JAN-2007 Summary: (provided by applicant) Insulin resistance is a hallmark of type 2 diabetes mellitus. The prevalence of insulin resistance and diabetes is increasing at an alarming rate, in part, because of a rapid increase in obesity in all populations. The goals of the proposed program are to (a) further our understanding of obesity-associated insulin resistance, and (b) prepare the PI for an independent research career. We will approach the research questions by creating and studying mouse models in which triglyceride synthesis is increased in only adipose tissue or only muscle. Two transgenic mouse models with tissue-specific overexpression of diacylglycerol acyl transferase (DGAT)

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Insulin Resistance

will be studied. DGAT is a key enzyme in triglyceride (TG) synthesis. Overexpression of this enzyme in cells leads to increased intracellular fat accumulation. Mouse models with DGAT overexpression will enable the PI to closely examine if and how insulin resistance develops secondary to a primary increase in triglyceride synthesis in each tissue. By separately and specifically introducing a DGAT transgene into the mouse?s adipose tissue and muscle, to increase fat content in the respective tissues, these mouse models will enable the investigators to better dissect the usually complex processes involving multiple tissues and organ systems in the interaction between obesity and insulin resistance. The Specific Aims of this project are to answer the following two fundamental questions involved in this relationship: (1) whether simple obesity caused by an increased capacity of TG synthesis in adipose tissue can alter plasma lipid and/or hormone and cytokine levels, eventually leading to insulin resistance, (2) whether enhanced TG deposition in muscle alone is sufficient to cause muscle and systemic insulin resistance. This project will be conducted at Columbia University College of Physicians and Surgeons in a highly enriched research environment, particularly with respect to lipid metabolism and diabetes research. The PI has had previous basic science training in cell biology, and more recent training in internal medicine and clinical endocrinology. The proposed research will be performed under the mentorship of Dr. Henry Ginsberg, who has a long and outstanding record in research involving both diabetes and lipoprotein metabolism. The mentor also has extensive training experience. Additionally, as part of the program, the PI will acquire new research skills, including the performance of lipoprotein turnover studies and insulin clamps in transgenic mice, and the use of microarray gene expression methods. Related formal course work will also be included in the overall program. The establishment and studies of the two transgenic mouse models, together with the specific technologies he will acquire during the course of this project, will provide the PI with an outstanding base from which to launch a career as an independent translational research scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: DIABETES MECHANISMS

IN

HEMOCHROMATOSIS:

PREVALENCE

AND

Principal Investigator & Institution: Mcclain, Donald A.; Professor and Director; Internal Medicine; University of Utah Salt Lake City, Ut 84102 Timing: Fiscal Year 2002; Project Start 01-MAR-2002; Project End 31-OCT-2006 Summary: Although the hemochromatosis gene (HFE) has been identified there is little information about the diabetes that often accompanies the disease. We hypothesize nondiabetic homozygotes for mutations in HFE will exhibit a defect in insulin secretion as iron overload develops. This notion is supported by preliminary data obtained in HFE mutant mice. The insulin deficiency will progress to type 2 diabetes only if insulin resistance also occurs, either from cirrhosis or inheritance of type 2 diabetes genes. Insulin resistance from cirrhosis is hypothesized to result from excess carbohydrate delivery to peripheral tissues, resulting in excess hexosamine generation, an established cause of insulin resistance. Our specific aims are to: 1. Determine the prevalence of impaired glucose intolerance (IGT) and diabetes in clinically unselected individuals with hemochromatosis by oral glucose tolerance criteria. 2. Determine if a defect in insulin secretion exists in nondiabetic homozygotes with or without iron overload. This will be accomplished using the frequently sampled intravenous glucose tolerance test (FSIVGTT) with insulin levels. Reversibility of the defect will be examined after subjects have undergone phlebotomy. The hypothesis will be verified in studies of isolated islets from mice carrying disrupted or mutant HFE genes. 3. Using animal models, determine

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if diabetes in hemochromatosis results only when insulin resistance is superimposed on an iron- mediated defect in insulin secretion. 4. Determine the sequence and relative contributions of insulin resistance and hepatic glucose production (HGP) in the evolution of diabetes in human hemochromatosis. Insulin resistance and HGP will be quantified by the hyperinsulinemic euglycemic clamp and stable isotope techniques in subjects with hemochromatosis who have normal or IGT, with or without hepatic involvement. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EFFLUX ATHEROGENESIS

PROTEINS

AND

INSULIN

RESISTANCE

IN

Principal Investigator & Institution: Hajjar, David P.; Professor of Biochemistry and Dean; Weill Medical College of Cornell Univ New York, Ny 10021 Timing: Fiscal Year 2003; Project Start 15-APR-2003; Project End 31-MAR-2008 Summary: CD36 is a broadly expressed 88 kD transmembrane glycoprotein which functions as a scavenger receptor, adhesion and signaling molecule and a facilitator of fatty acid transport. Previous work by our group and others determined that CD36 was a major mediator of macrophage foam cell formation and atherogenesis. Recently, a paradox has emerged: significant protection against lesion development and progression was observed in experimental conditions where CD36 was rendered absent genetically and when CD36 was upregulated by pharmacological means. Using stem cell transfer of CD36/apoE bone marrow into apoE null animals, we found that the atheroprotective effect afforded by complete absence of CD36 was not fully realized. Thus, a major hypothesis of this application is that CD36 has atheroprotective properties independent of its role as a scavenger receptor. Based on emerging data, we focus on the role of CD36 in efflux pathways and in modulating insulin-resistance, both of which are stimulated by drugs which activate PPARs, transcription factors which regulate CD36 expression. We hypothesize that CD36 is a critical player in maintenance of vessel wall homeostasis, and that entry of cholesterol into macrophages via CD36 facilitates removal of pro-atherogenic modified LDL from the intima, and ultimately allows lipid clearance through efflux pathways. Elucidation of the regulation of CD36 in relationship to the major efflux pathways is a major goal of our studies. Insulin resistance is a separate risk factor for atherogenesis and results in its premature development. We hypothesize that a portion of the protective role of CD36 in atherogenesis is related to its effect on glucose and fatty acid metabolism. We will utilize unique animal models we have on hand to explore the differential impact of CD36 on atherosclerosis based on scavenger receptor function or its role as a facilitator of fatty acid transport and determinant of insulin sensitivity. These approaches will enable us to design more specific treatment regimens which will ultimately impact on human health and disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ENDOTHELIAL DYSFUNCTION DUE TO HIV-1 PROTEASE INHIBITORS Principal Investigator & Institution: Dube, Michael P.; Medicine; Indiana Univ-Purdue Univ at Indianapolis 620 Union Drive, Room 618 Indianapolis, in 462025167 Timing: Fiscal Year 2002; Project Start 30-SEP-2002; Project End 31-JUL-2007 Summary: (provided by applicant): HIV-1 protease inhibitor (PI) agents have revolutionized HIV care, but have led to marked abnormalities in metabolism. These changes appear to place patients with HIV infection at considerably increased

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Insulin Resistance

cardiovascular risk. In addition to insulin resistance and hyperlipidemia, endothelial dysfunction occurs and will heighten these risks. Endothelial dysfunction is a critical initial step of atherogenesis that subsequently contributes to the progression and clinical manifestations of atherosclerosis. Preliminary data show that the PI indinavir impairs endothelium-dependent, nitric oxide-mediated, vasodilation in normal subjects. To further define the factors contributing to endothelial dysfunction, identify antiretroviral agents with lesser cardiovascular risk, and identify potential interventions, this project addresses these Specific Aims: (1) Establish the physiologic mediators of endothelial dysfunction caused by indinavir: The hypothesis that insulin resistance mediates endothelial dysfunction due to indinavir will be tested. Normal subjects will receive indinavir for 4 weeks and undergo measurements of endothelium-dependent vasodilatory response both before and during hyperinsulinemia. (2) Compare the effects of PIs with divergent metabolic effects on endothelial function: To test the hypothesis that PIs with lesser tendencies to provoke insulin resistance or dyslipidemia will have lesser effects on endothelial function, normal subjects will be randomized to receive either amprenavir or atazanavir. Similar tests of endothelial function will be performed. (3) Determine if non PI-based combination therapy results in less endothelial dysfunction than a PI-based regimen. The hypothesis that a PI-based antiretroviral combination regimen will induce endothelial dysfunction, but a non-PI-based regimen will not, will be tested. HIV-infected subjects will be randomized to a PI-based regimen that is expected to cause dyslipidemia and insulin resistance, or a non-PI-based regimen that should not. Subjects will cross over to the other therapy after 12 weeks of treatment to establish the reversibility of the endothelial dysfunction. The results of these studies will provide a better understanding of the causes of increased cardiovascular risk among HIV-infected patients, foster the development of antiretroviral drugs that lack adverse effects on cardiovascular risk, and identify potential interventions to test for reduction of risks in HIV-infected patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ESTROGENS AND INSULIN RESISTANCE IN WOMEN Principal Investigator & Institution: Olefsky, Jerrold M.; Professor; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 01-JUL-2002; Project End 31-MAY-2007 Summary: (provided by applicant): There are genetic and environmental causes of insulin resistance, and clearly these two inputs can be additive and interactive. A high fat intake is an important environmental factor which can cause, or exacerbate, insulin resistance and enhance the risk for the development of Type II diabetes. Our recent studies have shown that lipid/heparin infusions lead to insulin resistance in men, but not in pre-menopausal women. We also have preliminary data showing that postmenopausal women are fully susceptible to fat-induced insulin resistance and that estrogen replacement therapy re-establishes the protective state. In addition, we have conducted a series of studies in rats, demonstrating that estrogenization (endogenous or exogenous) will protect females from fat -induced insulin resistance. Based on these findings, we propose that men and non-replaced post-menopausal women will exhibit fat-induced insulin resistance, whereas, adequately estrogenized women will be protected. We will test these ideas, not only by employing the lipid/heparin infusion glucose clamp technique, but also by placing experimental subjects on control and high fat diets. It is also possible that adequate estrogen can ameliorate the effects of other physiologic causes of insulin resistance. Thus, we also will conduct studies to determine whether estrogenization can protect women from the insulin resistance

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induced by obesity and aging. Using muscle biopsy samples collected during the glucose clamp studies, we will conduct experiments aimed at identifying cellular mechanisms for these protective effects of estrogens. We also propose an extensive series of animal studies, in which we will explore in more detail the mechanisms of estrogen protection from fat-induced insulin resistance. We will conduct studies in normal male and female rats, ovariectomized rats, and old estrogen deficient female rats+/- treatment with estradiol, an estrogen antagonist, or estrogen receptor isoform specific agonists. Studies in mice with deletion of the alpha or beta forms of the estrogen receptor, as well as muscle specific estrogen receptor specific knockout animals are also proposed. We will also determine whether the fat cell secreted protein ACRP3O is modulated by estrogen status, and whether the insulin sensitizing effects of ACRP3O are responsible for the estrogen induced protection from insulin resistance. If the concepts contained in this application prove correct, then these findings could have significant implications concerning the mechanisms of insulin resistance as well as the treatment and possibly prevention of this disorder. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ETIOLOGY, HORMONAL CRITERIA OF 3 BETA HSD DEFICIENCY Principal Investigator & Institution: Pang, Songya; Professor; Pediatrics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2002; Project Start 01-JUN-1998; Project End 31-MAY-2004 Summary: (adapted from the applicants abstract) The clinical spectrum of 3bhydroxysteroid dehydrogenase (3b-HSD) deficiency (def) congenital adrenal hyperplasia (CAH) ranges from the severe form manifesting ambiguous genitalia, saltwasting, and hypogonadism to the less severe form manifesting premature pubarche (PP), pubertal onset hirsutism and menstrual disorder. Three hypotheses are advanced in this proposal: 1) Hormonal diagnosis (Dx) for the mild late-onset variant of 3b-HSD def, mild or severe, may reveal hormonal criteria which differ from the past published criteria for diagnosing the late-onset disorder; 2) Study of adrenal (Ad) 3b-HSD activity in carriers for 3b-HSD def may support or exclude the existence of an Ad 3b-HSD isoenzyme; and 3) The hormonal features of mildly decreased Ad 3b-HSD activity, leading to late-onset disorder in the past, may be associated with the insulin resistance of polycystic ovary syndrome (PCOS). We propose 5 specific aims: 1) the hormonal criteria via genotypic proof for mild to severe 3b-HSD def by a) analysis of the type II 3b-HSD gene encoding Ad and gonadal 3b-HSD in patients with various clinical/hormonal spectra of decreased Ad 3b-HSD activity; b) characterizing the mutant gene function in vitro, and c) correlating the genotype to hormonal/clinical phenotype of mild and severe variants of 3b-HSD def; 2) Ad 3b-HSD activity in the carriers of 3b-HSD def by a) identifying hormonal profiles in family members of patients with the 3b-HSD gene mutations b) comparing Ad hormonal profiles in carriers to the genotype; 3) prenatal diagnosis of 3b-HSD CAH in fetuses at risk by a) type II 3b-HSD gene analysis from amniotic and the proband's cells, b) hormonal analysis of amniotic fluid, c) fetal outcome verification; 4) association between the hormonal marker of mildly decreased Ad 3b-HSD activity and the insulin resistance of PCOS by examining A0 insulin sensitivity (SI) in the patients and control subjects, b) comparing SI to the Ad/ovarian components of androgen secretion; 5) long term outcome by periodic examinations of growth, maturation of H-P-O axis sensitivity and Ad 3b-HSD activity hormonally in girls with PP and the hormonal marker of mildly decreased Ad 3b-HSD activity. The proposed study will help to define the hormonal criteria essential to accurately diagnose patients with variants of 3b-HSD def CAH, examine the potential

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Insulin Resistance

existence of an Ad 3b-HSD isoenzyme, verify accuracy of prenatal Dx of 3b-HSD def, and determine whether the hormonal features of mildly decreased Ad 3b-HSD activity are associated with insulin resistance and are a marker of PCOS from childhood to adulthood. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: EXERCISE AND ENERGY/SUBSTRATE UTIL IN BLACKS WITH NIDDM Principal Investigator & Institution: Schuster, Dara P.; Associate Professor; Internal Medicine; Ohio State University 1960 Kenny Road Columbus, Oh 43210 Timing: Fiscal Year 2002; Project Start 15-APR-1998; Project End 31-MAR-2004 Summary: African Americans (AA) have a 2-3 fold higher prevalence of type 2 diabetes mellitus (DM), greater disease-associated morbidity and mortality and earlier age of onset than Caucasian Americans (CA). The etiology for these differences is unclear but has been related to insulin resistance and an increased prevalence of obesity. Thus, investigations into racial differences in metabolic and energy aspects of type 2 DM in AA will provide important data on the increased prevalence of both obesity and type 2 DM in the AA population when compared to CA. The aims of the study include: 1) To examine racial differences in substrate utilization, energy expenditure, insulin sensitivity, glucose effectiveness and beta cell function before and after chronic exercise in AA and CA subjects with type 2 DM, 2) To determine the effects of chronic excercise on the resting metabolic rate (RMR), postprandial thermogenesis and substrate oxidation in CA and AA subjects with type 2 DM, 3) To compare the effects of resistance vs. Aerobic training on substrate oxidation and energy expenditure and 4) to determine whether the sequential pattern of exercise is associated with different metabolic and energy consequences in CA an dAA subjects with type 2 DM. The proposed study is a prospective exercise intervention program in AA and CA subjects with type 2 DM. The study population will consist of 75 AA and 75 CA subjects with type 2 DM. The time frame for study participation will be 26 weeks. On study day 1, each subject will undergo screening laboratory data, assessment of glucose turnover rates with D-3 3H glucose infusion and concomitant IGTT and indirect calorimetry. On study day 2, each subject will have a dual energy x-ray absorptiometry (DEXA) scan and a magnetic resonance imaging (MRI) scan for assessment of body composition and body fat distribution. On study day 3, insulin sensitivity, glucose effectiveness and beta-cell function will be assessed using the Bergman Minimal Model Methodology. The subjects will then be randomly allocated to begin either 8 weeks of aerobic or resistance training with a crossover to the other exercise training program for an additional 8 weeks. Each metabolic and anthropometric study will be prformed four times; upon entry to the study, after completion of each of the exercise programs, and 8 weeks after the exercise intervention. This study will provide insights into the metabolic abnormalities assoicated with type 2 DM in AA and the importance of exercise intervention in the AA and CA population. The findings of the present study could be the basis of prescribing an effective exercise modality in AA patients with type 2 diabetes mellitus. I believe my past experience has prepared me for a career in academic research as an independent investigator. The proposed K08 grant will help me to achieve these goals as wellas become competivitie for Public Health Service and other national funding. This project is a continuum of previous research in which I have been involved while it examines and area of glucose metabolism in which little is known, the racial differences in the effects of exercise on glucose metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FACTORS THAT MODIFY INSULIN ACTION Principal Investigator & Institution: Buse, Maria G.; Professor; Medicine; Medical University of South Carolina 171 Ashley Ave Charleston, Sc 29425 Timing: Fiscal Year 2002; Project Start 01-MAY-1978; Project End 31-MAR-2003 Summary: "Glucose toxicity" accounts for insulin resistance in uncontrolled Type I diabetes (IDDM) and contributes to insulin resistance in Type II diabetes (NIDDM). Sustained hyperglycemia or hyperinsulinemia cause insulin resistance; glucose and insulin act synergistically in down- regulating insulin-stimulated glucose transport. A hypothesis to be tested in 3T3-Ll adipocytes is that glucose/insulin induced glucose transport desensitization reflects altered subcellular trafficking of the glucose transporter, GLUT4, which may involve impaired GLUT4 translocation and inappropriate association of GLUT4 containing vesicles (GCV) with the plasma membrane. Products of the hexosamine synthesis pathway (HNSP) have been implicated in glucose-induced insulin resistance; glutamine-fructose-6-P amidotransferase (GFAT) is the rate limiting enzyme and UDP-N-acetyl glucosamine (UDP-GlcNAc) the major product. The role of HNSP will be tested by examining whether conditions which increase or decrease flux via HNSP augment or mitigate, respectively, glucose induced insulin resistance. O-GlcNAcylation is a reversible process, involving O-glycosylation of proteins on Ser/Thr residues with monosaccharide GlcNAc. It usually involves phosphorylation sites and may be regulatory. Based on preliminary data in muscles of a mouse model of insulin resistance, over-expressing GLUTI in muscle, the hypothesis will be tested that increased flux via HNSP promotes O-GlcNAcylation of critical proteins involved in insulin- stimulated glucose transport. These may include GSV-associated proteins, possibly GLUT4 itself and/or proteins associated with GSV docking and fusion. Since adaptive regulation usually involves multiple sites, we will test the hypothesis that glucose-induced insulin resistance represents in part down-regulation of the insulin receptor (IR) signaling cascade, attempt to identify the major regulatory sites and critically assess the possible contribution of HNSP to the glucose effect. If warranted, the involvement of modulators of IR signal transduction, I.E. protein kinase C (PKC) isoforms, and candidate protein tyrosine phosphatases (PTP-ases: PTP-1B, SH-PTP2 and LAR) will be examined. GFAT activity is allosterically regulated by UDP-GlcNAc, and is modulated in vivo in muscle by the hormonal and metabolic milieu. The pre- and posttranslational regulation of GFAT expression will be studied in muscles of rodent models. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FATTY PRODUCTION

ACID

REGULATION

OF

LIVER

LIPOPROTEIN

Principal Investigator & Institution: Ginsberg, Henry N.; Professor; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): Lipotoxicity involves the excess delivery of fatty acids (FA) to sites other than adipose tissue. In vivo, fatty acids (FA) can arrive at the liver bound to albumin or as components of TG (TG)-enriched remnant lipoproteins (chylomicron and VLDL). In the latter instances, FA can be liberated from remnants by the action of hepatic lipase bound to capillaries in the hepatic vascular bed or released from lysosomes after receptor-mediated internalization of remnant lipoproteins. In addition to exogenously derived FA, increased availability of FA may result form their

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Insulin Resistance

synthesis in the liver from acetylCoA via lipogenesis. The latter pathway has been linked recently to insulin resistance and hyperinsulinemia. The liver is unique in that it is able to "unload" excess FA in bulk form by assembling and secreting apoBlipoproteins. There are few data, however, concerning the effects of FA from each of the sources described above on the two-step process of apoB-lipoprotein assembly: the first step involves the targeting of nascent apoB across the ER membrane and assembly of a lipid-poor primordial lipoprotein, while the second step involves the bulk addition of core lipid to the primordial particle and the formation of the mature TG-rich apoBlipoprotein. Importantly, it is not known if each of the pathways involved in providing increased FA within the hepatocyte impacts equally on FA synthesis and oxidation, genes involved in TG synthesis, or genes involved in the assembly and secretion of apoB-lipoproteins. The link between insulin resistance/hyperinsulinemia and increased VLDL secretion is also incompletely defined. In particular, the relative importance of hepatic lipogenesis versus plasma FA uptake by the liver in the increased apoBlipoprotein secretion observed in insulin resistant animal models and humans has not been studied. The experiments proposed in this project are directed at unanswered questions related to FA regulation of apoB-lipoprotein assembly and secretion, including: (1) the effects of plasma albumin-delivered FA on each of the steps in apoBlipoprotein assembly and the expression of genes involved in maintaining hepatic lipid homeostasis; (2) the effects TG-rich remnant-like particle-delivered FA on apoBlipoprotein assembly and gene expression; and (3) the relative importance of insulin resistance/hyperinsulinemia versus increased plasma FA availability in the reaulation of apoB-lipoprotein assemblv and secretion. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FLOTILLINS AND INSULIN-STIMULATED GLUCOSE TRANSPORT Principal Investigator & Institution: Bickel, Perry E.; Internal Medicine; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 01-FEB-2002; Project End 31-JAN-2007 Summary: With the epidemic of obesity and the population's aging the prevalence of type 2 diabetes mellitus is increasing. Insulin resistance is a hallmark of type 2 diabetes. This application's long-term objectives are to understand how insulin's signals are communicated within cells and how this process is defective in insulin resistant states. The adipocyte plays a central role in insulin resistance, and skeletal muscle is the major site of glucose disposal after a meal. Preliminary results in adipocytes lead to the hypothesis that the membrane protein flotillin-1 recruits specific signaling molecules to a compartment of the plasma membrane and that this recruitment is required for the increase in cell surface glucose transporters that occurs in response to insulin. These events constitute a second signaling pathway required for insulin-stimulated glucose transport that is independent of phosphatidylinositol 3-kinase. Specific Aim 1 is to define the function of flotillin-1 in glucose metabolism by manipulating its expression in cultured adipocytes and muscle cells. Relationships between flotillin-1 expression level and indices of glucose metabolism and insulin action will be determined. Specific Aim 2 is to define the function of flotillin-1 in glucose metabolism with genetically engineered mice. Mice that overexpress flotillin-1 in adipose tissue and in skeletal muscle and mice that express no functional flotillin-1 will be generated and their phenotypes carefully analyzed with respect to glucose and lipid metabolism. These genetically engineered mice will be valuable reagents to study the physiology of whole body glucose homeostasis. Specific Aim 3 is to investigate the regulation of flotillin-1 by identifying the proteins that interact with it in the yeast two-hybrid system. Completion of these

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aims should yield testable hypotheses about the role of flotillin-1 in human health and disease and in the pathophysiology of type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: FOXA2 IN METABOLISM Principal Investigator & Institution: Stoffel, Markus; Professor; Lab/Metabolic Diseases; Rockefeller University New York, Ny 100216399 Timing: Fiscal Year 2003; Project Start 30-SEP-1998; Project End 31-JUL-2008 Summary: (provided by applicant): Obesity results from a massive expansion of white adipose tissue and recruitment of adipocyte precursor cells and is a common cause of insulin resistance and diabetes. Obesity may arise from increased fat cell size due to lipid accumulation or increased number of adipocytes arising from differentiation of preadipocyes to mature adipocytes. The processes that control adipogenesis include the coordinated expression of a complicated transcription factor network and numerous cellular and hormonal signals. We have recently identified the winged-helix forkhead transcription factor Foxa2 (Hnf-3_) to be expressed de novo in visceral and subcutaneous fat of genetic mouse models of obesity and diet-induced obesity. In these insulin resistant mice, the expression of Foxa2 correlates with serum insulin concentrations. Expression of Foxa2 in preadipocytes blocks adipocyte differentiation by directly activating the gene encoding adipocyte differentiation factor-1 (Pref-1). In addition, Foxa2 is a potent transcriptional activator of "insulin sensitizing" genes. We hypothesize that Foxa2 is a counter regulatory factor in the development of obesity and may be a "biomarker" of insulin resistance. To test this hypothesis we are proposing a series of molecular and genetic studies to elucidate the role of Foxa2 in adipocytes in vitro and in vivo. In aim 1 we will examine the role of Foxa2 in adipocyte differentiation and gene expression in vitro. In aim 2 we will generate and characterize animal models that either lack Foxa2 expression or overexpress Foxa2 in adipocytes. In aim 3 we are proposing to study two functional domains of Foxa2 that are important for its transcriptional activity. In aim 4 we will generate and characterize tissue-specific mutant "knock-in" mice that express a constitutive active form of Foxa2 in pancreatic islets, adipose tissue and liver, due to the loss of a putative Akt-dependent phosphorylation site. Lastly, we will perform a feasibility study to test if FOXA2 expression in adipose tissue of humans correlates with insulin resistance and therefore may be useful as a biomarker (aim 5). Together, this proposal will 1.) Help to establish the role of Foxa2 in adipocyte differentiation and obesity, 2.) Elucidate novel, posttranscriptional mechanisms that are important for Foxa2 activity, 3.) Investigate the link between FOXA2 adipocyte expression and obesity/insulin resistance in humans and 4) contribute to our basic understanding of transcriptional pathways that are regulated by insulin. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: FREE FATTY ACIDS AND HEPATIC INSULIN RESISTANCE Principal Investigator & Institution: Boden, Guenther; Professor; Medicine; Temple University 406 Usb, 083-45 Philadelphia, Pa 19122 Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-JAN-2008 Summary: (provided by applicant): Hepatic insulin resistance resuIting in increased endogenous glucose production (EGP) is a major factor in the pathogenesis of type 2 diabetes (T2DM) Increased plasma levels of free fatty acids (FFAs) which are characteristically seen in obese individuals, have been established to cause peripheral

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Insulin Resistance

(muscle) as well as hepatic insulin resistance. Most of the research efforts in recent years have focused on peripheral insulin resistance. Mainly due to methodological problems, hepatic insulin resistance has not received much attention. Recently, however, several methods have become available which allow non-invasive measurement of in vivo rates of gluconeogenesis (GNG) and glycogenolysis (GL), the two components of EGP. Using the 2H2O method, we have recently shown in healthy volunteers that acute elevations of plasma FFAs cause hepatic insulin resistance through inhibition of insulin suppression of GL. In the current application, we plan to expand these findings. In Specific Aim 1, we propose to assess dose dependency, duration and possible gender differences of the effects of acute elevation of plasma FFAs on insulin suppression of GL/EGP in healthy subjects and in patients with mild and severe T2DM. These studies will involve measurements of rates of GL, GNG and EGP during euglycemic-hyperinsulinemic clamping (in normal controls) or during isoglycemic-hyperinsulinemic clamping (in patients with T2DM) with and without simultaneous infusion of heparinized lipid (at different rates of infusion) to acutely raise plasma FFAs to different levels. In Specific Aim 2, we propose to evaluate effects of prolonged elevation of plasma FFAs on hepatic insulin sensitivity. The experimental approach will be to lower plasma FFAs overnight (12 h) with Niaspan (a nicotinic acid analog) and to measure insulin suppression of GL/EGP the next morning (during hyperinsulinemic clamping) in obese patients with mild or severe T2DM. In Specific Aim 3, we will address the mechanism by which elevated FFAs cause hepatic insulin resistance. Specifically, we will test the hypothesis that FFA mediated hepatic insulin resistance is associated with intrahepatic accumulation of diacylglycerol (DAG), activation of protein kinase C (PKC), with increased serine and decreased tyrosine phosphorylation of IRS-1/2, and a decrease in PI3 kinase responses to insulin. The experimental approach will be to sacrifice rats at various time intervals during hyperinsulinemic-euglycemic clamping performed with and without lipid/heparin infusions and determine hepatic concentrations of DAG, PKC activity and isoforms, IRS1/2, tyrosine phosphorylation and PI3 kinase activity. These studies will hopefully provide much needed information relative to important details and mechanisms of FFA induced hepatic insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENE EXPRESSION IN PREDIABETES: POTENTIAL ROLE OF PGC-1 Principal Investigator & Institution: Patti, Mary E.; Assistant Professor of Medicine; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2007 Summary: (provided by applicant): Since both genotype and environmental risk factors for diabetes, including obesity and inactivity, converge to influence cellular function at the level of gene and protein expression, we hypothesize that alterations in gene expression in nondiabetic individuals at high risk for developing diabetes ("prediabetes") mediate this risk. In our recent array studies of differential gene expression in skeletal muscle from Mexican-American subjects, we identified a pattern of coordinate reduction in expression of multiple nuclear respiratory factor (NRF)regulated genes of oxidative metabolism and mitochondrial function in insulin resistant and diabetic subjects. We have now identified a potential molecular mechanism for these changes: decreased expression of PGC-1, a coactivator of both NRF and PPARgamma-dependent transcription linked to mitochondrial biogenesis and function. Quantitative RT-PCR demonstrates that PGC-1 expression is reduced in insulin resistant and diabetic subjects and correlates with obesity, insulin resistance, and free fatty acid

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levels. Taken together, these data form the basis of our hypothesis that reductions in PGC-1 and NRF-dependent metabolic gene transcription play an important role in metabolic changes characteristic of insulin resistance and diabetes progression, including inabililty to modulate lipid oxidation, intramuscular lipid accumulation, and further insulin resistance. We will test this hypothesis in 2 additional populations at high risk for diabetes: subjects with a family history of diabetes and African-American ethnicity. Moreover, we will test the specific hypotheses that obesity and inactivity mediate risk in prediabetes via reduction in PGC-1 and NRF-dependent gene expression, and evaluate whether weight loss and physical training can increase PGC-1 expression and reverse abnormal patterns of metabolic gene expression in parallel with improved insulin sensitivity. Finally, since it is difficult to dissect the contribution of individual metabolic risk factors to reductions in PGC-1 expression in humans, we will utilize cultured cells to test whether nutrient excess and/or insulin resistance can directly reduce PGC-1 expression, and determine whether experimental reductions in PGC-1 expression can directly induce intracellular triglyceride accumulation and/or insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GENETIC LIPODYSTROPHIES

AND

METABOLIC

BASIS

OF

FAMILIAL

Principal Investigator & Institution: Garg, Abhimanyu; Professor of Internal Medicine; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 15-MAY-1999; Project End 31-MAR-2003 Summary: Obesity is a major health problem in the U.S. However, how adipose tissue disorders cause insulin resistance and related metabolic diseases is not known. Study of single gene disorders of adipose tissue may elucidate the mechanisms involved in these processes. Congenital generalized lipodystrophy (CGL) is an autosomal recessive disorder that results in almost complete absence of adipose tissue. Familial partial lipodystrophy, Dunnigan variety (FPLD) is an autosomal dominant disorder characterized by gradual loss of subcutaneous adipose tissue in both the upper and lower extremities during early adolescence, and excessive adipose tissue on the face and neck. Other common features include insulin resistance, diabetes mellitus, hypertriglyceridemia, low levels of high density lipoprotein, acanthosis nigricans and in some women, hirsutism and menstrual abnormalities. The genetic basis and pathophysiology of the metabolic complications in these disorders is not known. The project therefore has two aims: 1) to characterize metabolic abnormalities in patients with CGL and FPLD and 2) to identify the molecular basis of these disorders. To accomplish these aims, we have collected a number of well-characterized pedigrees. We will study body fat distribution by anthropometry and whole body magnetic resonance imaging and will measure insulin sensitivity, plasma lipoproteins, free fatty acids, glycerol and other metabolic variables. We have localized the FPLD gene to chromosome 1q21-22 by genome-wide linkage analysis. Similar studies are underway to localize the gene for CGL. Following chromosomal localization and fine mapping, candidate genes, already mapped or identified by positional cloning into these regions will be examined for mutations using the single strand conformation polymorphism (SSCP), denaturing high performance liquid chromatography (DHPLC) or direct sequencing. The identification of gene defects will allow us to define the normal role of these genes in insulin action and body fat distribution and will lead to a better understanding of how common adipose tissue disorders such as obesity cause insulin resistance and other metabolic complications.

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Insulin Resistance

Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: GLUCOSE TRANSPORTER REGULATION IN OBESITY AND DIABETES Principal Investigator & Institution: Kahn, Barbara B.; Chief; Beth Israel Deaconess Medical Center St 1005 Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 01-FEB-1992; Project End 31-JAN-2006 Summary: Recent studies challenge long-held paradigms about the role of specific insulin target tissues in whole body insulin action and in the pathogenesis of insulin resistance. Studies in this application will investigate the importance of the Glut4 glucose transporter in muscle and adipose tissue, and the dynamic interactions by which altering glucose transport in one of these tissues may cause insulin resistance in other insulin target tissues including liver. The overall goal is to determine the role of glucose transport in adipose tissue and in muscle in whole body glucose homeostasis. Our preliminary data indicate that markedly reducing Glut4 expression selectively in adipose tissue causes insulin resistance and glucose intolerance which are as severe as knocking out Glut4 from muscle. This is important since in humans with obesity and type 2 diabetes, Glut4 expression is down-regulated in adipocytes but not in skeletal muscle. We also find that mice with muscle specific Glut4 knockout eventually become insulin resistant in fat and liver. We will investigate the molecular mechanisms for these effects. Specific aims are: 1) To determine the mechanisms by which altering Glut4 expression selectively in adipocytes affects whole body glucose homeostasis. 2) To determine what genes/molecules mediate the effects of altered Glut4 expression in adipocytes on whole body glucose homeostasis. 3) To determine the role of brown adipose tissue in the insulin resistance caused by reduced Glut4 expression is adipose tissue. 4) To determine the mechanisms by which altering Glut4 expression selectively in muscle affects insulin action in other tissues. 5) To determine whether combined knockout of Glut4 from adipose tissue and muscle will lead to greater insulin resistance than knockout from either tissue alone and how this is affected by genetic background. These studies will lead to a better understanding of the mechanisms for regulation of glucose homeostasis and the role of impaired glucose transport, which is present in adipocytes and muscle of humans with obesity and type 2 diabetes, in the pathogenesis of insulin resistance. Our goal is to find new therapeutic targets to prevent or ameliorate type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: GLYCEMIC INDEX, OBESITY, INSULIN RESISTANCE AND CVD RISK Principal Investigator & Institution: Ludwig, David S.; Assistant Professor of Pediatrics; Children's Hospital (Boston) Boston, Ma 021155737 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2006 Summary: (provided by applicant): The prevalence of obesity has risen dramatically among children in the U.S. since the 1960s. Effective treatment of childhood obesity is widely recognized as instrumental to public health efforts to combat type 2 diabetes and heart disease. Evidence from animal studies, short-term human studies and epidemiology suggests that diets designed to minimize the rise in postprandial blood glucose, that is low glycemic index, may be useful in the treatment of obesity and related complications. This project proposes two studies involving obese adolescent subjects age 13 to 18 years: 1) a randomized controlled trial examining the effectiveness

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and practicality of a low glycemic index diet in the treatment of obesity and prevention of related complications; 2) a cross-over feeding study investigating the physiological effects of weight-maintaining diets differing in glycemic index on insulin resistance and CVD risk factors under controlled conditions. Study 1 involves 90 subjects randomly assigned to receive standard dietary treatment or a macronutrient-controlled low glycemic index diet. Each subject and at least one parent will received intensive nutritional counseling for 6 months, with follow-up for an additional 6 months. Both diet groups will receive identical treatment intensity, behavioral modification and physical activity recommendations. The primary endpoint will be change in percent body fat by dexa-scan at 12 months; other outcomes include insulin resistance and CVD risk factors. Compliance will be assessed by interviewer-administered, 24-hour dietary recalls. Study 2 involves 24 subjects who will be randomly assigned to received marconutrient-controlled low or high glycemic index diets prepared in a metabolic kitchen for 4 weeks. Subjects will be admitted to the GCRC at baseline and at the end of each dietary treatment for measurement of insulin sensitivity by hyperinsulinemic euglycemic clamp, endothelium-dependent flow-mediated dilation of the brachial artery and other cardiovascular disease-related outcomes. The two studies are expected to provide complementary information regarding the effects of dietary glycemic index on childhood health. The project's key personnel and consultants include individuals with a diversity of expertise and perspective, ensuring a rigorous and impartial evaluation of study hypotheses. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HEPATIC FATTY ACID METABOLISM AND INSULIN RESISTANCE Principal Investigator & Institution: Stefanovic-Racic, Maja; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2009 Summary: (provided by applicant): Insulin resistance is a hallmark feature of type 2 diabetes mellitus (DM) and is also present in many obese individuals and the majority of those with the metabolic syndrome. Fasting plasma free fatty acids (FFA) are frequently elevated in these subjects and significant controversy surrounds the role of hepatic FFA oxidation in the development of insulin resistance. Previous studies have been limited by the absence of a specific activator of this pathway. However, our preliminary data demonstrate that this issue can be addressed directly for the first time by overexpression of the enzyme carnitine palmitoyltransferase I (CPT I), a major intracellular regulator of beta-oxidation. This proposal has two primary goals. The first is to provide the applicant with the skills necessary to become an independent clinical investigator in the field of lipid metabolism and type 2 DM. Training aims; 1. To expand the candidate's theoretical background in the biochemistry of metabolic disorders. 2. To gain experience in the design and interpretation of metabolic studies. 3. To learn many of the practical techniques necessary to pursue a career in metabolic research. The second goal is to perform novel research into the role of L-CPT I in hepatic fatty acid metabolism, particularly as it relates to the development of insulin resistance, liver steatosis and type 2 DM. Research aims: In Aim 1, we will test the hypothesis that increased activity of L-CPT I in hepatocytes in vitro will promote fatty acid oxidation, while reducing acyl-CoA esterification, intracellular triglyceride (TG) accumulation and very low-density lipoprotein (VLDL) secretion. In Aims 2, 3 and 4, CPT I will be overexpressed in vivo, in the liver of normal rats, high-fat fed obese/insulin resistant rats and ZDF obese/diabetic rats, respectively. Elevated hepatic L-CPT I is expected to have similar effects on lipid metabolism as proposed for in vitro studies. We

36

Insulin Resistance

hypothesize that such alterations will decrease or prevent lipid accumulation in the liver. This is expected to: (1) enhance insulin sensitivity in normal rats (Aim 2); (2) ameliorate the disregulation of liver fatty acid metabolism associated with the development of insulin resistance in the high-fat fed animals (Aim 3); and (3) prevent or reverse the abnormalities of fatty acid metabolism that accompany the fully diabetic phenotype in ZDF rats (Aim 4). Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIGH FAT DIET ALTERATIONS IN MUSCLE INSULIN SIGNALING Principal Investigator & Institution: Yaspelkis, Ben B.; Kinesiology; California State University Northridge 18111 Nordhoff St Northridge, Ca 91330 Timing: Fiscal Year 2004; Project Start 01-APR-2000; Project End 31-MAR-2007 Summary: (provided by applicant): To better understand how insulin resistance develops, a variety of models have been utilized. The high fat fed rodent model displays many commonalities to the abdominal obesity syndrome found in insulin resistant adults. However, the basis of skeletal muscle insulin resistance in this model is unclear due to reports that PI 3-kinase activity is decreased, and equivocal if Akt activation, atypical Protein Kinase C phosphorylation, GLUT4 protein concentration and GLUT4 translocation are altered. The insulin signaling cascade and glucose transporter effector system is considerably more complex than what has been previously evaluated and more importantly, the mechanism by which high fat feeding induces these alterations has not been addressed. In addition, while skeletal muscle insulin resistance can be reversed, the basis for these improvements in a high fat fed rodent model have not been fully elucidated. Therefore, the aims of this proposal are to determine: 1) the mechanism of chronic high fat feeding induced skeletal muscle insulin resistance, how the defects are manifested in the insulin signaling cascade and glucose transporter effector system and if the IkB-alpha pathway contributes to the development of skeletal muscle insulin resistance and 2) if those factors associated with high fat feeding-induced skeletal muscle insulin resistance can be corrected or if improvements in insulin-stimulated glucose transport result from a compensatory mechanism. The resolution of these issues has implications for advancing our understanding of how dietary composition induces impairments in carbohydrate metabolism and how skeletal muscle insulin resistance can be corrected. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: HIV PROTEASE INHIBITORS AND GLUCOSE TRANSPORT Principal Investigator & Institution: Mueckler, Michael M.; Professor; Cell Biology and Physiology; Washington University Lindell and Skinker Blvd St. Louis, Mo 63130 Timing: Fiscal Year 2002; Project Start 15-JAN-2002; Project End 31-DEC-2004 Summary: (Provided by the applicant): The advent of HIV protease inhibitor (PI) therapy was a major advance in the treatment of HIV infection. Combined treatment of HIV-infected patients with reverse transcriptase inhibitors and PIs (intensive antiretroviral therapy, IART) has been shown to delay the onset of overt disease and to prolong survival. Current guidelines recommend the use of IART for the treatment of all newly diagnosed cases of HIV infection. Unfortunately, IART is associated with the development of numerous metabolic abnormalities, including peripheral lypodystrophy, hyperlipemia, insulin resistance, glucose intolerance, and type 2 diabetes. The reported incidence of type 2 diabetes in PI-treated patients is at least 10fold greater than that in the general age- and sex-matched population and is particularly

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alarming considering the relatively young age of the patient populations and the rapidity of diabetes onset after the start of therapy. PIs have recently been shown to rapidly and selectively suppress the activity of Glut4, the insulin-responsive glucose transporter, an effect that can directly account for the insulin resistance and increased incidence of diabetes associated with PI therapy. The long-term goal of this proposal is to elucidate the relationship between the effect of PIs on Glut4 and the metabolic abnormalities associated with IART and to determine the mechanism of the effect of PIs on Glut4 activity. To accomplish these goals, the following specific aims will be pursued: 1) To determine the acute effect of PIs on whole body glucose disposal and glucose transport in skeletal muscle. This aim will directly test the hypothesis that Pls acutely induce whole-body insulin resistance via the inhibition of skeletal muscle Glut4. 2) To determine whether PIs suppress insulin-stimulated glucose transport by direct binding to Glut4. This aim will ascertain whether the PI effect is due to competitive or noncompetitive binding to Glut4 or binding to a molecule involved in the regulation of Glut4 activity in the plasma membrane. 3) To determine whether PIs suppress the activity of Glut isoforms other than Glut4. This aim will address a potentially important clinical issue: whether PIs, as a result of the inhibition of one or more of the other 8 known Glut isoforms, may have iatrogenic effects that have not yet been detected. 4) To determine the structural determinants of Glut4 interaction with PIs. This aim will identify specific Glut4 domains and amino acid residues involved in its predicted binding to PIs. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: HIV SYNDROME X & PROTEASE INHIBITORS: HUMAN STUDIES Principal Investigator & Institution: Reaven, Gerald M.; Professor of Medicine; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-SEP-2000; Project End 31-JUL-2005 Summary: This proposal is based on the premise that insulin action varies widely in patients with HIV/AIDS, and that the untoward effects of protease inhibitors (Pis) occur in individuals with pre- existing insulin resistance. It is also postulated that type 2 diabetes, is more likely to develop in patients co-infected with hepatitis-C virus (HCV). To test these hypotheses we will determine glucose tolerance, lipoprotein, insulin action on muscle and adipose tissue, insulin secretory function, and plasma concentration of soluble cellular adhesion molecules in 150 individuals, 125 patients with HIV/AIDS (50 percent co-infected with HCV) in whom treatment with Pis is soon to be initiated, and 25 subjects with HCV only. The results of these studies will: 1) define the pre-treatment variation in insulin action and secretion in these patients; 2) test the hypothesis that preexisting insulin resistance and hyperinsulinemia determines prevalence of risk factors for type 2 diabetes and coronary heart disease (CHD): and 3) compare risk factors for CHD and type 2 diabetes in HCV-positive and HCV-negative patients with HIV/AIDS. All baseline measurements will be repeated three months after treatment with Pis. These data will provide a prospective assessment of the effect of Pis on relevant variables, as well testing the hypotheses that: 1) the more insulin resistant and hyperinsulinemic an individual at baseline, the greater the untoward impact of PI: 2) the lipolytic effect of Pis results in day-long elevations in plasma FFA concentrations, that correlate closely with the decrease in insulin action and dyslipedemia in PI-treated patients; and 3) the increase in risk factors for type 2 diabetes will be accentuated in patients co-infected with HCV. Patients with HIV/AIDS will then be studied to see if replacing saturated fat (SF) with monounsaturated (MF)/polyunsaturated (PF), rather than carbohydrate (CHO), is more likely to maximally attenaute the abnormalities in PI-treated patients

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Insulin Resistance

secondary to insulin resistance and hyperinsulinemia and lower LDL-cholesterol concentration. Specifically, patients will be studied after two randomly assigned dietary periods of four weeks (divided by a two-week washout period), consuming diets containing (as percent of calories) either 15 percent protein. 55 percent CHO and 30 percent fat, or, 15 percent, 40 percent CHO and 45 percent fat. SF will be less than 10 percent of calories in both diets, and the MF/PF ratio kept constant. Measurements will be made of fasting and postprandial plasma glucose, insulin, FFA, triglyceride, and lipoprotein at hourly intervals from 8 AM to 4 PM. It is postulated that all CHD risk factors will be accentuated on the 55 percent CHO diet. The results of these studies will help explain why untoward metabolic and clinical events occur with PI treatment, and define the diet most likely to decrease risk of type 2 diabetes and CHD in these patients. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IMPAIRED BETA CELL GENE EXPRESSION IN A MODEL OF NIDDM Principal Investigator & Institution: Griffen, Steven C.; Assistant Professor; Medicine; University of California Davis Sponsored Programs, 118 Everson Hall Davis, Ca 95616 Timing: Fiscal Year 2002; Project Start 01-FEB-2000; Project End 31-JAN-2004 Summary: NIDDM results from at least two defects, namely reduced insulin secretion from pancreatic beta-cell and resistance to insulin action. At least 25% of the nondiabetic population has insulin resistance in the diabetic range. What distinguishes those who eventually develop diabetes if the failure to overcome the insulin resistance by increasing insulin production and secretion. The nature of the impaired beta-cell function in the majority of cases of NIDDM remains unknown. The Zucker fatty rat has severe insulin resistance and hyperlipemia, but does not develop diabetes. A sub-line derived from these rats, the Zucker diabetic fatty (ZDF) rat has similar insulin resistance but the males develop diabetes due to impaired insulin secretion and in this regard are similar to most humans with NIDDM. The proposed studies will investigate the nature of the beta-cell defect in the ZDF rat model of NIDDM. Preliminary experiments have demonstrated a defect in insulin gene transcription in these animals. The activity of key elements in the insulin promoter will be tested in transfected primary ZDF rat beta-cells. Extracts of nuclear proteins will be screened for alterations in the quantities of transcription factors which are known to be key regulators of the insulin promoter. The effects of free fatty acids on gene expression in the ZDF beta-cell will also be determined. These studies will define the beta-cell defect in the ZDF rat and may help give insight into the defects in insulin production and secretion seen in NIDDM. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INFLUENCE ADOLESCENCE

OF

INSULIN

ON

BP

CHANGE

DURING

Principal Investigator & Institution: Sinaiko, Alan R.; Professor; Pediatrics; University of Minnesota Twin Cities 200 Oak Street Se Minneapolis, Mn 554552070 Timing: Fiscal Year 2002; Project Start 05-MAY-1995; Project End 31-MAY-2004 Summary: (Adapted from the Investigator's Abstract) This research application is a continuation of a project initiated in 1995 to study insulin resistance in children. The primary objectives are (1) to define the relation of insulin resistance (defined by the euglycemic insulin clamp) during childhood and adolescence to the development of the insulin resistance syndrome (i.e., hypertension, dyslipidemia, obesity, and insulin resistance) in young adulthood; and (2) to define the relation of the insulin resistance

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syndrome within families and the importance of genetics to that relation. The original cohort consists of 357 children who have had two euglycemic insulin clamp studies (at mean ages 13 and 15 years). The specific aims are: to (1) repeat anthropometric and blood pressure measurements at mean ages 18, 19, and 20 and obtain insulin clamps, lipid levels, echocardiograms, and DEXA at mean age 21 in the children; and (2) obtain the measurements, blood and DNA samples, echocardiogram, and insulin clamp in the parents and siblings of the children. Statistical genetics methods will be used to estimate heritability and genetic correlations among the insulin resistance syndrome traits. These data will address the hypotheses that 1) insulin resistance in childhood will predict insulin resistance and cardiovascular risk factors in young adulthood; 2) insulin resistance in parents will be associated with insulin resistance and cardiovascular risk factors in their children; 3) in fat children, BMI and insulin resistance at mean age 13 will predict cardiovascular risk, but in thin children only insulin resistance will be a similar predictor; 4) insulin resistance has significant heritability; and 5) there are significant genetic correlations between insulin resistance and the insulin resistance traits. It is anticipated that at least 300 of the original cohort of 357 who have had two euglycemic insulin clamps will complete the five years of this continuation. The investigators state that the significance of this project lies in its potential to define the factors influencing development of the insulin resistance syndrome and provide the basic clinical data required to begin to study genetic patterns of cardiovascular disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN ACTION IN MUSCLE & FAT CELL Principal Investigator & Institution: Lawrence, John C.; Professor; Pharmacology; University of Virginia Charlottesville Box 400195 Charlottesville, Va 22904 Timing: Fiscal Year 2002; Project Start 01-APR-1981; Project End 31-MAR-2006 Summary: Insulin lowers blood glucose by stimulating glucose uptake and storage in various target tissues, the most important being liver, skeletal muscle, and fat. The failure to respond appropriately to insulin results in a rise in blood sugar. Type II diabetes mellitus develops if beta cells become unable to release enough insulin to compensate for the insulin resistance. Determining the processes involved in the normal response to insulin will be essential for understanding insulin resistance, and the overall objective of this project is to define mechanisms involved in the actions of insulin in skeletal muscle and fat cells. Initial aims are to investigate the stimulation of glycogen synthesis by insulin. This effect is of particular importance in the control of blood glucose levels, as most of the glucose taken up following a meal is deposited as glycogen in skeletal muscle. Experiments in Aim 1 are proposed to investigate both the mechanism through which insulin activates glycogen synthase (GS), the enzyme that synthesizes glycogen from uridine diphosphoglucose (UDPG), and the importance of increasing GS activity in the stimulation of glycogen synthesis. Treating rats with insulin results in a marked decrease in muscle UDPG, implying that the activity of UDPG pyrophosphorylase (PPL) may limit the rate of glycogen synthesis. Objectives of Aim 2 are to determine whether UDPG PPL is subject to hormonal and/or metabolic control, and to investigate the potential limiting role of UDPG PPL in glycogen synthesis in rodent and human muscles. In the last two Aims we will investigate new targets of insulin action. We have recently discovered an adipocyte protein, designated betaip140, which is phosphorylated in response to insulin and coimmunoprecipitates with the beta isoform of protein kinase B (PKB). By purifying betaip140 and sequencing peptides by tandem mass spectrometry, we have shown that betaip140 is the product of the Kiaa0188 gene, recently identified by genetic fine mapping as a candidate gene for the

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Insulin Resistance

fld mouse phenotype. Mice homozygous for the fld gene exhibit insulin resistance, glucose intolerance, and markedly diminished adipose tissue mass. Aim 3 is to investigate the potential interactions between betaip140 and PKBbeta, to define the mechanisms controlling betaip140 phosphorylation, and to determine the role of betaip140 in insulin action. Many other proteins that are phosphorylated in response to insulin can be detected, but have not been identified. This represents a serious gap in our understanding of insulin action, since at least some of the proteins are likely to represent downstream targets that are involved in the important metabolic responses to insulin. The objective of Aim 4 is to identify these new targets. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN AND THE POLYCYSTIC OVARY SYNDROME Principal Investigator & Institution: Nestler, John E.; Professor and Chairman; Internal Medicine; Virginia Commonwealth University Richmond, Va 232980568 Timing: Fiscal Year 2002; Project Start 01-AUG-1997; Project End 31-JUL-2005 Summary: The polysystic ovary syndrome (PCOS) is a poorly understood disorder that affects approximately 6-10 percent of women of reproductive age. PCOS is characterized by hyperandrogenism and chronic anovulation, and is the leading cause of female infertility in the United States. Women with PCOS are also at high risk for developing type 2 diabetes, presumably due to the insulin resistance that accompanies the syndrome. Our long-term goal is to elucidate the relationship between insulin resistance and PCOS, especially as it relates to hyperandrogenism. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action and a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in individuals with impaired glucose tolerance or type 2 diabetes. Our studies indicate that D-chiro-inositol (DCI) administration improves glucose intolerance while reducing circulating insulin in women with PCOS, and is also associated with decreases in serum androgens and improved ovulatory function. In addition, our in vitro studies in human thecal cell cultures suggest that the IPG signaling system plays a role in transducing insulin's stimulation of ovarian androgen biosynthesis. These studies have led us to focus our short- term goals on an assessment of the role of the IPG signaling system in PCOS, and pursue a unifying hypothesis to explain the above experimental observations. Our hypothesis is that women with PCOS are DCI deficient, perhaps related to an intracellular defect in the conversion of myoinositol (MYO) to DCI. This results in a decrease in a DCI-containing IPG mediator (DCI-IPG) and an increase in a MYO-containing IPG mediator (MYO-IPG) bound to the outer leaflet of the cell membrane. We further propose that the resulting deficient insulin-mediated release of DCI-IPG contributes to insulin resistance in PCOS, whereas the simultaneous hyperinsulinemia mediated increased release of MYO-IPG at the level of the ovary acts to stimulate ovarian androgen biosynthesis. If our proposed studies confirm a role for IPG's in insulin resistance and hyperandrogenism of PCOS, they will substantially enhance our understanding of the disorder's pathogenesis and are likely to provide insights into novel treatment strategies directed specifically at the IPG system and normalization of its function. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INSULIN MEDIATED GLUCOSE TRANSPORT DISRUPT BY ETHANOL. Principal Investigator & Institution: Nagy, Laura E.; Associate Professor; Nutrition; Case Western Reserve University 10900 Euclid Ave Cleveland, Oh 44106

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Timing: Fiscal Year 2003; Project Start 01-APR-1998; Project End 31-MAR-2008 Summary: (provided by applicant): Non-insulin dependent diabetes mellitus (type 2 diabetes) is the most common metabolic disease among older North Americans. Epidemiological studies suggest that chronic alcohol consumption is a risk factor for type 2 diabetes. Chronic ethanol consumption is associated with insulin resistance and impaired glucose tolerance; however, the mechanisms by which ethanol disrupts glucose homeostasis are not well understood. In the past granting period, we have investigated the molecular and cellular mechanisms by which acute and chronic ethanol disrupt glucose transport by adipose and muscle, two major sites of insulin-stimulated glucose disposal. Insulin-stimulated glucose transport is dependent on phosphatidylinositol-3 kinase (PI-3 kinase). However, we have found that long-term ethanol feeding decreases both insulin- and endothelin-1-stimulated glucose uptake by PI-3 kinase independent mechanisms in rat adipocytes. We have also discovered that TNF( is required for chronic ethanol-induced suppression of glucose transport in adipocytes. TNF( is a potent inducer of insulin resistance. Since chronic ethanol exposure is associated with increased expression of TNF( we hypothesized that TNF( may play a role in ethanol-induced insulin resistance. Consistent with this hypothesis, adipocytes from transgenic mice lacking the TNF( receptor I do not develop insulin resistance after ethanol feeding. We have also found that co-culture with ethanol sensitizes 3T3-L1 adipocytes in culture to TNF(-induced insulin resistance. The objective of the current application is to further explore the mechanisms by which ethanol disrupts the regulation of glucose transport, focusing on the novel targets for ethanol action we have identified including PI 3-kinase independent signaling mechanisms and the role of TNF( in chronic ethanol-induced insulin resistance. We will 1) investigate the effects of chronic ethanol feeding on in vivo glucose production and utilization using tracer methodologies, 2) identify the insulin-stimulated PI 3-kinase independent signaling pathways that disrupt hormone-stimulated glucose transport in adipocytes after chronic ethanol exposure, 3) investigate the mechanisms by which chronic ethanol prevents the final fusion of the GLUT4 vesicle with the plasma membrane and 4) determine the role of increased inflammatory cytokine expression in the development of chronic ethanol-induced insulin resistance in adipocytes. Investigation of the mechanisms by which chronic ethanol disrupts glucose transport provide information useful for development of strategies to either prevent or reverse the long-term effects of ethanol on glucose homeostasis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RECEPTOR SUBSTRATES AND INSULIN ACTION Principal Investigator & Institution: Kahn, C Ronald.; Director; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-DEC-1983; Project End 31-MAY-2008 Summary: (provided by applicant): This is a competitive renewal of NIH grant DK33201-19 entitled "Insulin Receptor Substrates and Insulin Action" which focuses on studying the role of phosphorylation, in particular of the insulin receptor substrates and their partners, in the mechanism of insulin action. Over the past four years we have studied the similarities, differences and potentially complementary roles of various insulin receptor substrates in coupling the insulin receptor tyrosine kinase to downstream effector systems through the creation and characterization of knockout mice and knockout cell lines; studied the role of the IRS proteins in adipocyte differentiation, glucose transport and control of apoptosis; defined a role for SOCS proteins in insulin resistance; and begun to determine the subcellular compartmentalization and

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differential partnering of the major IRS family members;. This work has led to the realization that IRS proteins mediate different insulin signaling pathways by providing complementary information, that the exact balance of signaling proteins may affect insulin action both positively and negatively, and that these pathways can be altered in a variety of genetic and nongenetic ways, in insulin resistant states. The specific aims for the next five years are to: 1) Define the role of specific IRS proteins and their downstream partners in control of gene expression by using Affymetrix oligonucleotide microarrays and cells lacking specific IRS proteins or in which insulin signaling has been blocked by specific pathway inhibitors. 2) Determine the role of the subcellular compartmentalization and trafficking, and the interaction of the IRS proteins and their downstream partners in intact cells using immunofluorescence confocal imaging, 3dimensional real time imaging, and FRET analysis. 3) Define the role of the SOCS proteins as inhibitors of IRS mediated signaling in acquired and genetically programmed insulin resistance in vivo using anti-sense and by creating insulin resistance in mice heterozygous for deletion of SOCS-1 and SOCS-3. 4) Determine if the genetic modifiers of insulin resistance in the IR/IRS-1 double heterozygous knockout mouse are similar to or different from those in acquired insulin resistance. Identify the chromosomal loci and the specific genes in these loci which modify insulin resistance in the double heterozygous mouse leading to marked differences in diabetic phenotype in C57B1 and 129Sv mice. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE /DIET OF HISPANIC WOMEN W/ BREAST CAN Principal Investigator & Institution: Duarte-Gardea, Maria O.; University of Texas El Paso El Paso, Tx 79968 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Background: Breast cancer is the most common cancer among women. A relationship has been hypothesized between insulin resistance and breast cancer. To our knowledge, no study has investigated the relationship among insulin resistance, energy and fat intake, and breast cancer in Hispanic women. The purpose of this project is to test the hypothesis that fasting insulin and other markers of insulin resistance, along with energy intake and dietary fat, will be significantly higher among Hispanic women diagnosed with breast cancer compared to those with no indication of cancer. Specific aims: Our aims are to compare the following characteristics among women with and without breast cancer: Aim 1) markers of insulin resistance and Aim 2) total energy and total fat intake. Aims 3) demographic, anthropometric, and reproductive, and Aim 4) lifestyle and dietary factors and their association with diagnosis of breast cancer. Design/Methods: A prospective case-control study of Hispanic women attending the University Breast Care Center at Texas Tech University Health Sciences Center at El Paso for routine breast examination will be conducted. Markers of insulin resistance including obesity, waist/hip ratio, blood pressure, acanthosis nigricans, fasting insulin, fasting glucose, and lipid profile will be performed in four hundred eligible participants. Subjects will complete a three-day food record to determine total energy and fat intake. Case and control groups will be formulated once the data are collected and after mammogram and pathology reports have been filed. The case group includes 100 subjects with breast cancer. Three controls (matched by age +/5 years) and menopausal status) for each case will be located from the pool of total participants. We will perform correlation and factor analyses to identify variables and/or factors which would best represent each of the four classes of independent

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variables as outlined in the specific aims section. We will then use logistic regression analysis to examine the relationship between the categorical response (diagnosed with and without breast cancer) with the set of independent variables identified above. The proposed work will advance the understanding of the associations of insulin resistance, diet and breast cancer in Hispanic women. Individual risk factors (anthropometric, health, reproductive, lifestyle and dietary) may be identified. There is a need for research that focuses on a comprehensive approach to insulin resistance, dietary lifestyle choices, and breast cancer and that emphasizes a fat-caloric intake-insulin resistance linkage. Such information is critical for the design of health education interventions that seek the adoption of healthy lifestyle in low income Hispanic population through community-based culturally relevant and tailored prevention programs, and public policy recommendations. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND ADENOMAS OF THE COLORECTUM Principal Investigator & Institution: Byers, Tim E.; Professor of Preventive Medicine; Preventive Med and Biometrics; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: There is considerable evidence that insulin and/or insulin-like growth factors (IGFs) can increase risk of colorectal neoplasia. Epidemiologic risk factors for colorectal neoplasia are similar to those for insulin resistance syndromes, and prospective studies have shown both diabetes and higher levels of IGF-1 to be associated with colorectal cancer risk. No previous studies have included direct measures of insulin resistance, nor have any included complete ascertainment of colorectal neoplasia by direct examination of the entire colorectum. This study will assess the relationship between insulin resistance and colorectal neoplasia by taking advantage of a unique opportunity to examine a multi-ethnic cohort on whom prior measures of insulin sensitivity have been made. The Insulin Resistance and Atherosclerosis Study (IRAS) is a cohort study supported by the National Heart Lung and Blood Institute. IRAS examined 1628 people of average age 55 in 1991-1994 for atherosclerosis risk factors. The cohort, assembled in four clinical centers (Alamosa, Co., Los Angeles, Oakland, and San Antonio) was established to be multi-ethnic (34 percent Hispanic, 28 percent African American, and 38 percent non-Hispanic white), bi-gender, and varied in diabetes risk. In 1998-1 999 over 85 percent of the surviving cohort was re-examined. Both of the examinations have included measures of self-reported risk factors for atherosclerosis (diet, physical activity, tobacco use, family history) as well as anthropometry and, most importantly, oral glucose tolerance testing and frequently-sampled intravenous glucose tolerance tests (FSIGT). The FSIGT is a sensitive and specific measure of insulin resistance. All surviving cohort members (estimated 1518) will be invited to have a screening colonoscopy. Feasibility data indicate that 1000 will agree to have a colonoscopic exam, among whom we estimate 240 (range 206-274) will have adenomas. Mucosal biopsies will be taken from the cecum and rectum of all subjects, and all adenomas will be removed and examined for histologic features, Ki-ras mutations, proliferation, and apoptosis. Serum samples will be assayed for insulin, IGF-1, IGFBPI, and IGFBP3 levels for all cohort members at both the time of colonoscopy, as well as at the time of two earlier examinations (199 1-4 and 1998-9) using stored serum samples. This study offers the advantage of the availability of prospective measures of glucose tolerance, insulin resistance, measurements of most colorectal neoplasia risk factors, and the availability of stored blood samples from a multi-ethnic and bi-gender cohort. Complete colorectal

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visualization of this entire cohort will enable unbiased estimates of colorectal neoplasia risk related to these factors. This study therefore offers a time-efficient and a costefficient method to test the hypothesis that colorectal neoplasia risk is increased substantially by factors related to insulin resistance, and to examine the biologic mechanisms whereby that risk is increased. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND COLON CANCER IN BLACKS AND WHITES Principal Investigator & Institution: Keku, Temitope O.; Associate Professor; Medicine; University of North Carolina Chapel Hill Aob 104 Airport Drive Cb#1350 Chapel Hill, Nc 27599 Timing: Fiscal Year 2002; Project Start 17-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): The long-term goals of this project are to define the interactions between insulin resistance, genetic and environmental risk factors in the etiology of colon cancer and to achieve further career development training for the applicant in molecular epidemiology and bioinformatics. Dr. Keku, the applicant, is an Assistant Professor at UNC. Her mentors are Drs. Robert Millikan and Kay Lund. Dr. Millikan is an established molecular epidemiologist. He is the Principal Investigator of the Carolina Breast Cancer Study and also part of an international collaboration investigating the interactions between sunlight and genetic factors in the etiology of malignant melanoma. Dr. Lund is a Professor of Molecular Biology and Physiology and an expert on the IGF system as it relates to GI disease. They propose a mentored career training for Dr. Keku in molecular epidemiology and bioinformatics utilizing the resources at the UNC School of Public Health and the Department of Cell and Molecular Physiology in the School of Medicine. The study proposed as part of the mentored career development training is a case-control study of insulin resistance (insulin/IGF) and colon cancer in African Americans and whites. Colon cancer is the most common gastrointestinal malignancy in the United States. The rise in the incidence and mortality of colon cancer in African Americans poses a serious public health problem. The specific aims of this study are: 1)To examine the association between insulin/IGF axis and colon cancer in African American and white subjects with and without colon cancer. 2) To evaluate the role of genetic polymorphisms in the insulin/IGF axis and their relationship to colon cancer and associated risk factors. 3) To examine the association between the insulin/IGF-axis and factors related to insulin resistance in African American and white subjects with and without colon cancer. The proposed study will utilize available specimens and measurements from a population based case-control study of colon cancer (NCI R01 CA66635). We will use plasma and DNA specimens to determine insulin, IGF-I, IGF-II, IGFBP-1, IGFBP-3, glucose and C-peptide levels and for genotyping assays respectively. The results of the laboratory assays will be merged with lifestyle/dietary information and analyzed for associations. The proposed project will advance the understanding of the role of insulin resistance in colon cancer among African Americans and whites. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INSULIN RESISTANCE AND POLYCYSTIC OVARY SYNDROME Principal Investigator & Institution: Brown, Ann J.; Medicine; Duke University Durham, Nc 27706 Timing: Fiscal Year 2002; Project Start 15-SEP-2002; Project End 31-JUL-2007

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Summary: (provided by applicant): This career development proposal details a plan for the Principal Investigator to obtain the training and experience necessary to develop an independent career as a clinical investigator. By conducting the proposed study, the PI will develop skills that will enable her to study the effects of exercise on insulin resistance in polycystic ovary syndrome (PCOS), and that will be relevant to many career pathways. PCOS is a common disorder affecting up to 10% of young women. It is characterized clinically by hirsutism and oligo/amenorrhea. Recent studies have documented significant insulin resistance in this population suggesting an important predisposition to long-term complications such as diabetes and cardiovascular disease. The early onset and large affected population create a powerful opportunity to harness the positive effects of lifestyle changes for purposes of disease prevention. However, the hirsutism and obesity associated with PCOS may create psychological barriers to change. For this reason, effective management may require a tailored approach that takes into account psychosocial issues as well as metabolic profile. Physical activity is an ideal intervention for this group. Exercise reduces insulin resistance, improves cardiovascular health and enhances sense of wellbeing. However, the type, duration and intensity of exercise that will optimally reduce insulin resistance, and that is well tolerated, has not been established. This study is meant to address these issues by answering the following questions about women with PCOS: 1. In a randomized controlled clinical trial, does a 12 week program of monitored exercise of moderate intensity, without weight loss, significantly improve insulin sensitivity as measured by an intravenous glucose tolerance test? What is the relative magnitude of the acute effect compared to the chronic effect of exercise on insulin sensitivity? 2. Does exercise that reduces insulin resistance also decrease androgen levels? 3. Does exercise improve indicators of perceived body image, quality of life, stress and depression? Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE AND VASCULAR DYSFUNCTION Principal Investigator & Institution: Raji, Annaswamy; Brigham and Women's Hospital 75 Francis Street Boston, Ma 02115 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-DEC-2006 Summary: (provided by applicant) Epidemiological studies have shown that Asian Indians (AI) are insulin resistant (IR) and at risk for diabetes and coronary artery disease (CAD) when compared to Caucasians (C) of northern European ancestry. The increased risk of CAD in AI is not explained by the traditional risk factors like hypertension and lipid abnormalities suggesting that other factors play a role. A preliminary study by our group demonstrated that compared to C matched for body mass index (BMI) and age, AI were more IR and had altered body fat distribution. Recently there has been considerable interest in the role of insulin resistance in the pathogenesis of other physiological disorders, including endothelial dysfunction. Independent data suggests that IR states like obesity, type 2 diabetes and as well as young normoglycemic IR first degree relatives of diabetics have endothelial dysfunction. Based on these data, this project has its primary goal to test the hypothesis that healthy AI have IR, altered body fat distribution and endothelial dysfunction compared to C matched for age and BMI. We also hypothesize that Al have greater endothelial dysfunction compared to C with similar degrees of insulin resistance. The secondary goal is to determine whether insulin sensitizers can improve IR and endothelial dysfunction in AI compared to C. We hypothesize that reversing insulin resistance using insulin sensitizers will correct endothelial dysfunction to a lesser degree in AI when compared to C with comparable insulin resistance. Healthy AI, C, and first degree relatives of Caucasian diabetics

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matched for BMI and age will undergo euglycemic hyperinsulinemic clamp to assess IR, brachial artery ultrasound to asses endothelial function in the basal and insulin stimulated states, CT scan to measure abdominal fat. It is anticipated that AI will be IR and have decreased endothelium dependent vasodilation in the basal and insulin stimulated states. AI will have greater degree of endothelial dysfunction compared to C with similar degrees of IR. The ability of the insulin sensitizers to improve IR and endothelial function will be examined in both AI and C. Subjects will be placed on pioglitazone for 16 weeks and will undergo all the tests done for the initial study. It is anticipated that there will be a substantial improvement of IR, endothelial function, and body fat distribution in Al compared to C matched for age and BMI. When compared to C with similar IR, we expect that AI will have lesser degree of improvement of their endothelial function, reflecting the presence of residual vascular dysfunction that contributes to their excess risk of CAD. There may be a substantial benefit to understand the underlying mechanism of IR and endothelial dysfunction in AI. This will enable us to initiate specific therapy to prevent diabetes and CAD in this ethnic group. Expertise and teaching from my mentors and a rich research environment at the Brigham & Women's Hospital will enable me to become an independent physician scientist. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INSULIN RESISTANCE IN PCOS--SEQUELAE AND TREATMENT Principal Investigator & Institution: Legro, Richard S.; Associate Professor; ObstetricsGynecology; Pennsylvania State Univ Hershey Med Ctr 500 University Dr Hershey, Pa 17033 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2006 Summary: (Adapted from the applicant's description): The immediate goals of the PI are to expand the focus of his research from familial forms of polycystic ovary syndrome (PCOS), and genetic influences on the development of the syndrome into areas with even greater clinical impact. Specifically the goals of this application are to 1) identify other unrecognized morbidity that results from insulin resistance in PCOS and in the long term. 2) expand the clinical trials of improving insulin sensitivity as a primary treatment modality in PCOS. Another long-term goal is to develop within the medical center a cadre of investigators interested in PCOS patient-oriented research. The overall hypothesis of this proposal is that insulin resistance is the fundamental pathophysiologic defect in women with PCOS, that its effects can be protean and unrecognized, and that metabolic abnormalities worsen with age. Our preliminary studies suggest that insulin resistance is major contributor to both the etiology of PCOS and its association with sleep apnea. We propose further studies to clarify the role of insulin resistance in both PCOS and control female populations on sleep disorders. We theorize that there is enhanced steroidogenesis in endometrial glandular and stromal cells from women with PCOS and this is further stimulated by hyperinsulinemia. We intend to study these hypotheses in endometrial tissue form PCOS women and appropriate controls. Our preliminary experience suggests that insulin resistance over time will lead to a worsening of glucose tolerance and other metabolic markers in PCOS women with an improvement in reproductive abnormalities such as anovulation and hyperandrogenemia. We propose to identify clinical interventions in PCOS women that will improve insulin sensitivity and manifestations of the syndrome. Improving insulin action through diet and exercise, with and without weight loss, will result in lowered circulating insulin levels, lowered androgens and increased ovulatory frequency rate in PCOS women. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INSULIN RESISTANCE IN TISSUE SPECIFIC IKKB TRANSGENICS Principal Investigator & Institution: Lee, Jongsoon; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Our studies in insulin resistant cells and animals, and type 2 diabetic patients showed that the IkappaB kinase, IKKbeta, plays a central role in acquired insulin resistance. In 3T3-L1 adipocytes and Fao hepatoma cells, activation of IKKbeta by treatment of TNF or by transfection of upstream kinase, NIK, or constitutively active IKK, induced cellular insulin resistance-decreased insulinstimulated Tyr phosphorylation of IR and IRSs. Inhibition of IKKbeta by specific inhibitors- high doses of salicylates (NaS) or aspirin (ASA)- or by transfection of dominant negative IKKbeta reversed TNF-induced insulin resistance. Treatment of high doses of NaS or ASA to type 2 diabetes patients or obese and insulin resistant animals reversed insulin resistance as judged by glucose tolerance test (GTT), insulin tolerance test (ITT) and hyperinsulinemic, euglycemic clamp studies. Hyperglycemia, hyperinsulinemia, and dyslipidemia are normalized by ASA treatment. Insulin signaling studies conducted with tissues isolated from the rodents show that insulinstimulated Tyr phosphorylation of IR and IRS are increased due to decrease in inhibitory Ser/Thr phosphorylation of IRSs. Heterozygous deletion (IkkBeta +/-) in mice reduced fasting glucose and insulin concentrations, and protected against the development of insulin resistance during high-fat feeding and in obese Lep-ob/ob mice. We also found that obese animals have higher IKK kinase activity than control animals. To study which tissue(s) are important for IKK-mediated insulin resistance and for the reversal of insulin resistance by salicylates, we generated mice expressing constitutively active IKKbeta in fat, muscle and liver with the hypothesis that increasing IKKbeta activity in animal tissues may itself induce insulin resistance. We now have colonies of all three tissue transgenic mice and found that fat- and liver-specific transgenic mice have developed insulin resistance as early as 4 week-old. We will characterize these mice to determine which tissue is responsible for IKKbeta-induced insulin resistance and how activation of IKKbeta in one tissue can induce whole body insulin resistance. These experiments will validate IKKbeta as a major mediator of insulin resistance and as a useful target for the discovery of new drugs to treat type 2 diabetes and insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: INTEGRATED CONTROL OF MUSCLE GLUCOSE UPTAKE IN VIVO Principal Investigator & Institution: Wasserman, David H.; Professor & Director; Molecular Physiol & Biophysics; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 15-FEB-1999; Project End 31-JAN-2004 Summary: The research described in this proposal aims to study the mechanisms by which diet composition and regular exercise influence basal and insulin- stimulated muscle glucose uptake (MGU) in vivo. MGU will be assessed in terms of three serial steps: delivery to glucose to the muscle, transport of glucose across the sarco-lemma, and phosphorylation of glucose intracellularly. Each of these steps has been studied in isolation, and much is known about their regulation. These protocols bridge the biochemical and hemodynamic observations with the whole body measurements of insulin action made in healthy and insulin resistant states. The experimental model used is the conscious rat, fed chow or a high fat diet that produces insulin resistance. In some

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protocols, rats will undergo exercise training, an intervention which increases insulinstimulated MGU. The control of MGU will be assessed in vivo using novel isotopic (30[3H]methylglucose, [U-14C]mannitol,2-deoxy- [3H]glucose) techniques in combination with methods for sampling blood and tissues and measuring hemodynamics. The thread that links the proposed experiments is that the control of MGU is distributed between glucose delivery, transport and phosphorylation. An extension of this distributed control is that conditions of insulin resistance or increased insulin action can be caused at each step involved in the control of MGU. The specific aims of the proposed experiments are to determine in the whole organisms: 1) The key site(s) of regulation (extracellular, sarcolemma, intracellular) of MGU in chow-fed rats and the site(s) that are dysfunctional in rats made insulin resistant by high fat feeding; 2) The mechanism(s) by which insulin-stimulated MGU is improved following exercise training; 3) The mechanism(s) by which muscle morphological differences due to fiber type affect MGU; and 4) How barriers to MGU correspond to and are affected by hemodynamics and the expression and compartmentation of the primary skeletal muscle isozyme of hexokinase. The hope is that, by identifying sites of regulation and dysfunction, these studies will allow optimal sites of therapy to be identified and targeted so that people with insulin resistance can be treated most effectively. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: INTERPLAY BETWEEN GONADAL STEROIDS AND INSULIN IN MEN Principal Investigator & Institution: Hayes, Frances J.; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JUN-2000; Project End 31-MAR-2005 Summary: (taken from the application) The overall goal of this proposal is to define the causal determinants of the inverse relationship between insulin resistance and testosterone in men. Conducting studies in normal men, lean first degree relatives of type II diabetic patients, obese men with normal glucose tolerance, and men with type II diabetes will permit determination of whether the interaction between insulin resistance and testosterone is independent of body weight and glucose tolerance. Given the significant cardiovascular morbidity and mortality associated with obesity and type II diabetes, a clearer understanding of the interplay between testosterone and insulin resistance has important public health implications and may potentially facilitate the development of new therapeutic strategies for these extremely common metabolic disorders. Specific Aims 1-3 of this proposal will address the impact of insulin resistance on the reproductive axis in the male and will specifically: i) define the dose response relationship between increasing insulin resistance and testosterone secretion in men; ii) localize the defect induced in the hypothalamic-pituitary-gonadal (HPG) axis by insulin resistance using frequent blood sampling studies as well as GnRH and hCG testing after endogenous gonadotropin blockade with a GnRH antagonist; and iii) examine the impact on the HPG axis of reducing insulin resistance with a thiazolidinedione in men with type II diabetes. Specific Aims 4 and 5 will address the impact of testosterone on insulin resistance and will specifically: iv) define the doseresponse relationship between increasing testosterone and insulin resistance by measuring insulin sensitivity with a glucose clamp after induction of hypogonadism with a GnRH agonist and again after both physiologic and pharmacologic testosterone replacement; and v) examine the impact of testosterone treatment on insulin resistance and glycemic control in type II diabetes. The selective and sequential manipulation of sex steroid and insulin levels as outlined in this proposal will permit precise definition

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of the relationship between testosterone and insulin resistance in men to be established and their causative determinants unequivocally defined. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SYNDROME

INTRAMYOCELLULAR

LIPIDS

IN

HIV-LIPODYSTROPHY

Principal Investigator & Institution: Torriani, Martin; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-JUL-2008 Summary: (provided by applicant): The HIV lipodystrophy syndrome is a recognized complication of highly active antiretroviral therapy (HAART) that is characterized by fat redistribution and insulin resistance. Studies using 1H-magnetic resonance spectroscopy (1H-MRS) have shown strong correlation of insulin resistance with concentrations of intramyocellular lipids (IMCL) in patients with type 2 diabetes, obesity, and HIV-lipodystrophy syndrome. However, very few studies have investigated IMCL overaccumulation as a potential mechanism of insulin resistance in HIV-positive patients, and the ability of IMCL to predict insulin resistance compared to detailed measures of insulin dynamics and body-composition. Furthermore, the effect of HAART and lipolytic blockade on muscle lipid metabolism remains unknown. Investigation of mechanisms and surrogate markers of insulin resistance is critical in patients with HIV infection to guide preventive strategies for long-term increased cardiovascular risk. My first hypothesis is that IMCL are increased among insulin resistant, HIV-infected patients with the lipodystrophy syndrome, and IMCL correlates strongly with sensitive indices of fat redistribution and insulin resistance. We will quantify IMCL using 1H-MRS in HIV-infected patients with and without lipodystrophy and healthy controls, and examine relationships with detailed measures of body composition, insulin dynamics and glucose homeostasis. My second hypothesis is that lipid accumulation occurs prior to development of overt insulin resistance and is a critical pathophysiological component of the development of insulin resistance in HIVinfected patients. IMCL levels will be determined with 1H-MRS before and after initiation of HAART in acute and chronic therapy-na'fve HIV-infected patients. My third hypothesis is that chronic lipolytic blockade with Acipimox will decrease fat accumulation in muscle and improve insulin resistance in HIV-infected patients with lipodystrophy syndrome. We will measure IMCL levels during chronic therapy with Acipimox and examine relationships with dyslipidemia, insulin resistance and lipolysis rate. In summary, this proposal will utilize 1H-MRS as a novel technique to investigate metabolic changes of muscle in the HIV-lipodystrophy syndrome and determine the role of IMCL in the pathogenesis of insulin resistance in this population, in addition, the natural history of IMCL will be followed in HIV-infected patients before and after the introduction of HAART and during chronic lipolytic blockade. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRAS FAMILY STUDY--GENETICS OF INSULIN RESISTANCE Principal Investigator & Institution: Wagenknecht, Lynne E.; Professor; Public Health Sciences; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: Insulin resistance is an important risk factor for atherosclerosis. There is evidence indicating that much of the variation in insulin resistance can be attributed to genetic sources. Visceral adiposity, another important risk factor for atherosclerosis, is

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strongly correlated with insulin resistance, and this trait also appears to be under substantial genetic control. The overall goals of the proposed research project are to: 1) identify the genetic determinants of insulin resistance and visceral adiposity; and 2) determine the extent to which insulin resistance, visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. To address these goals, we will enroll 160 families of African-American and Hispanic background using participants of the Insulin Resistance Atherosclerosis Study (IRAS) as index cases. Approximately 1280 additional family members will be recruited to the study for a total of 1440 participants. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. Metabolic cardiovascular disease risk factors will also be assessed. A panel of 370 microsatellite markers will be genotyped to provide data for a genome-wide scan to detect chromosomal regions containing quantitative trait loci (QTLs) that influence phenotypic variation for insulin resistance and visceral adiposity. We will then saturate the regions of linkage identified in these analyses with additional markers and then utilize linkage disequilibrium to localize further the QTLs. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory and a genetics laboratory. Wake Forest University will be responsible for serving as the coordinating center for the study, with the responsibility for coordinating the data collection and data management and conducting statistical analyses. This project will contribute substantially to our understanding of the genetic determinants of insulin resistance, visceral adiposity, and, consequently to risk of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: IRAS FAMILY STUDY--MOLECULAR GENETICS Principal Investigator & Institution: Bowden, Donald W.; Professor; Biochemistry; Wake Forest University Health Sciences Winston-Salem, Nc 27157 Timing: Fiscal Year 2002; Project Start 15-AUG-1999; Project End 31-JUL-2004 Summary: Insulin resistance is an important risk factor for atherosclerosis. Insulin resistance varies widely within populations, and substantial evidence indicates that much of this variation can be attributed to genetic sources. Visceral adiposity, another important atherosclerosis risk factor, is strongly correlated with insulin resistance, and this trait also appears to be under substantial genetic control. The overall goals of the proposed research project are to: 1) identify the genetic determinants of insulin resistance and visceral adiposity; and 2) determine the extent to which insulin resistance, visceral adiposity, and metabolic cardiovascular disease risk factors share common genetic influences. To address these goals, we will enroll 160 families of African-American and Hispanic background who are participating in the Insulin Resistance Atherosclerosis Study (IRAS). Approximately 1280 additional family members will be recruited. Insulin resistance will be measured using the frequently sampled intravenous glucose tolerance test, and visceral adiposity will be measured using computed tomography. A panel of other metabolic cardiovascular disease risk factors will also be assessed. A panel of 370 microsatellite markers will be genotyped from DNA, and a genome-wide scan will be performed at the Mammalian Genotyping Service to detect chromosomal regions containing loci that influence phenotypic variation. We will then saturate the regions of linkage identified in these analyses with additional markers and will then perform linkage disequilibrium analyses in effort to localize further the putative loci. The organization of this study will be similar to that of IRAS, with three clinical centers, a coordinating center, a central laboratory and a

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genetics laboratory. This Molecular Genetics component of the study will (1) carry out genomic DNA isolation and quality control, (2) fill significant gaps and correct errors in data from the whole genome screen, and (3) carry out detailed analysis of chromosome regions which show evidence for linkage. This project will contribute substantially to our understanding of the genetic determinants of insulin sensitivity, and consequently to risk of atherosclerosis. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LEPTIN INDUCED REVERSAL ON INSULIN RESISTANCE IN OBESITY Principal Investigator & Institution: O'doherty, Robert M.; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 15-FEB-2001; Project End 31-JAN-2005 Summary: (Adapted from the applicant's abstract) Skeletal muscle resistance is a major contributor to the hyperglycemia, hyperinsulinemia and dyslipidemia associated with type II diabetes and obesity. Recent work has implicated leptin, the adipocyte-derived hormone, in improving insulin sensitivity. Thus, leptin administration to leptin-deficient ob/ob mice corrects hyperglycemia and hyperinsulinemia, while elevating leptin in normal rats increases insulin sensitivity. Based on these observations the effects of leptin on the metabolic abnormalities of the high-fat fed rat, a model of diet-induced obesity that more closely resembles human obesity than monogenetic obesity models, were investigated. These studies, performed by the P.I. and discussed in this proposal, demonstrate that a gene therapy intervention that elevates plasma leptin levels reverses the skeletal muscle insulin resistance and other metabolic abnormalities associated with diet-induced obesity. However, the mechanisms underlying these effects are unknown. This proposal, therefore, focuses on identification of the mechanisms underlying leptininduced reversal of skeletal muscle insulin resistance in diet-induced obesity. Three specific aims will test the hypotheses that skeletal muscle insulin resistance by leptin. These variables have been implicated in the pathogenesis of insulin resistance and the determination of muscle insulin sensitivity, and are altered by leptin. Identification of the mechanisms mediating leptin-induced reversal of muscle insulin resistance may serve as a platform for the rational design of pharmaceutical or genetic therapy of insulin resistance in human obesity and type II diabetes. Specific Aims: 1. To determine the role of altered lipid metabolism in mediating leptin-induced improvements in insulin sensitivity. 2. To determine the role of altered activity of the insulin signaling pathway in mediating leptin-induced improvements in insulin sensitivity. 3. To determine the role of altered metabolic gene expression in mediating leptin-induced improvements in insulin sensitivity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: LIPID METABOLISM IN OBESITY, WEIGHT LOSS AND EXERCISE Principal Investigator & Institution: Houmard, Joseph A.; Professor and Director; Human Performance Laboratory; East Carolina University 1000 E 5Th St Greenville, Nc 27858 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2005 Summary: (Adapted from the applicant's abstract):The long-term objective of this research is to better understand defects in human skeletal muscle that contribute to the morbidity and mortality evident with obesity. There is evidence that lipid metabolism in the skeletal muscle of obese individuals is altered in a manner favoring lipid storage. For

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example, some data indicate that obese skeletal muscle has a reduced capacity to oxidize lipid. There is also evidence that muscle-associated triglyceride concentration increases with obesity. These are important observations as the accumulation of lipid in skeletal muscle is associated with insulin resistance. The storage of lipid in skeletal muscle may thus predispose obese individuals toward insulin resistance and the many conditions linked with insulin resistance (hypertension, coronary artery disease, diabetes mellitus). Despite these important implications, the cellular mechanism that promotes lipid accretion in obese skeletal muscle is not evident. In the current application experiments are proposed that will determine the mechanism(s) responsible for promoting lipid storage in skeletal muscle with obesity and if intervention compensates or corrects the initial defect(s). The primary hypothesis is that postabsorptive (fasting) lipid metabolism in skeletal muscle is altered with obesity in a manner that promotes lipid accumulation in this tissue. This hypothesis is based upon preliminary work, where it was observed that lipid oxidation is depressed in the muscle of obese individuals in conjunction with reductions in oxidative enzyme activities. These preliminary data form the basis for the working hypothesis that lipid oxidation is depressed in skeletal muscle with obesity which promotes lipid storage. The secondary hypothesis is that weight loss does not enhance lipid oxidation, but reduces muscle triglyceride stores by an alternative mechanism. The tertiary hypothesis is that exercise training reverses the initial decrement in lipid oxidation evident with obesity, promoting lipid utilization. To test these hypotheses it will be determined: Specific Aim I - if postabsorptive lipid metabolism is impaired in skeletal muscle from obese individuals in a manner that promotes the accumulation of lipid; Specific Aim II - if the impairment in postabsorptive lipid metabolism in the skeletal muscle of obese individuals is corrected or compensated for with weight loss and; Specific Aim III - if exercise training enhances postabsorptive lipid metabolism in obese individuals and the cellular mechanisms responsible. Findings will be important as little is known concerning the mechanisms responsible for the defects in lipid metabolism with obesity and the impact of intervention. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: LIPID METABOLISM IN THE ETIOLOGY OF TYPE 2 DIABETES Principal Investigator & Institution: Dobbins, Robert L.; Internal Medicine; University of Texas Sw Med Ctr/Dallas Dallas, Tx 753909105 Timing: Fiscal Year 2002; Project Start 01-JUN-2001; Project End 31-MAR-2004 Summary: (Scanned from the applicant's description) Type 2 diabetes mellitus has major clinical and social impact, but its underlying pathophysiology is poorly understood. Since the disease is diagnosed as a disorder of carbohydrate metabolism, i.e., hyperglycemia, the possible contribution of abnormal lipid metabolism to its etiology has been largely overlooked. The predominant, obesity-related form of diabetes is characterized by hyperinsulinemia, resistance to insulin-mediated glucose disposal in skeletal muscle, and elevated plasma free fatty acid and triglyceride levels. It has been suggested that a derangement of lipid metabolism is an early event contributing to the development of both hyperinsulinemia and insulin resistance. Our laboratory has demonstrated the essential role that plasma fatty acids play in sustaining normal glucose-stimulated insulin secretion in fasted subjects, and has also utilized novel 1-H NMR spectroscopic techniques to illustrate the strong correlation between intramyocellular lipid (IMCL) content and skeletal muscle insulin resistance. In the current proposal, we seek to expand on this theme by investigating the effects of highfat feeding, pharmacologic inhibition of lipid oxidation, and leptin administration on insulin secretion and insulin sensitivity in rats and determining how these changes

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might be linked to alterations in muscle and islet triglyceride content. Because deficiencies of leptin and/or leptin signaling can precipitate the development of obesity/diabetes mellitus, it is conceivable that the primary function of leptin is to control lipid oxidation and lipolysis in a manner that prevents tissue lipid accumulation, thus maintaining normal glucose metabolism. We will administer leptin intracerebroventricularly to rats consuming a high fat diet and determine if this reverses the development of hyperinsulinemia and insulin resistance. Parallel measurements of IMCL, muscle P13-kinase activation and islet triglyceride levels will seek to establish a direct link between fat dissipation and improved function in these tissues. Future studies will explore the biochemical pathways through which leptin regulates lipid metabolism. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MECHANISMS OF CVD AND ENDOTHELIAL DYSFUNCTION IN OBESITY Principal Investigator & Institution: Hsueh, Willa A.; Professor of Medicine and Chief; Medicine; University of California Los Angeles 10920 Wilshire Blvd., Suite 1200 Los Angeles, Ca 90024 Timing: Fiscal Year 2003; Project Start 15-AUG-2003; Project End 31-MAY-2007 Summary: (provided by applicant): Endothelial cell (EC) dysfunction occurs early in the process of insulin resistance and, indeed, may be an integral component of the dysmetabolic syndrome. We hypothesize that adipokines contribute to both insulin resistance and EC dysfunction, possibly by increasing sensitivity to Angiotensin ll (Angll), in part by altering the balance between the activity of the phosphoinositol-3kinase (Pt3K) and mitogen activated protein kinase (MAPK) pathways. As a result, the progression of insulin resistance to type 2 diabetes parallels the progression of EC dysfunction to atherosclerosis. Specific Aims will be to determine: 1) The relationship of circulating adipokines to EC function in insulin sensitive (IS) vs. insulin resistant (IR) Mexican Americans (MA). The IR MA will include the spectrum of insulin resistance: early IR, IGT, and type 2 diabetes. EC function will be measured by coronary PET scanning. 2) Whether IR subjects have increased sensitivity to AngII infusion vs. age and gender-matched IS subjects as measured by blood pressure, suppression of plasma renin activity, increasing circulating hsCRP and adipokine levels, and stimulation of plasma aldosterone 3) The effect of AnglI AT1 receptor blocker (ARB) administration on insulinmediated glucose uptake, EC function, and circulating adipokines and inflammatory markers in IR subjects. 4) The correlations of insulin sensitivity and EC function with measurements of inflammatory gene expression, MAPK and PI3K activity in subcutaneous fat biopsies of IS vs. IR subjects and of (IR) subjects before and after treatment with an ARB. 5) The correlation of EC function with insulin sensitivity, circulating adipokines, and fat adipokine expression in the Zucker lean vs. obese rat models. The results of these investigations will help to 1) identify potential mechanisms by which adipokines alter signaling mechanisms and increase sensitivity to Angll to impair EC function and 2) determine the effect of RAS inhibition on adipokine levels and expression as related to insulin-mediated glucose uptake and EC function. These studies potentially have direct clinical applications as they promise to determine where in the spectrum of insulin resistance and EC dysfunction RAS inhibition is warranted to prevent development of the endpoints of diabetes and atherosclerosis. Early intervention is critical if we are to prevent these two major diseases, which may, indeed, be the same disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MENTORED DEVELOPMENT AW

PATIENT

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Principal Investigator & Institution: Barry-Carr, Darcy; Obstetrics and Gynecology; University of Washington Grant & Contract Services Seattle, Wa 98105 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): Pre-eclampsia, a hypertensive disorder unique to pregnancy, is a leading cause of maternal and neonatal morbidity and mortality. Endothelial dysfunction is a central feature in the pathophysiology of pre-eclampsia. Mechanisms that have been suggested to contribute to the endothelial dysfunction of pre-eclampsia include insulin resistance and a hyperdynamic circulation (high cardiac output). Insulin resistance and high cardiac output persist postpartum, suggesting that these women have an underlying disorder. However, it is unclear whether these abnormalities are related and whether insulin resistance has a role in producing hemodynamic alterations and endothelial dysfunction in these women. The investigator hypothesizes that postpartum women who have a history of pre- eclampsia are insulin resistant and have associated alterations in hemodynamics and endothelial function. Furthermore, she hypothesizes that insulin resistance has a causal role in producing these changes. Two specific aims have been identified to address these hypotheses: 1) to determine whether the insulin resistance present in postpartum women with a history of pre-eclampsia is associated with altered hemodynamics and endothelial dysfunction; and 2) to determine whether reversing insulin resistance in women with a history of pre-eclampsia, is associated with improvements in hemodynamics and endothelial function, thus suggesting that insulin resistance is a causative factor in women with these abnormalities. A casecontrol study will address the first specific aim. A double-blind, placebo-controlled, randomized study will address the second specific aim by using an insulin sensitizing agent, rosiglitazone, as an interventional tool. The results of these studies could provide a rationale for future investigations aimed at determining whether treating insulin resistance in women with a history of pre-eclampsia will decrease the risk of recurrent pre- eclampsia in subsequent pregnancies and reduce the prevalence of the long-term metabolic and cardiovascular complications in these women as they age. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MENTORED DEVELOPMENT AW

PATIENT-ORIENTED

RESEARCH

CAREER

Principal Investigator & Institution: Mclaughlin, Tracey L.; Medicine; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2005 Summary: PROPOSAL (Adapted from the applicant's abstract): The goal of the proposed research is to define the roles played by resistance to insulin-mediated glucose disposal (insulin resistance) and circulating insulin concentrations as factors affecting: 1) the ability of obese individuals to lose weight; and 2) risk for CHD in both non-diabetic individuals and patients with Type 2 diabetes. These issues are important, as the prevalence of obesity in the U.S. has reached epidemic proportions, and is contributing to an increase in Type 2 diabetes and CHD. While obesity, insulin resistance, and diabetes are highly associated, it is not clear whether insulin resistance and compensatory hyperinsulinemia play important roles in the tendency to gain weight and/or inability to lose weight. The role of hyperinsulinemia in CHD is also unclear. In this regard, the specific aims of the proposed research are as follows: 1) to compare

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insulin resistant versus insulin sensitive nondiabetic, overweight individuals with respect to their ability to lose weight on a low calorie diet. CHD risk factors before and after weight loss will also be assessed to determine the degree to which insulin resistance is associated with increased CHD risk in non-diabetic overweight individuals, as well as the impact that differences in insulin resistance have on the metabolic benefits of weight loss. 2) To determine if weight loss and its associated metabolic benefits vary as a function of the relative amounts of dietary fat and carbohydrate in hypocaloric diets. Because high carbohydrate diets increase insulin secretion, the relationship between dietary composition and change in circulating insulin concentrations will be analyzed with respect to both weight loss and CHD risk factors. 3) To quantify and compare the improvement in glycemic control and CHD risk factors associated with weight loss in obese Type 2 diabetics, while being treated with: a) an insulin secretagogue (sulfonylurea); or b) an insulin sensitizer (thiazolidenedione). Manipulation of plasma insulin concentrations with these medications will provide a mechanism by which to evaluate the impact of circulating insulin concentrations on the described outcome measurements. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MODULATION OF VISCERAL FAT BY ESTROGENS AFTER MENOPAUSE Principal Investigator & Institution: Kohrt, Wendy M.; Professor; Medicine; University of Colorado Hlth Sciences Ctr P.O. Box 6508, Grants and Contracts Aurora, Co 800450508 Timing: Fiscal Year 2002; Project Start 15-FEB-2000; Project End 31-JAN-2005 Summary: Excess abdominal visceral fat is associated with increased risk for coronary artery disease (CAD), Type 2 diabetes mellitus (DM), and hypertension. Although premenopausal women are largely protected against abdominal obesity, visceral fat accumulation increases after the menopause and there are concomitant deleterious changes in risk factors for CAD and Type 2 DM. Estrogen replacement attenuates increases in body weight and waist girth in postmenopausal women. However, it is not known whether estrogen use prevents or diminishes the visceral fat accumulation that occurs after menopause. It is possible that protective effects of estrogen on visceral fat metabolism contribute to the currently unknown component of the cardioprotective actions of estrogens. The specific aims of the proposed studies are to determine in postmenopausal women whether: 1) estrogen use augments reductions in visceral fat; 2) estrogen use attenuates increases in visceral fat; 3) changes in visceral adiposity are related to changes in whole body and regional resistance to the suppression of lipolysis by insulin and whether this relationship is altered by estrogens; and 4) changes in visceral adiposity are associated with changes in certain risk factors for CAD and Type 2 DM independent of an in addition to the effects of estrogen. An additional aim is to determine whether raloxifene exerts similar effects as estrogens on visceral fat. Faloxifene is a popular selective estrogen receptor modulator that is being promoted as a safer alternative to estrogen not only for its osteogenic effects but also for possible cardioprotective effects. To meet these aims, 108 healthy but overweight postmenopausal women, aged 50- 60 years, will be randomly assigned a placebo, estrogen, and weight reduction program and subsequent increases in adiposity will be measured through a 12-month follow-up period during which time the hormone/drug treatment will continue. Changes in risk factors for CAD and Type 2 DM (blood lipids and lipoproteins, glucose tolerance, insulin resistance) in response to reductions and gains in visceral adiposity will be measured. Because insulin resistance is a prominent

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characteristic of abdominal obesity, the effects of estrogen/raloxifene and of changes in visceral, adiposity on the glucoregulatory and anti-lipolytic actions of insulin will be evaluated during hyper-insulinemic, euglycemic clamp procedures. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOLECULAR DEFECTS OF INSULIN SIGNALING IN PCOS Principal Investigator & Institution: Azziz, Ricardo; Professor and Chairman; CedarsSinai Medical Center Box 48750, 8700 Beverly Blvd Los Angeles, Ca 900481804 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2005 Summary: (provided by applicant): The polycystic ovary syndrome (PCOS) affects about 4% of reproductive-aged women, and is one of the most common causes of oligoovulatory infertility. Between 50% and 70% of women with PCOS demonstrate insulin resistance, independent of body weight, and the resulting compensatory hyperinsulinemia leads to the hyperandrogenic features of the disorder. Overall, little is know about the molecular aspects of the insulin signaling defects of PCOS. Previous studies have indicated that insulin-stimulated glucose transport is deficient, suggesting an alteration along the PI-3 kinase/Akt/GLUT-4 cascade. Alternatively, mitogenic activity in response to insulin appears to be normal in the fibroblasts of these patients, suggesting that the MAPK pathway may be unaffected in PCOS. Based on these observations we have hypothesized that abnormal insulin receptor (IR) signaling in adipose tissues is a frequent abnormality in women with PCOS; and that the defect is present downstream from the IR, affecting the PI-3 kinase/Akt/GLUT-4, but not the MAPK, pathway. We have also hypothesized that the insulin resistance of PCOS may be more closely related to abnormalities of visceral (omental) than subcutaneous fat. Our Specific Aim is to determine whether abnormal IR signaling is present in the adipocytes of patients with PCOS. Specifically, we will test our hypothesis by studying the abdominal subcutaneous and omental adipose tissues of 10 normal-weight or pre-obese PCOS patients and 10 age/race/body massmatched controls. In these tissues we will determine: i) the total amount and the degree of phosphorylation in response to insulin of the IR, the IR substrate-1 and 2 proteins (IRS-1/2), and of critical intermediate proteins (i.e., Akt, GSK-3, and FKHR of the PI-3 kinase/Akt cascade; c-Raf, MEK-1, ERKI/2, and p90RSK of the ERKI/2 cascade; JNK of the SAPK/JNK cascade; and p38 MAPK of the cascade of the same name) and the translational regulator p70 S6; and ii) the total amounts of GLUT-4 and IRS-associated PI-3 kinase. We should note that this systematic approach to investigating insulin signaling is critical at this early stage in the study of the mechanisms underlying insulin resistance in PCOS. Long term, these studies have the potential of eventually elucidating the etiologic mechanism(s) in some, or most, patients; helping to develop targeted therapies; and guiding the search for molecular markers for PCOS. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: MOLECULAR PHARMACOLOGY OF INSULIN RESISTANCE IN BURNS Principal Investigator & Institution: Martyn, J Jeevendra.; Professor; Massachusetts General Hospital 55 Fruit St Boston, Ma 02114 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-MAR-2006 Summary: (provided by applicant) The hypermetabolic state of burns is associated with uncontrolled catabolism of proteins, fat and carbohydrates, and affects morbidity and mortality. The associated major metabolic anomaly is resistance to the effects of insulin,

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the pivotal anabolic hormone. Among the signaling cascades activated by insulin, the insulin receptor (IR), insulin receptor substrates (IRSs), phosphatidylinositol-3phosphate kinase (PI 3-K) and Akt/PKB are central for energy metabolism and glucose homeostasis. Activated Akt/PKB in turn inhibits its downstream molecule, glucose synthase kinase-3 (GSK-3), resulting in increased protein and glycogen synthesis. Altered activation of all these signaling molecules occurs following burn injury, but the molecular mechanisms inducing these changes have not been elucidated. Many cytokines are expressed locally and systematically following burn injury, leading to increased expression of inducible nitric oxide (iNOS), and release of high levels of nitric oxide (NO). Based on compelling and convincing preliminary data, we hypothesize that iNOS, via release of NO with superoxide, plays an important role in insulin resistance of burn by altered signaling via IR, IRSs, PI 3-K, Akt/PKB and GSK-3. The following Specific Aims will test the above hypothesis in burn/sham-injured rodents in vivo, in cultured cells and in reconstituted in vitro systems: Specific Aim 1 will test the hypothesis that iNOS is required for insulin resistance. Specific Aim 2 will test the hypothesis that the exaggerated production of NO by iNOS decreases tyrosine kinase activity of IR and tyrosyl phosphorylation of IRSs. The molecular mechanism of inactivation of JR and IRSs (S-nitrosylation vs. nitration) will also be identified. Specific Aim 3 will test the hypothesis that the exaggerated production of NO by iNOS alters the kinase activity of Akt/PKB, the further downstream molecule of PI 3-K, independent of IR and IRSs. The molecular mechanisms responsible for inactivation (post-translational modifications) of Ak/IPKB by NO will also be identified. Specific Aim 4 will test the hypothesis that exaggerated production of NO by iNOS increases activity of GSK-3, due to effects related to both decreased AktJPKB activity and direct effects of NO on GSK-3. The direct role of NO on activation of GSK-3 (independent of AktIPKB) will be tested with NO donors and scavengers. The in vivo studies will include the use of burn and sham-injured rats, and iNOS knock out (-/-) and wild type (+/+) mice. Insulin mediated signaling changes, and the post-translational modifications in the signaling molecules enumerated above with and without specific iNOS inhibitor (1400W) will be evaluated. Functional changes, evaluated using 2-deoxyglucose uptake in muscle and adipocyte, will be correlated to signaling changes. Using adipocyte and myocyte cell lines and primary cultures from iNOS -/- and iNOS +/+ mice, the role of iNOS/NO will be evaluated with and without NO donors or scavengers. The role of NO will be confirmed in in vitro reconstitution system containing active signaling molecules. The posttranslational modifications (nitration vs. S-nitrosylation) associated with 1NOS/NO will be studied by biochemical, spectrophotometric and immunoblot techniques. Several lines of evidence suggest that protein S-nitrosylationl-denitrosylation and tyrosine nitration/denitration may serve as regulatory components. The involvement of NO in insulin resistance will be assessed in the light of this new concept. The immediate shortterm goals of these studies are, therefore, to characterize the molecular and biochemical mechanisms inducing insulin resistance, so that in the long-term, insulin resistance of burn injury in humans can be reversed. The studies together will thus provide significant insights into the pathogenesis of insulin resistance and provide information on novel therapeutic strategies to treat burn, and other stress or inflammation-induced insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MOUSE MODELS OF INSULIN RESISTANCE Principal Investigator & Institution: Accili, Domenico; Professor of Medicine; Medicine; Columbia University Health Sciences New York, Ny 10032 Timing: Fiscal Year 2002; Project Start 15-AUG-2000; Project End 31-JUL-2005

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Summary: (adapted from the applicant's abstract) Insulin resistance and beta cell failure play key roles in the pathogenesis of type 2 diabetes. The goal of this application is to understand the pathophysiology of these metabolic abnormalities by introducing mutations into genes important for insulin action and/or beta cell function in mice. Over the last five years, the PI's laboratory has developed several transgenic and knockout mice with mutations in the insulin receptor signaling pathway. These murine models have elucidated the metabolic role of insulin receptors in the whole animal and in insulin-dependent tissues, as well as their role in embryonic growth. Moreover, mice with combined mutations of the insulin receptor and its substrate IRS-1 have elucidated in vivo signaling mechanisms and genetic interactions leading to type 2 diabetes. The PI proposes to continue to characterize gene function using genetically engineered mice, expanding the repertoire of available mutations and completing detailed metabolic studies of existing strains. There are four aims in this proposal. In Aim 1, the PI proposes to address the pathophysiology of insulin resistance in the adult mouse by generating a model of inducible gene knockout using a novel strategy based on the Crelox binary mutagenesis system, and by characterizing mice with liver-restricted expression of insulin receptors. Studies described in Aim2 will address the role of IRS-1 and IRS-2, the two main substrates of insulin and IGF-1 receptor signaling, in insulin action. To this end, the PI will characterize mice with combined null mutations of insulin and IGF-1 receptor, IRS-1 and IRS-2, and generate an insulin receptor "knock-in" mouse with a single amino acid substitution in the Juxtamembrane domain (Y972F) to dissect the specificity of IRS-1 vs. IRS-2 signaling. In Aim 3, crosses among mice with mutations of insulin receptor, IGF-1 receptor, insulin receptor-related receptor as well as IRS-1 and IRS-2 will be used to investigate the signaling mechanism(s) required for beta cell growth and insulin secretion. Aim 4 is based on preliminary studies in which the PI identified murine quantitative trait loci (QTLs) that affect plasma insulin level by interacting with a null mutation of the insulin receptor gene. Additional mapping of the QTLs is proposed as a preliminary to positional cloning of the relevant genes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: MUSCLE GLUCOSE METABOLISM IN DIABETES AND EXERCISE Principal Investigator & Institution: Dohm, Gerald L.; Professor; Biochemistry; East Carolina University 1000 E 5Th St Greenville, Nc 27858 Timing: Fiscal Year 2002; Project Start 01-JAN-1997; Project End 31-DEC-2004 Summary: The long range objective of this research is to understand the molecular mechanism of insulin resistance in muscle tissue of obese individuals and diabetic patients. The most likely cause of insulin resistance in human muscle is decreased insulin receptor tyrosine kinase activity. The hypothesis is that hyperinsulinemia causes activation of PKC-beta which then serine/threonine phosphorylates and inactivates the insulin receptor to cause insulin resistance in muscles of obese individuals. It was previously demonstrated that: (1) insulin resistance can be induced by incubating insulin sensitive muscle with an activator of PKC. (2) Insulin action and insulin receptor kinase activity are restored in insulin resistant muscles that are treated with a PKC inhibitor. (3) PKC-beta is increased in muscle of obese individuals. (4) Insulin causes membrane associated PKC-beta to be increased in insulin resistant muscles. (5) Overexpression of PKC-beta decreases insulin signaling, and knockout of PKC-beta increases insulin signal transduction, in heart of transgenic mice. This proposal will continue to focus on the insulin receptor and PKC-beta to gain evidence to support the hypothesis. Specific Aim 1: To determine the phosphorylation pattern on the insulin receptor. Specific Aim 2: To investigate the role of hyperinsulinemia in activation of

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PKC-beta and phosphorylation of insulin receptors. Specific Aim 3: To study insulin action in muscle of PKC-beta knockout mice. Specific Aim 4: To study the serine/threonine phosphatase(s) that reactivates the insulin receptor. It will be possible to study these mechanisms because a large number of obese patients are available for study. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: NIACIN, N-3 FATTY ACIDS AND INSULIN RESISTANCE Principal Investigator & Institution: Harris, William S.; Professor; St. Luke's Hospital 4401 Wornall Rd Kansas City, Mo 64111 Timing: Fiscal Year 2003; Project Start 20-FEB-2003; Project End 31-JAN-2008 Summary: (provided by applicant): The insulin resistance syndrome (IRS) afflicts approximately 47 million Americans. Its principal components include central obesity, elevated triglycerides, decreased high density lipoprotein cholesterol (HDL-C) levels, fasting hyperglycemia, and/or hypertension. Individuals with the IRS are at significantly increased risk for developing type 2 diabetes mellitus and/or coronary heart disease (CHD). While diet and exercise can improve some manifestations of the IRS, pharmacotherapy is often needed to normalize other components. In recent studies from our laboratory, niacin and fish oil (n-3 fatty acids, FA) used in combination in individuals with the IRS improved the lipid phenotype, but also, unexpectedly, the mealinduced suppression of free fatty acid (FFA) flux (an important indicator of adipose tissue insulin sensitivity). This project will explore the clinical efficacy of combined (and mono-) therapy with n-3 FA and niacin on CHD risk factors, on triglyceride and FFA kinetics and on glucose disposal rates in subjects with the IRS. We will conduct a single, randomized, parallel-arm, placebo-controlled trial. Subjects with the IRS (per the NCEP ATP-itl guidelines) will be randomly allocated to one of four intervention groups after a one-month dual placebo run-in period. The groups will be: n-3 FA (3.4 g/d), crystalline niacin (3 g/d), the combination, or duat placebo. The latter two groups will include 20 subjects each while the two-monotherapy arms will have 10 subjects each. Effects on endpoints will be determined at baseline and after four months of treatment. The CHD risk factors include serum lipids and lipoproteins; lipoprotein(a); subfractions of HDL and of low density tipoproteins; tissue plasminogen activator and plasminogen activator inhibitor-1; and blood pressure. Triglyceride kinetics will be determined by bolus injection of 2H/5-glycerol, and FFA kinetics by isotope dilution using a constant infusion of 3H-palmitate in the fasting state, after a standard mixed meal and during the hyperinsulinemic-euglycemic clamp procedure used to evaluate glucose disposal rates. At the completion of these studies, we expect to have detailed information on the potential therapeutic efficacy and the kinetic mechanisms of action of these two nutritional agents. This should lead to more effective therapy for the dyslipidemia of insulin resistance and ultimately to reduced risk for CHD in this burgeoning patient population. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: NIDDM SUSCEPTIBILITY GENES IN A BIRACIAL COHORT Principal Investigator & Institution: Brancati, Frederick L.; Professor; Medicine; Johns Hopkins University 3400 N Charles St Baltimore, Md 21218 Timing: Fiscal Year 2001; Project Start 30-SEP-1999; Project End 31-JUL-2004 Summary: (Adapted from the Investigator's Abstract) Type 2 diabetes mellitus and its atherosclerotic complications impose a substantial burden on health of Americans in

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general and on African Americans in particular. Recent discoveries in molecular genetics have lead to the identification of functional variations in several candidate genes for susceptibility to obesity, insulin resistance, and/or diabetes. These include genes which code for beta-2and beta-3 adrenergic receptors, insulin receptor substrate 1, fatty acid binding protein 2, frataxin, and leptin receptor. If their role as novel susceptibility factors is confirmed, these variants promise to illuminate the pathophysiologic basis of diabetes and diabetes related cardiovascular diseases, accelerate the development of chemopreventive agents, and facilitate the conduct of prevention trials by marking individuals at high risk. Unfortunately many previous association studies of these mutations in human populations have been limited by small, selected study samples; by limited cross-sectional data on behavioral factors and on cardiovascular risk phenotype; and by paucity of data on African Americans. The investigators, therefore, propose to conduct an epidemiologic study of functional variants in 10 candidate genes for susceptibility to type 2 diabetes, obesity, and insulin resistance. The main objective will be to detect modest effects consistent with polygenic nature of diabetes but with better sensitivity and precision than previous association and linkage studies. The study sample will a community based cohort of 3,250 African Americans and 3,250 Whites aged 45 to 64 who are participants in the ongoing Atherosclerosis Risk in Communities (ARIC) study. Supported by NHLBI the ARIC study has assembled an extensive data base including behavioral assessment (e.g. diet and physical activity), anthropometry, laboratory blood tests (e.g. oral glucose tolerance test and serum lipids), and carotid ultrasonography as well as clinical events and mortality. Using race specific case-control, cross-sectional, and longitudinal analyses the investigators will determine if these putative diabetes alleles are associated with incident and prevalent diabetes, with obesity and weight gain, with hyperinsulinemia in non-diabetic individuals with the presence of an adverse cardiovascular risk factor profile, and with atherosclerosis progression and cardiovascular disease incidence over 12 years of follow up. The investigators will assess how behavioral and environmental factors such as obesity, diet, and physical activity, influence the expression of genetically conferred risk. Strength of this proposal include the close collaboration between clinical, epidemiologic, and laboratory researchers, a wealth of prospectively collected data from an NIH sponsored study, and a sample size large enough to detect modest gene effects and to investigate gene-gene and gene-environmental interactions. Most important, this study will provide unique information on the expression of diabetes susceptibility genes in the general population and possibly suggest genetic explanations for the excess prevalence of type 2 diabetes and obesity in African Americans. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PHYSICAL ACTIVITY ON INSULIN RESISTANCE IN THE ELDERLY Principal Investigator & Institution: Evans, William J.; Professor; Geriatrics; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2002; Project Start 30-SEP-2001; Project End 31-JUL-2004 Summary: (provided by applicant) Advancing age is associated with insulin resistance, glucose intolerance, and Type 2 diabetes. Regular higher-intensity aerobic exercise reduces insulin resistance and lowers the risk of Type 2 diabetes. Nonetheless, recent cross-sectional data, based on ACSM/CDC physical activity recommendations for moderate-intensity activity on most if not all days of the week (i.e., 1000 kcal/wk), demonstrate that insulin levels are lower with regular moderate-intensity activity in middle-aged adults, suggesting a reduction in insulin resistance. Despite these crosssectional data, few well-controlled prospective studies have determined if these

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recommendations are appropriate to reduce insulin resistance in the elderly. Because higher-intensity aerobic exercise is not practical for a large percentage of the elderly, data are needed to determine the efficacy of moderate-intensity exercise on reducing insulin resistance. Therefore, the primary aim of this study will be to examine the influence of 1000 kcal/wk of moderate versus higher-intensity aerobic exercise on insulin-simulated glucose disposal. A secondary aim will examine if moderate and higher-intensity aerobic exercise differentially influence non-exercising activity. Recent data in the elderly suggest that regular higher-intensity activities may reduce nonexercising activity during rest of the day. We will recruit 57, 65-90 y old women and men, who will be randomized into one of the following three groups: 1) Moderateintensity activity (1000 kcal/wk at 50 percent VO2peak; 2) Higher-intensity activity (1000 kcal/wk at 75 percent VO2peak); 3) Control. Subjects will complete 12 wk of aerobic cycling with pre and post-testing for insulin-stimulated glucose disposal via the hyperinsulinemic/euglycemic clamp, glucose tolerance by an OGTT, and body composition using dual energy x-ray absorptiometry. Physical activity levels will be assessed by structured questionnaire every 3 weeks. Our primary hypothesize is that 1000 kcal/wk of moderate or higher-intensity activity will be equally effective decreasing insulin resistance in the elderly. Our secondary hypothesis is that higherintensity activity will decrease non-exercising physical activity in the elderly. This New Investigator application will provide data to base future aerobic exercise recommendations in elderly adults. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: POLYCYSTIC ADOLESCENTS

OVARIAN

SYNDROME

IN

OVERWEIGHT

Principal Investigator & Institution: Hoeger, Kathleen M.; Obstetrics and Gynecology; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2002; Project Start 01-APR-2002; Project End 31-MAR-2004 Summary: (provided by applicant): Polycystic Overy Syndrome (PCOS) is a broadspectrum disease characterized by chronic anovulation and androgen excess, affecting 48% of women. Onset of the disorder is recognized to occur around the time of puberty but is often not diagnosed until adulthood. More than half of women with PCOS are obese, and insulin resistance appears to be an important part of its underlying pathophysiology. Long-term consequences in PCOS are now recognized to include increased risk of development of type 2 diabetes mellitus and cardiovascular disease. This has led to an interest in reduction of insulin resistance as a long-term treatment strategy. This reduction in insulin resistance can be accomplished by weight reduction or by insulin sensitizers such as metformin. To date, however, there are limited data on the effectiveness of insulin sensitizers and no data on the impact of weight reduction in adolescents with PCOS. Adolescence is a time of tremendous physical and psychosocial change. Obesity in adolescence is often predictive of lifelong obesity. The constellation of hirsutism, irregular bleeding, and obesity, often seen in adolescents with PCOS, could potentially have lifelong social and health consequences. A successful weight reduction strategy with improvement in insulin sensitivity at the onset of the symptoms of PCOS could have substantial long-term health benefits. The applicant hypothesizes that weight loss and metformin in the overweight adolescent with PCOS can reduce insulin resistance and improve the symptoms and metabolic profile associated with PCOS. Accordingly, a randomized, placebo-controlled, parallel-group trial comparing metformin and intensive lifestyle modification is proposed to gather preliminary data on the rate of ovulation, changes in testosterone and insulin and impact on

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cardiovascular risk of weight reduction and metformin as compared to placebo in a total of 30 subjects. Data obtained from this pilot trial on recruitment rates, drop-out, compliance, and estimated treatment effect sizes will be used to refine power calculations for a large-scale randomized trial focused on a comparison of metformin and weight reduction in obese adolescents. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: PREVENTING TYPE 2 DIABETES IN AT-RISK YOUTH Principal Investigator & Institution: Grey, Margaret; Independence Foundation Professor of Nur; None; Yale University 47 College Street, Suite 203 New Haven, Ct 065208047 Timing: Fiscal Year 2003; Project Start 01-SEP-2003; Project End 31-MAY-2007 Summary: (provided by applicant): With the increasing prevalence of type 2 diabetes (T2DM) in youth, and the potential for these youth to experience the devastating complications of diabetes at an early age, new approaches to diabetes prevention must be developed and tested. In this investigation we propose to: (1) Using a prospective, randomized clinical trial design, we will determine the effect of school-based, multifaceted intervention (nutrition and exercise education, coping skills training, Advanced Practice Nurse (APN) coaching, and infrastructure change) on Body Mass Index (BMI), insulin resistance, adiposity, lipids, health behaviors, depression, and selfefficacy in inner city youth at high risk for T2DM. Responses in the experimental group over 12 months will be compared to those youth who receive a delayed intervention. (2) Secondarily, we will examine the effects of baseline characteristics (age, gender, baseline health behaviors, depression) and family behaviors on the response to the intervention; and (3) Finally, we will explore the experience of youth and family in management of obesity and insulin resistance in the prevention of type 2. To achieve these aims, we will enroll 240 high-risk 6th grade middle school youth. High risk is defined as BMI >85th percentile. Schools will be randomized to experimental or delayed intervention conditions. The experimental intervention is a community-based, multifaceted intervention program that we have extensively pilot-tested and will be conducted in the middle schools in the very high-risk community of New Haven. Data will be collected pre intervention and at 4 and 13 months following using the primary outcome of BMI, insulin resistance. Revised Godin-Shephard Activity Survey and accelerometer data, Eating Habits Questionnaire, Health Behavior Questionnaire, Children's Depression Inventory for the youths and the Health Promoting Lifestyle Profile for the parents. A purposive sample of families will participate in a series of open-ended interviews. Analyses will include repeated measures ANOVA generalized estimating equation method, and grounded theory approaches. It is expected that this important and timely study will provide valuable information to help youth manage obesity, and potentially prevent T2DM and its long-term physical and psychosocial complications. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: PROTEOMIC ANALYSIS OF DIABETIC NEPHROPATHY Principal Investigator & Institution: Klein, Jon B.; Professor; Medicine; University of Louisville University of Louisville Louisville, Ky 40292 Timing: Fiscal Year 2002; Project Start 03-JUL-2002; Project End 31-MAY-2004 Summary: (provided by applicant): Diabetics now account for more than 40% of patients with end-stage renal disease (ESRD) and the number of diabetics with renal failure is expected to grow in the coming years. Diabetic nephropathy occurs following

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alterations in all structures of the kidney including blood vessels, interstitium, tubules and glomeruli. To better understand the cellular mechanisms of diabetic nephropathy we will perform proteomic analysis of renal tissue in two very different models of diabetes, 0VE26 transgenic mice and db/db mice, both of which display characteristics of human ESRD. The db/db model is initially insulin resistant and resembles human Type II diabetes. 0VE26 mice are severely hypoinsulinemic and thus are more similar to human Type I diabetics. The intent of this two-model analysis is to distinguish proteins critical to the process of diabetic nephropathy from proteins that are merely characteristic of insulin deficiency or insulin resistance. In an initial analysis of 0VE26 diabetic kidneys, we have identified 80 proteins in the murine renal proteome and demonstrate increased expression of three groups of proteins:1.) Serine protease inhibitors;2.) Cell cycle regulatory proteins;3.) Smooth muscle contractile elements. Increased expression of these proteins is consistent with previous studies that described increased matrix and endothelial proliferation in diabetic nephropathy. However, these preliminary data also identify potential novel mechanisms by which diabetic nephropathy progresses. This suggests the hypothesis to be tested that proteomic analysis can identify novel mechanisms of diabetic nephropathy. The Specific Aims that will address this hypothesis are to: 1. Produce proteome maps of kidneys from diabetic mice with insulin resistance and hypoinsulinemia. 2. Produce proteome maps of glomeruli from diabetic mice with insulin resistance and hypoinsulinemia. We will produce proteome maps using high-resolution two-dimensional gel electrophoresis. Extracted renal proteins from our hypoinsulinemic transgenic 0VE206 mouse model and the obese hyperinsulinemic db/db mouse model will be resolved by electrophoresis and identified by peptide mass fingerprinting. Comparison of the renal and glomerular proteome in hypoinsulinemic and insulin resistance diabetes to normal kidney may reveal candidates for disease mechanisms, therapeutic targets and biomarkers whose validity can be tested in further hypothesis driven research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESISTANCE

PROTEOMICS:

INACTIVITY-INDUCED

MUSCLE

INSULIN

Principal Investigator & Institution: Booth, Frank W.; Professor; Veterinary Biomedical Sciences; University of Missouri Columbia 310 Jesse Hall Columbia, Mo 65211 Timing: Fiscal Year 2002; Project Start 28-SEP-2001; Project End 31-JUL-2003 Summary: (provided by applicant): Insulin resistance and type 2 diabetes are epidemic in adults, and are now even occurring in adolescents. A decrease in physical activity has played an important role in this increase in diabetes as documented in many epidemiological and physiological papers. Of great significance are recent publications showing that increased contractile activity signals an enhanced glucose uptake through an insulin-independent signaling pathway, likely AMP kinase, but the complete pathway remains to be delineated. The importance of these observations is that they raise the probability that unexpected novel proteins linking physical inactivity to insulin resistance will be found. As the post-genome era begins with the sequencing of the human genome, tools are now available to discover the identity of proteins currently unassociated with the signaling of insulin resistance by mechanisms other than insulin modification. This proposal focuses on those proteins differentially expressed when either normal voluntary running ceases due to the removal of a running wheel from the cage, or when high fat diets are consumed. These models mimic current lifestyles of sedentary activity and/or high fat consumption. Specific aim I will use 2-D gel electrophoresis to experimentally determine differentially expressed proteins in skeletal

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muscle that have undergone decreased physical activity. Specific aim 2 will also employ 2-D gel electrophoresis to determine differentially expressed proteins in the skeletal muscle of rats that have undergone decreased physical activity while eating a high fat diet. One hypothesis is that both inactivity and high blood lipids will cause unique, but not identical, sets of proteins related to insulin resistance to be expressed in skeletal muscle. Many of these proteins will heretofore be unidentified as playing a role in skeletal muscle insulin resistance. Identifying the expressed proteins associated with insulin resistance in skeletal muscle will permit the development of new hypotheses, whose functions and interactions with other proteins will be the focus of future grant applications. Such new hypotheses could lead to new therapies against diabetes. Outcomes of this proposal will better establish that healthy active skeletal muscles interact with other organ systems to prevent the metabolic disorders of type 2 diabetes, atherosclerosis, and obesity. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RACE, LIPOPROTEIN LIPASE AND OBESITY AFTER MENOPAUSE Principal Investigator & Institution: Goldberg, Andrew P.; Professor; Medicine; University of Maryland Balt Prof School Baltimore, Md 21201 Timing: Fiscal Year 2003; Project Start 01-APR-2003; Project End 31-MAR-2008 Summary: (provided by applicant): This study is designed to determine the cellular mechanisms underlying the paradoxical association of insulin resistance with decreased visceral adiposity and circulating triglyceride (TG) levels in African-American (AA) compared to Caucasian (CAU) postmenopausal women. This will provide insight into mechanisms underlying racial differences in obesity and its associated metabolic dysfunction (insulin resistance, type 2 diabetes, dyslipidemia, hypertension). The hypothesis is that postmenopausal AA women have a higher skeletal muscle lipoprotein lipase (SM-LPL) and a lower adipose tissue LPL (AT-LPL) activity that leads to the preferential accumulation of TG in muscle (SM-TG), while the converse exists in CAU women. We also postulate that a weight loss (WL) intervention, by preferentially decreasing SM-LPL activity in AA and AT-LPL activity in CAU, will promote reductions of SM-TG in AA and of visceral adiposity in CAU to improve lipoprotein lipid profiles and insulin sensitivity. Specific aims determine whether: 1) decreased visceral (omental and mesenteric) and subcutaneous abdominal (SAT) AT-LPL activity and increased skeletal muscle LPL activity in rectus abdominis and vastus lateralis are the cellular mechanisms underlying racial differences in visceral obesity and SM-TG accumulation in AA compared to CAU postmenopausal women using tissue obtained during elective abdominal surgery and by needle biopsy, and 2) WL, by reducing SM (vastus lateralis - and SAT-LPL activity, is associated with a decrease in SM and visceral fat accumulation to increase in vivo insulin action (hyperinsulinemic euglycemic clamp) and the in vitro antilipolytic response to insulin in a homogeneous population of healthy obese AA and CAU postmenopausal women. We will study healthy, obese (BMI = 30-40 kg/m2), sedentary 50-65 year old postmenopausal women not on hormonereplacement therapy. We will measure AT- and SM-LPL activity, SM-TG content, visceral fat and mid-thigh low density lean tissue area (CT scans) insulin sensitivity in abdominal adipocytes as insulin suppression of lipolysis and in whole body estimated by hyperinsulinemic euglycemic clamps and using the Homeostasis Model Assessment of Insulin Resistance (HOMA IR), total body fat (DXA), lipoprotein lipids, oral glucose tolerance and obesity-related hormones (leptin, insulin, SHBG, free testosterone). Collectively, these results will determine whether racial differences in the tissue-specific LPL activity, the key enzyme for hydrolysis and the ensuing storage of circulating TGs,

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establish a metabolic setting in obese AA of increased SM-TG (due to increased SM-LPL and decreased visceral fat) and in obese CAU of increased visceral fat (due to increased AT-LPL) that predisposes them to insulin resistance and risk for type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: REGIONAL ADIPOSITY AND SYNDROME X IN SPINAL CORD INJURY Principal Investigator & Institution: Braunschweig, Carol L.; Human Nutrition and Dietetics; University of Illinois at Chicago 1737 West Polk Street Chicago, Il 60612 Timing: Fiscal Year 2003; Project Start 01-JAN-2003; Project End 31-DEC-2004 Summary: (provided by applicant): Total and abdominal obesity frequently occur following SCI. Excessive total body adiposity, particularly excessive visceral abdominal adipose tissue (VAAT), and thigh skeletal muscle adiposity (TSKMAT), measured by magnetic resonance imaging (MRI), have been associated with a low-grade systemic inflammation and the metabolic syndrome (MS) (also called syndrome X) which has been defined as the presence of three or more of the following features: waist circumference (WC) greater than 40 inches, fasting triglycerides of at least 150 mg/dl, glucose equal or greater than 110 mg/dl, HDL cholesterol equal or less than 40 mg/dl and/or blood pressure of at least 130/85 mmHg. People with the MS are predisposed to developing insulin resistance and increased risks for diabetes mellitus, hypertension, and cardiovascular disease. Individuals with SCI have higher prevalence rates for these diseases than able-bodied individuals, however, measures of VAAT or TSKMAT volumes and their relation to a measure for inflammation, features of the MS or insulin resistance have not been reported for this population. This is unfortunate given that body fat distribution and inflammatory status are both modifiable risk factors. The purpose of this pilot investigation is to explore the association between measures of adiposity (total, abdominal, VAAT and TSKMAT), a sensitive marker of inflammation (CRP), features of the MS, and insulin resistance in paraplegic men compared to similar able-bodied men. The investigators propose a cross sectional investigation of community dwelling males (N = 60) recruited from urban SCI rehabilitation and trauma centers to determine whether the volume of VAAT, its anthropometric surrogates (WC and/or sagittal diameter), and/or the volume of TSKMAT predict concentrations of CRP, levels and numbers of features of the MS, and insulin resistance in paraplegic men and whether these variables are similar in direction, magnitude and association to those observed in able-bodied men. Four groups of men more than one year post SCI or trauma, frequency matched for age and ethnicity (15/group; 30 paraplegic SCI and 30 able-bodied men with a history of trauma resulting in a hospital stay over 5 days), will be recruited as follows: group 1 lean SCI (WC 40 inches), group 3 lean able-bodied (WC 40 inches). Correlation analysis, multiple regression, and analysis of variance will be used to determine the association between CRP, the MS, insulin sensitivity, and various measures of regional adiposity between these groups. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: RENAL SODIUM TRANSPORT IN THE OBESE ZUCKER RAT Principal Investigator & Institution: Ecelbarger, Carolyn A.; Professor; Medicine; Georgetown University Washington, Dc 20057 Timing: Fiscal Year 2003; Project Start 01-JUN-2003; Project End 31-MAY-2008 Summary: (provided by applicant): Obesity and insulin resistance are associated with hypertension. Inappropriate retention of sodium by the kidney is likely to play a major

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role. We previously showed that the obese Zucker rat (a model for these disorders) have increased renal protein abundance for three major sodium transport proteins: the alpha1 subunit of Na-K-ATPase, the thiazide-sensitive NaCI cotransporter (NCC or TSC) and the beta-subunit of the epithelial sodium channel (ENaC). In contrast, as, they aged, obese rats developed renal hypertrophy along with diabetes and had a relative decrease in many important salt and water transport proteins, as compared to age-matched controls. We suggest that dysregulation of several important hormone systems in sodium balance may play a role in both alterations in sodium transport protein expression, as well as, the rapid develop of nephropathy. Candidate systems include the renin-angiotensin-aldosterone system (RAAS) and insulin (and or insulin resistance). We hypothesize that dysregulation of major sodium transport proteins of the kidney in the obese Zucker rat with age, is due at least in part to increased RAAS activity, and hyperinsulinemia, which in combination, result in inappropriate sodium retention and elevated blood pressure. Our specific aims include: 1) to determine if angiotensin II At1a receptor expression, binding, and activity is upregulated in the obese Zucker rat and whether this upregulation plays a role in changes in renal sodium transporter regulation, blood pressure, and renal hypertrophy; 2) to determine if enhanced mineralocorticoid receptor (MR) activity plays a role in increased whole kidney protein abundance of the thiazide-sensitive NaCI cotransporter (NCC), blood pressure, and renal hypertrophy, in the obese Zucker rat; 3) to determine the cellular location and sensitivity of the renal insulin receptor in obese Zucker rats relative to lean age-mates; 4) to determine whether treatment of insulin resistance with a PPAR-gamma agonist will decrease relative renal protein abundance of NCC, beta-ENaC, and Na-K-ATPase, as well as reduce blood pressure and renal hypertrophy in the obese Zucker rat, and whether these effects are reversed with short-term insulin infusion. These studies will allow us to determine the importance of each of these potential regulatory hormone systems in dyregulation of sodium transporter expression, sodium balance, and blood pressure in these obese rats. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: RESISTIN'S ROLE IN OBESITY RELATED INSULIN RESISTANCE Principal Investigator & Institution: Steppan, Claire M.; Medicine; University of Pennsylvania 3451 Walnut Street Philadelphia, Pa 19104 Timing: Fiscal Year 2002; Project Start 01-AUG-2001; Project End 31-JUL-2004 Summary: (provided by applicant) This proposed research plan describes a 3 year training program for the development of an academic career. The candidate has completed four years of post-doctoral fellowship training and will expand her training during this time period to progress to an academic position. This proposal will define the role of resistin in obesity-related insulin resistance. Mitchell A. Lazar, M.D., Ph.D. will mentor the applicant's scientific development. Dr. Lazar is a recognized leader in the field of nuclear receptors and adipogenesis. Dr. Lazar is the Chief of Endocrinology, Metabolism and Diabetes and the Director of the Penn Diabetes Center. To enhance the training, the applicant will enlist the expertise of Morris Birnbaum, M.D., Ph.D., Howard Hughes Professor and Rexford Ahima, M.D., Ph.D., assistant professor and Director of the Physiology Core of the Penn Diabetes Center. In addition to performing research, the Principal Investigator will benefit from lectures, seminars, and advisory committee meetings. The proposed research will focus on a newly identified hormone that is secreted from adipocytes and which has been shown to antagonize the effects of insulin. The proposed experiments will entail analyzing components in the insulin signaling cascade downstream of insulin binding to determine the mechanism of

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antagonism of insulin action by resistin (Specific Aim 1). In order to address the role of resistin in insulin resistance associated with obesity (Specific Aim 2), we will study the in vivo regulation of resistin in several different animal models of obesity. We plan to study obesity models in which leptin signaling is impaired (ob/ob, db/db) and intact (Agouti, Cpe-fat). The proposed research plan will reveal detailed information about resistin's role in obesity and diabetes. The scientific environment of the University of Pennsylvania provides the ideal opportunity for the candidate to develop her career by executing the proposed research while utilizing the expertise and resources of Dr. Mitchell A. Lazar. Such an environment should allow the candidate to maximize her potential to establish herself as an independent investigator. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF CAVEOLAE IN SIGNALING IN FAT CELLS Principal Investigator & Institution: Pilch, Paul F.; Professor; Biochemistry; Boston University Medical Campus 715 Albany St, 560 Boston, Ma 02118 Timing: Fiscal Year 2002; Project Start 15-AUG-2001; Project End 31-JUL-2005 Summary: (provided by applicant) Obesity is the major factor predisposing people to insulin resistance and type II diabetes, despite the fact that it is the failure of skeletal muscle to respond to insulin which prevents glucose uptake and results in hyperglycemia and diabetes. From a mechanistic viewpoint, it is the availability of lipids (fatty acids) from fat stores that produces muscle insulin resistance, in part if not entirely. Insulin resistant skeletal muscles contain more fat than normal muscle, and acute perfusion of fatty acids into muscle will rapidly produce this resistance. Indeed, Richard Bergman and colleagues have postulated that inhibition of lipid release from fat cells is rate limiting with respect to insulin's organismal actions (the so-called single gateway hypothesis to explain the rate limiting step of insulin action). Dennis MeGarry has also emphasized the role of free fatty acids in muscle insulin resistance and the failure, in diabetes, of insulin to suppress fatty acid release from adipocytes. Moreover, the recent discovery of the role of the adipocyte with regard to leptin secretion has added further to the importance of this cell in the regulation of metabolic homeostasis. Thus, while there remains incomplete agreement about cause and effect in type II diabetes, no one would argue that obesity and fat cell metabolism are not critically relevant. The mechanism(s) by which fatty acids are taken up (and released) by adipocytes is not clear. Published data as well as data in this application suggest that structures abundant in adipocytes, called caveolae, may be the Site of lipid (fatty acid) entry and egress in these cells and may play a role in regulating lipid flux. Caveolae (little caves) are sac like structures that protrude into the cell interior from the cell surface. They are an anatomical feature of most cells whose overall physiological role is still unclear and controversial. It has been shown that caveolae bind fatty acids, and caveolae have been postulated as the site of cholesterol release from cells. We have raised a novel monoclonal antibody with which we can irnmuno-isolate caveolae. We are using this new tool to characterize the composition and physiological function of caveolae. In support of a role for caveolae in lipid metabolism, we have identified a putative fatty acid Lransporter (FAT/CD36) as a major protein component. We propose three specific aims: 1. to further characterize the protein constituents of caveolae in primary and cultured adipocytes. 2. to determine the physiological function of these proteins. 3. to modulate the expression of caveolae and determine the effects of this on the function of specific proteins as weU as on overall fat cell metabolism. Such studies address fundamental questions concemin2 insulin resistance as well as the cell biologv of caveolae.

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Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE ATHEROSCLEROSIS

OF

FATTY

ACID

BINDING

PROTEINS

IN

Principal Investigator & Institution: Linton, Macrae F.; Professor; Medicine; Vanderbilt University 3319 West End Ave. Nashville, Tn 372036917 Timing: Fiscal Year 2002; Project Start 01-AUG-2000; Project End 31-JUL-2004 Summary: Insulin resistance is a condition associated with a cluster of abnormalities including hypertension, glucose intolerance, hypertriglyceridemia, obesity and premature coronary artery disease. Understanding the molecular basis of the link between insulin resistance and these pathological states has been a difficult task. Elevated plasma levels of free fatty acids are a common hallmark of insulin resistance. Cytoplasmic fatty acid binding proteins (FABP) are small cytoplasmic proteins that bind a variety of fatty acids and are expressed in a tightly regulated, tissue specific manner. Proposed functions of cytoplasmic FABP include trapping and trafficking of fatty acids within cells and cell signaling. Targeted disruption of the aP2 allele has been shown to uncouple obesity and insulin resistance, indicating an important role for aP2 in the insulin resistance. Preliminary studies indicate that aP2 promotes atherosclerosis and macrophage foam cell formation in apoE deficient mice. Mall, a closely related FABP, is also expressed by adipocytes and macrophages and is up-regulated in aP2 deficient mice. The goal of this project is to investigate the impact of aP2 and mall-deficiency on insulin resistance and atherosclerosis. To this end, murine bone marrow transplantation will be used to generate mice chimeric for aP2 and or mall expression by macrophages and or adipocytes allowing the investigation of the relative cell-specific contributions of expression of these genes to atherosclerosis and insulin resistance. Finally, in vitro studies will investigate the role of aP2 and mall in macrophage foam cell formation. By providing new insights into the link between insulin resistance and atherosclerosis, these studies may lead to new therapeutic approaches to diabetes and coronary artery disease. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROLE OF SH2-B IN GLUCOSE METABOLISM Principal Investigator & Institution: Rui, Liangyou; Physiology; University of Michigan at Ann Arbor 3003 South State, Room 1040 Ann Arbor, Mi 481091274 Timing: Fiscal Year 2004; Project Start 15-FEB-2004; Project End 31-DEC-2007 Summary: (provided by applicant): Insulin is the primary hormone regulating glucose homeostasis. It binds to and activates the insulin receptor (IR), which subsequently tyrosine phosphorylates and activates multiple cell signaling proteins including IRS proteins, APS and SH2-B. Defects in activation of IR and/or its downstream signaling molecules result in insulin resistance, which is associated with and may be a driving force for type 2 diabetes. The long-term goal of my research program is to elucidate the molecular mechanisms of insulin signaling and resistance. We recently identified SH2-B as a binding protein for IR as well as for JAK2, a cytosolic tyrosine kinase required for cytokine action. SH2-B binds to JAK2 via its SH2 domain, and enhances JAK2 kinase activity; however, its role in insulin action is unclear. To study the physiological function of SH2-B in vivo, we generated mutant mice lacking SH2-B. Initial inspection revealed that the mutant mice homozygous for the SH2-B null allele develop insulin resistance and type 2 diabetes. Moreover, hepatic IRS2 is reduced significantly in SH2-B deficient mice. We hypothesize that SH2-B enhances IR activation and IRS2 expression

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independently, and that both contribute to maintaining normal insulin sensitivity in animals. To test this hypothesis, we shall determine whether deletion of SH2-B impairs insulin-stimulated IR activation and the subsequent phosphorylation of its substrates and activation of downstream pathways, and whether reintroduction of recombinant SH2-B can rescues normal insulin signaling and physiological responses in SH2-B deficient cells and tissues. We shall determine whether SH2-B activates IRS2 promoter independent of insulin stimulation. We shall use a variety of methods to identify molecular mechanisms by which SH2-B potentiates IR activation and promotes IRS2 expression. Thus, the Specific Aims of this proposal are to: 1. Determine whether SH2-B directly enhances insulin physiological responses and signal transduction in mice, tissues and cultured cells. 2. Determine whether and how SH2-B enhances IR activation in mice, tissues and cultured cells. 3. Determine whether and how SH2-B enhances the IRS2 expression in mice, tissues and cultured cells. The results of this proposal will lead to identification of SH2-B-initiated signaling events that may serve as targets for drug intervention of insulin resistance and type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: ROSIGLITAZONE IN POLYCYSTIC OVARY SYNDROME Principal Investigator & Institution: Cataldo, Nicholas A.; Assistant Professor of Obstetrics and Gy; Gynecology and Obstetrics; Stanford University Stanford, Ca 94305 Timing: Fiscal Year 2002; Project Start 01-APR-2001; Project End 31-MAR-2004 Summary: (Adapted from applicant's description): Polycystic ovary syndrome (PCOS) is a disorder affecting about 5% of reproductive-age women characterized by anovulation and excess production of androgens by the ovary. Anovulation causes menstrual irregularity and infertility, while excess androgens cause unwanted hair growth and may promote acne. Traditional treatments for PCOS have consisted of medication to stimulate ovulation if fertility is desired, or medication to suppress or block androgents or restore regular menstrual cycles if fertility is not an immediate goal, but these treatments are often mutually exclusive PCOS is frequently associated with a common metabolic disorder, insulin resistance, and like insulin resistance alone carries an increased risk of non-reproductive health problems such as the development of diabetes or atherosclerosis. Insulin resistance leads to excessive insulin secretion, and this may stimulate the ovary to hypersecrete androgens. In the last few years, published reports have described the treatment of PCOS with insulin sensitizers, medications developed to treat diabetes which can improve insulin resistance. These drugs can improve the hormonal abnormalities in PCOS and in some cases can restore regular menses and/or ovulation. Of the two marketed drugs tested to date, metformin has not been consistently effective, while troglitazone is effective but has been found to have an unacceptable risk of liver toxicity. This project will study rosiglitazone, a newly approved drug closely related to troglitazone in structure and action but without apparent toxicity, in an open-label, Phase II format. Subjects with PCOS wiII have insulin resistance identified by dynamic testing using the octreotide insulin suppression test, and after further evaluation of provoked insulin secretion will receive rosiglitazone daily in one of three doses for 12 weeks. Insulin resistance and insulin secretion, glucose tolerance, serum total and free testosterone, LH, and circulating lipids will be measured on rosiglitazone and compared to subjects' pretreatment values. The occurrence of ovulation will be evaluated by weekly serum progesterone levels. The dose of rosiglitazone and the time needed for its effect to develop will be determined. Associations between effects on metabolic parameters and effects on reproductive ones will be sought. The hypothesis of this study is that rosiglitazone can improve insulin

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sensitivity and lower circulating insulin, and thereby restore ovulation as well as correct elevated LH and testosterone. Rosiglitazone is potentially an appropriate and beneficial treatment for all women with PCOS and insulin resistance regardless of goals. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SKELETAL MUSCLE METABOLISM OF FATTY ACIDS Principal Investigator & Institution: Kelley, David E.; Professor; Medicine; University of Pittsburgh at Pittsburgh 350 Thackeray Hall Pittsburgh, Pa 15260 Timing: Fiscal Year 2002; Project Start 01-APR-2000; Project End 31-DEC-2004 Summary: Skeletal muscle has a crucial role in substrate metabolism and energy balance and perturbations can have major implications for health, as exemplified by the important role of skeletal muscle insulin resistance in obesity and Type 2 diabetes mellitus (DM). A major focus of the candidate's research has been to better understand the interaction between glucose and fatty acid metabolism in the pathogenesis of skeletal muscle insulin resistance. This research has led to the hypothesis that skeletal muscle in obesity and Type 2 DM has a reduced capacity for fat oxidation, that this impairment is most clearly manifest during fasting conditions and causes lipid accumulation within muscle; a process that aggravates insulin resistant glucose metabolism. The thrust of this proposal is to further test this hypothesis. We will seek to do this by developing several novel approaches to the clinical investigation of skeletal muscle metabolism of fatty acids. During the past 11 years of clinical investigation, the candidate has mastered the use of arterio-venous leg balance, radioactive fatty acid and glucose isotope dilution, systemic and regional (limb) indirect calorimetry, euglycemic insulin infusions and percutaneous muscle biopsy as methods to evaluate skeletal muscle physiology in Type 2 DM and obesity. All of these techniques have been in use for at least several decades. This field of clinical investigation could benefit considerably by application of exciting new modalities, including non-invasive imaging of metabolism and tissue composition. During the next five years, with the support of a MidCareer Investigator Award, the candidate will work within a multidisciplinary collaborative effort, including young colleagues to develop three methods: 1) a stable isotope method for in vivo determination of fatty acid uptake and oxidation in skeletal muscle; 2) spiral magnetic resonance imaging method for non-invasive determination of skeletal muscle lipid content; and 3) positron emission tomography (PET) imaging of skeletal muscle fatty acid uptake and oxidation. These methods will be used for testing the hypothesis of that skeletal muscle oxidation of fatty acids is decreased while fatty acid esterification is increased in obesity-related insulin- resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: SOCS PROTEINS - INHIBITORS OF HEPATIC INSULIN RECEPTORS Principal Investigator & Institution: Mooney, Robert A.; Professor; Pathology and Lab Medicine; University of Rochester Orpa - Rc Box 270140 Rochester, Ny 14627 Timing: Fiscal Year 2003; Project Start 01-MAR-2003; Project End 31-DEC-2006 Summary: (provided by applicant): Pro-inflammatory cytokines including interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNFa) are elevated in obesity and type 2 diabetes and have been shown to antagonize insulin action in cell and animal models. While TNFa has been strongly implicated in obesity-dependent insulin resistance in skeletal muscle and adipose tissue, the role of IL-6, TNFa, and IL-1 in hepatic insulin resistance is less understood. Recently, a family of eight cytokineinduced tyrosine kinase inhibitors called Suppressors of Cytokine Signaling (SOCS)

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have been described. We have now demonstrated in HepG2 cells that IL-6 induces expression of SOCS-3 in a temporal pattern that parallels its inhibitory effects on insulin receptor (IR) signal transduction. Ectopically expressed SOCS-3 also inhibits IR signaling in HepG2 cells. Importantly, when induced by IL-6, endogenous SOCS-3 complexes with the IR in these cells. The objective of this proposal is to develop experimental support for the hypothesis that cytokine-induced SOCS proteins (SOCS-3 being the prototype) are antagonists of IR signal transduction in the liver and contribute to insulin resistance. With the long term goal of defining the mechanism by which cytokines contribute to insulin resistance and type 2 diabetes, the following aims will be pursued: Specific Aim #1: Characterize the effect of cytokine (IL-1, IL-6 and TNFa)dependent induction of SOCS-3 on insulin receptor signal transduction in primary hepatocytes, HepG2 cells, and mouse models. Determine if SOCS-3 expression is necessary and/or sufficient for IL-6-dependent inhibition of IR signaling (using RNAi, dominant negative mutants, and transcriptional repression) in cells and animal models. Specific Aim #2: Define the molecular mechanism by which SOCS-3 inhibits IR signal transduction. Deletion and point mutations of SOCS-3 and IR will be constructed and their impact on SOCS-IR interactions and IL-6-mediated IR inhibition will be examined using structure-function analysis. This project focuses on the poorly understood antagonism by cytokines (especially IL-6) of IR signaling in the liver. SOCS proteins may potentially be an important contributors to regulation of insulin signaling and a possible target for therapeutic intervention in the treatment of insulin resistance and type 2 diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: STRUCTURE OF IRS PROTEINS IN INSULIN RESISTANCE Principal Investigator & Institution: Shoelson, Steven E.; Senior Investigator; Joslin Diabetes Center Boston, Ma 02215 Timing: Fiscal Year 2002; Project Start 30-SEP-1992; Project End 31-MAR-2003 Summary: Adapted from applicant's abstract): Insulin controls systemic metabolism by regulating glucose uptake, the synthesis and storage of glycogen and fat, and protein and DNA synthesis. Insulin=s cellular effects are mediate by the insulin receptor (IR) and its substrates. The known number of insulin receptor substrates (IRS proteins) has recently expanded to four, IRS-1, -2, -3, and -4. The activated IR phosphorylates IRS proteins directly. Tyrosine-phosphorylated IRS proteins bind and activate SH2 domain enzymes, including the PI 3-kinase, the phosphatase SHP-2, and the Grb2/Sos complex, to amplify and propagate insulin signals into cells. Insulin resistance- the ability of key targets (muscle and fat) to respond to insulin- is considered t be the initiating step in the pathogenesis of non-insulin dependent diabetes mellitus (NIDDM). Insulin resistance is also associated with common disease states such as hypertension, atherosclerosis, aging, obesity, and polycystic ovarian disease. Recent findings suggest that Ser/threonine phosphorylation of IRS proteins may cause insulin resistance in cells and in vivo. Hyperglycemia, hyperinsulinemia, TNF and leptin could influence insulin sensitivity through this mechanism. The proposed studies will provide a structural basis for understanding the early events in insulin action and test hypotheses that relate insulin resistance and Ser/Thr phosphorylation of IRS proteins. Specifically, we will (1) Determine high resolution structures of IRS protein homology domains (the approximately 270 residue region common to IRS proteins that encompasses the PH and PTB domains), (2) Determine physiological binding partners for the IRS-1, -2, -3, and -4 PH and PTB domains, (3) Determine high resolution structures of full-length IRS

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proteins (IRS-3 is being attempted first, but IRS-1 is planned, as well), and (4) Use IRS structures to analyze potential mechanisms of insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: SUBSTRATES AND INSULIN RECEPTOR ENDOCYTOSIS Principal Investigator & Institution: Najjar, Sonia M.; Associate Professor; Pharmacology and Therapeutics; Medical College of Ohio at Toledo Research & Grants Admin. Toledo, Oh 436145804 Timing: Fiscal Year 2002; Project Start 01-MAR-2000; Project End 31-JAN-2004 Summary: Impaired insulin action, or insulin resistance, is a hallmark of Non-InsulinDependent Diabetes Mellitus (NIDDM). Because insulin resistance is a major factor in the pathogenesis of NIDDM, understanding the mechanisms of insulin resistance has potential implications in identifying novel means to improve insulin sensitivity in individuals predisposed to NIDDM. Insulin binding to its receptor activates the tyrosine kinase of the receptor to cause phosphorylation of the receptor and of other substrates, such as ppl20, a plasma membrane glycoprotein in the hepatocyte. pp120 is phosphorylated on Ser503 in the intracellular domain by cAMP-dependent kinase in the absence of insulin, and this phosphorylation is required for its phosphorylation on Tyr488 by the insulin receptor kinase in response to insulin. The role of ppl20 in insulin action is not well understood. pp120 expression in cultured cells was correlated with increased rate of insulin clearance from the medium through a mechanism of receptormediated endocytosis, suggesting that pp120 is important in the process of insulin clearance from the portal circulation. In contrast, expression of phosphorylationdefective pp120 isoforms (truncated and the Y488F and S503A site-directed mutants) did not increase receptor-mediated insulin internalization, suggesting that the effect of p120 on insulin endocytosis depends on its phosphorylation state. Immunofluorescence and biotin-labeling studies suggested that pp120 exerts its effect by undergoing receptormediated internalization in response to insulin. Thus, it appears that pp120 takes part in a complex of proteins that target the insulin receptor to endocytosis vesicles. The complex formation between pp120, at Tyr488, and the insulin receptor, at Tyr960 of its juxtamembrane domain, appears to be mediated by intracellular proteins. We herein propose to identify these proteins. Additionally, we propose to address the role of ppl20 in the mechanism of insulin action in vivo. To this end, we have generated a transgenic mouse overexpressing a phosphorylation-defective S503A isoform of ppl20 in liver. The transgenic line will address whether expression of a phosphorylation-defective pp 120 is associated with a blunted ability to remove excess insulin from the portal circulation, causing peripheral hyperinsulinemia. Since hyperinsulinemia leads to receptor downregulation on target tissues, it is usually associated with insulin resistance. These proposed studies should provide novel insights into a potential mechanism of hyperinsulinemia, insulin resistance and diabetes. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THE METABOLIC SYNDROME IN PEDIATRIC OBSTRUCTIVE APNEA Principal Investigator & Institution: Waters, Karen A.; Children's Hospital at Westmead Locked Bag 4001 New South Wales, Timing: Fiscal Year 2002; Project Start 01-SEP-2002; Project End 31-JUL-2006 Summary: (provided by applicant): This project will evaluate the association between obstructive sleep apnea (OSA) in childhood, and the presence of the "metabolic

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syndrome". Our aims are: 1. To confirm the association between OSA in children and the presence of known risk factors for future cardiovascular disease. 2. To confirm that the physiological disruptions caused by OSA can induce the same metabolic abnormalities in an animal model, and 3. To confirm that treatment of OSA can reverse the abnormalities underlying the metabolic syndrome. The metabolic syndrome is a combination of hypertension, insulin resistance, and dyslipidemia. The first abnormality to appear in children is insulin resistance. The presence of insulin resistance in children has been associated with development of all three abnormalities in adulthood, and thus with increased risk for later cardiovascular disease. Studying OSA in children provides a unique opportunity to study the mechanisms underlying the association between OSA, the metabolic syndrome, and cardiovascular disease. The majority of children with OSA are NOT obese, so it is possible to determine the relative contribution of factors including obesity, chronic sympathetic activation, and chronic inflammation, if a sufficiently large group is studied. Children who present to a sleep unit already have some combination of symptoms suggestive of OSA. Therefore, a parallel study will seek to understand the earliest associations between OSA and the metabolic syndrome. To do this, piglets will be exposed to repetitive hypercapnic hypoxia, and equivalent studies of metabolic abnormalities will be undertaken. This component of the study will examine the specific sequence of disturbances underlying the metabolic syndrome, with the goal of determining preventative strategies that could be translated into the clinical setting. Finally, children who have OSA will undergo treatment, followed by re-evaluation. If treatment of OSA can reverse the metabolic disturbances present in association with OSA, this will support the need for early and aggressive intervention in childhood OSA. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE PATHOPHYSIOLOGY OF TYPE 2 DIABETES IN ADOLESCENTS Principal Investigator & Institution: Brickman, Wendy J.; Children's Memorial Hospital (Chicago) Chicago, Il 606143394 Timing: Fiscal Year 2002; Project Start 15-APR-2001; Project End 31-JAN-2005 Summary: (adapted from the application) In adults, type 2 diabetes represents a group of polygenic disorders with abnormalities in insulin sensitivity, insulin secretion, and hepatic glucose production. Recently, there have been increased reports of what appears to be type 2 diabetes in the pediatric population. This increase in type 2 diabetes in children has occurred amidst an environment of increasing insulin resistance, as noted by 1) the pubertal stage of many affected individuals, 2) the parallel increase in obesity within the pediatric population, 3) the parallel increase in sedentary lifestyle features, and 4) the frequent presence of acanthosis nigricans. However, all individuals with insulin resistance do not have type 2 diabetes. Little data is available on the pathophysiology of impaired glucose tolerance and type 2 diabetes in children and adolescents. In order to prove that type 2 diabetes in adolescents is characterized by severe insulin resistance and defects in B-cell function, adolescents with Type 2 diabetes followed at Children's Memorial Hospital will undergo a thorough history, physical examination, an oral gluocse tolerance and, in a subset of participants, a frequently sampled intravenous glucose tolerance test. In order to prove that adolescents with acanthosis nigricans and varying degrees of glucose tolerance are characterized by severe insulin resistance and defects in B-cell function, a group of adolescents with acanthosis nigricans will be recruited. Each will have a thorough history and targeted physical, and an oral glucose tolerance test to assess insulin sensitivity, insulin secretion, and glucose tolerance. A subset of these will also undergo a

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modified IVGTT as well. In order to prove that adolescents with insulin resistance have evidence of risk factors for later cardiovascular disease, a group of individuals with low insulin sensitivity will have cardiovascular studies to evaluate for pediatric antecedents of cardiovascular disease. A better understanding of the pathophysiology of type 2 diabetes and its development in adolescents, will enable us to predict which preventive and therapeutic interventions will be successful in hopes of improving the morbidity and mortality associated with type 2 diabetes and/or severe insulin resistance. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: THE ROLE OF PPARGAMMA EXPRESSION ON INSULIN ACTION Principal Investigator & Institution: Hevener, Andrea L.; Medicine; University of California San Diego 9500 Gilman Dr, Dept. 0934 La Jolla, Ca 920930934 Timing: Fiscal Year 2002; Project Start 15-FEB-2002; Project End 31-DEC-2004 Summary: (provided by applicant) Insulin resistance is a characteristic feature of obesity and type 2 diabetes mellitus. The PPARgamma nuclear receptor is the target of Thiazolidinediones (TZD), a class of anti-diabetic drugs known to ameliorate insulin resistance. Despite the known action of TZDs to improve insulin sensitivity, many aspects of PPARgamma biology remain relatively unclear. In this application we plan to utilize gene knockout technology to elucidate the physiologic and cellular mechanisms of PPARgamma biology relating to insulin action and glucose homeostasis. Previous studies from our laboratory have shown that animals heterozygous for a PPAR gene deletion (PPARgamma+/-) demonstrate enhanced insulin sensitivity in muscle and liver. This led us to hypothesize that the PPARgamma receptor and its natural ligands normally serve to dampen insulin action. We believe that PPARgamma gene deletion releases this dampening effect leading to heightened insulin sensitivity. Since the PPARgamma+/-mice display enhanced insulin sensitivity, (1) we will test the hypothesis that when crossed into genetically insulin resistant animals, the insulin resistance phenotype will be rescued. While it is known that TZDs improve the ability of insulin to stimulate glucose disposal, the site of TZD action remains unknown. (2) To assess the differential role of PPARgamma receptor expression in fat vs. muscle, our laboratory has used the Cre-Lox system to create animals with a PPARgamma gene deletion in either skeletal muscle (MCK-Cre mice), or adipose tissue (aP2-Cre mice). The phenotype of these animals will be studied in vivo and in vitro, with or without perturbations including: a) TZD treatment and b) high fat feeding. In summary, in this application we propose to utilize the techniques of mouse genetics combined with a variety of in vivo and in vitro studies to elucidate the role of PPARgamma nuclear receptors in whole body, skeletal muscle, and adipose tissue metabolism. We feel that the findings from the proposed investigations will improve our general understanding of insulin resistance and offer potential insights into new therapeutic modalities. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

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Project Title: THERAPEUTIC ADAPTATION OF INSULIN ACTION IN HUMANS Principal Investigator & Institution: Coker, Robert H.; Geriatrics; University of Arkansas Med Scis Ltl Rock Little Rock, Ar 72205 Timing: Fiscal Year 2004; Project Start 01-APR-2004; Project End 31-MAR-2008 Summary: (provided by applicant): This Mentored Research Scientist Development Award will allow Dr. Coker to extend his work in glucose metabolism performed in animal models into the pathogenesis of insulin resistance in humans. Dr. William J. Evans and Dr. Philip A. Kern will serve as the Co-Mentors for this project. Excessive

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caloric intake or the lack of physical activity contributes to a positive caloric balance, leading to excess visceral adipose tissue deposition. The pathogenic consequences of visceral obesity usually includes hepatic and skeletal muscle insulin resistance, hyperglycemia, and hyperinsulinemia, and abnormal lipid metabolism eventually leading to type 2 diabetes (T2D). Although caloric restriction and/or exercise training are known to decrease risks associated with T2D, it has been difficult to separate the independent influence of weight loss from exercise training on insulin resistance. We propose to examine the effects of a caloric restriction and/or aerobic exercise training on hepatic and peripheral insulin action using a somatostatin, multi-stage, euglycemic clamp technique in overweight, glucose intolerant men and women. We will recruit 60, 50-80 y old women and men, who will be randomized into one of the following four groups: 1) caloric restriction with weight loss, 2) exercise training without weight loss, 3) exercise training with weight loss, and 4) controls (no dietary or exercise intervention). Dr. Evans has extensive experience in the management of dietary control and exercise training studies. In addition, Dr. Kern will provide specific training in cellular/molecular biology. We will test the hypotheses that 1) caloric restriction will improve hepatic and peripheral insulin action, 2) exercise training without weight loss will only improve peripheral insulin action, 3) exercise training with weight loss will improve hepatic and peripheral insulin action, 4) hepatic insulin action will improve in proportion to the decrease in visceral fat, and that 5) weight loss and exercise training will induce changes in skeletal muscle lipid metabolism through different mechanisms. Since people with impaired glucose tolerance are much more susceptible to the development of T2D, understanding the specific influence of the above mentioned therapeutic regimens on the pathogenesis of insulin resistance has extremely important public health implications. Furthermore, the proposed studies, mentors, coinvestigators, and institutional commitment at the University of Arkansas for Medical Sciences provide an outstanding environment for Dr. Coker to develop into an independent basic scientist in diabetes research. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen •

Project Title: WHY HYPERTENSION?

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Principal Investigator & Institution: Kurtz, Theodore W.; Professor; Laboratory Medicine; University of California San Francisco 500 Parnassus Ave San Francisco, Ca 941222747 Timing: Fiscal Year 2002; Project Start 20-SEP-2000; Project End 31-JUL-2004 Summary: (Adapted from the application) Insulin resistance has been frequently observed in patients with essential hypertension, although the mechanisms responsible for the hypertension "metabolic syndrome" and clustering of cardiovascular risk factors remain poorly understood. Evidence from both family studies and experimental animals indicates that genetic risk factors may play a significant role in the clustering of cardiovascular risk factors. The spontaneously hypertensive rat (SHR), a widely studied experimental animal model of human essential hypertension, also demonstrates increased plasma insulin levels and insulin resistance when compared with other strains with low blood pressure. The PI and her collaborators have derived a novel SHR congenic strain that provides an opportunity to investigate the clustering of hypertension and insulin resistance. By transferring a piece of chromosome 4 from the normotensive Brown Norway rat onto the genetic background of the SHR rat, the applicant has bracketed a specific chromosomal segment approximately 37 cM in size, that improves both blood pressure and insulin resistance in the SHR. This segment also

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contains the Cd36 gene, which encodes a fatty acid transporter that was previously thought to be a candidate in the pathogenesis of insulin resistance and blood pressure. The PI proposes to use meiotic mapping in an interval specific segregating population to narrowly map the blood pressure locus on chromosome 4, derive a congenic subline that carries the relevant segment of chromosome 4 and test the potential role of Cd36 in blood pressure control and insulin resistance in transgenic SHR by overexpressing this gene. Website: http://crisp.cit.nih.gov/crisp/Crisp_Query.Generate_Screen

E-Journals: PubMed Central3 PubMed Central (PMC) is a digital archive of life sciences journal literature developed and managed by the National Center for Biotechnology Information (NCBI) at the U.S. National Library of Medicine (NLM).4 Access to this growing archive of e-journals is free and unrestricted.5 To search, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Pmc, and type “insulin resistance” (or synonyms) into the search box. This search gives you access to full-text articles. The following is a sample of items found for insulin resistance in the PubMed Central database: •

Agouti Regulation of Intracellular Calcium: Role in the Insulin Resistance of Viable Yellow Mice. by Zemel MB, Kim JH, Woychik RP, Michaud EJ, Kadwell SH, Patel IR, Wilkison WO.; 1995 May 23; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=41781

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Altered glycan-dependent signaling induces insulin resistance and hyperleptinemia. by McClain DA, Lubas WA, Cooksey RC, Hazel M, Parker GJ, Love DC, Hanover JA.; 2002 Aug 6; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=125016

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Association of insulin resistance with depression: cross sectional findings from the British women's heart and health study. by Lawlor DA, Smith GD, Ebrahim S.; 2003 Dec 13; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=292990

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Birth weight of offspring and insulin resistance in late adulthood: cross sectional survey. by Lawlor DA, Smith GD, Ebrahim S.; 2002 Aug 17; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=117884

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Chiro-Inositol Deficiency and Insulin Resistance: A Comparison of the ChiroInositol- and the Myo-Inositol-Containing Insulin Mediators Isolated from Urine, Hemodialysate, and Muscle of Control and Type II Diabetic Subjects. by Asplin I, Galasko G, Larner J.; 1993 Jul 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&rendertype=abstr act&artid=46839

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Adapted from the National Library of Medicine: http://www.pubmedcentral.nih.gov/about/intro.html.

With PubMed Central, NCBI is taking the lead in preservation and maintenance of open access to electronic literature, just as NLM has done for decades with printed biomedical literature. PubMed Central aims to become a world-class library of the digital age. 5 The value of PubMed Central, in addition to its role as an archive, lies in the availability of data from diverse sources stored in a common format in a single repository. Many journals already have online publishing operations, and there is a growing tendency to publish material online only, to the exclusion of print.

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Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. by Xu H, Barnes GT, Yang Q, Tan G, Yang D, Chou CJ, Sole J, Nichols A, Ross JS, Tartaglia LA, Chen H.; 2003 Dec 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=296998

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Conditional disruption of I[kappa]B kinase 2 fails to prevent obesity-induced insulin resistance. by Rohl M, Pasparakis M, Baudler S, Baumgartl J, Gautam D, Huth M, De Lorenzi R, Krone W, Rajewsky K, Bruning JC.; 2004 Feb 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=324533

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Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. by Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ.; 2003 Jul 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=166252

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Distribution of Serum Total Homocysteine and Its Association with Diabetes and Cardiovascular Risk Factors of the Insulin Resistance Syndrome in Mexican American Men: The Third National Health and Nutrition Examination Survey. by Gillum R.; 2003; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=194257

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Effects of disease modifying agents and dietary intervention on insulin resistance and dyslipidemia in inflammatory arthritis: a pilot study. by Dessein PH, Joffe BI, Stanwix AE.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=153842

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Elevated nucleocytoplasmic glycosylation by O-GlcNAc results in insulin resistance associated with defects in Akt activation in 3T3-L1 adipocytes. by Vosseller K, Wells L, Lane MD, Hart GW.; 2002 Apr 16; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=122766

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Gender differences in factors influencing insulin resistance in elderly hyperlipemic non-diabetic subjects. by Lichnovska R, Gwozdziewiczova S, Hrebicek J.; 2002; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=140144

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Hepatic glucokinase promoter polymorphism is associated with hepatic insulin resistance in Asian Indians. by Chiu KC, Chuang LM, Yoon C, Saad MF.; 2000; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29078

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Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1 --infected patients with lipodystrophy. by Behrens GM, Boerner AR, Weber K, van den Hoff J, Ockenga J, Brabant G, Schmidt RE.; 2002 Nov 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151608

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Inactivation of fatty acid transport protein 1 prevents fat-induced insulin resistance in skeletal muscle. by Kim JK, Gimeno RE, Higashimori T, Kim HJ, Choi H, Punreddy S, Mozell RL, Tan G, Stricker-Krongrad A, Hirsch DJ, Fillmore JJ, Liu ZX, Dong J, Cline G, Stahl A, Lodish HF, Shulman GI.; 2004 Mar 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=351314

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Insulin resistance is a poor predictor of type 2 diabetes in individuals with no family history of disease. by Goldfine AB, Bouche C, Parker RA, Kim C, Kerivan A, Soeldner JS, Martin BC, Warram JH, Kahn CR.; 2003 Mar 4; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=151408

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Leptin reverses insulin resistance and hepatic steatosis in patients with severe lipodystrophy. by Petersen KF, Oral EA, Dufour S, Befroy D, Ariyan C, Yu C, Cline GW, DePaoli AM, Taylor SI, Gorden P, Shulman GI.; 2002 May 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=150981

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Mice lacking dipeptidyl peptidase IV are protected against obesity and insulin resistance. by Conarello SL, Li Z, Ronan J, Roy RS, Zhu L, Jiang G, Liu F, Woods J, Zycband E, Moller DE, Thornberry NA, Zhang BB.; 2003 May 27; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=164531

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Monocyte chemoattractant protein 1 in obesity and insulin resistance. by Sartipy P, Loskutoff DJ.; 2003 Jun 10; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=165864

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Muscle-specific PPAR[gamma]-deficient mice develop increased adiposity and insulin resistance but respond to thiazolidinediones. by Norris AW, Chen L, Fisher SJ, Szanto I, Ristow M, Jozsi AC, Hirshman MF, Rosen ED, Goodyear LJ, Gonzalez FJ, Spiegelman BM, Kahn CR.; 2003 Aug 15; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=171387

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Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. by Zabolotny JM, Kim YB, Peroni OD, Kim JK, Pani MA, Boss O, Klaman LD, Kamatkar S, Shulman GI, Kahn BB, Neel BG.; 2001 Apr 24; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=33185

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PTG gene deletion causes impaired glycogen synthesis and developmental insulin resistance. by Crosson SM, Khan A, Printen J, Pessin JE, Saltiel AR.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154451

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Socioeconomic position in childhood and adulthood and insulin resistance: cross sectional survey using data from British women's heart and health study. by Lawlor DA, Ebrahim S, Davey Smith G.; 2002 Oct 12; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=128946

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The A54T polymorphism at the intestinal fatty acid binding protein 2 is associated with insulin resistance in glucose tolerant Caucasians. by Chiu KC, Chuang LM, Yoon C.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=31346

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The G-308A variant of the Tumor Necrosis Factor-[alpha] (TNF-[alpha]) gene is not associated with obesity, insulin resistance and body fat distribution. by Romeo S, Sentinelli F, Capici F, Arca M, Berni A, Vecci E, Mario UD, Baroni MG.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=56593

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The role of endothelial insulin signaling in the regulation of vascular tone and insulin resistance. by Vicent D, Ilany J, Kondo T, Naruse K, Fisher SJ, Kisanuki YY, Bursell S, Yanagisawa M, King GL, Kahn CR.; 2003 May 1; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=154437

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The vitamin D receptor polymorphism in the translation initiation codon is a risk factor for insulin resistance in glucose tolerant Caucasians. by Chiu KC, Chuang LM, Yoon C.; 2001; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=29095

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Thiazolidinediones and insulin resistance: Peroxisome proliferatoractivated receptor [gamma] activation stimulates expression of the CAP gene. by Ribon V, Johnson JH, Camp HS, Saltiel AR.; 1998 Dec 8; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=24521

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Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. by Kim JK, Fillmore JJ, Chen Y, Yu C, Moore IK, Pypaert M, Lutz EP, Kako Y, Velez-Carrasco W, Goldberg IJ, Breslow JL, Shulman GI.; 2001 Jun 19; http://www.pubmedcentral.gov/articlerender.fcgi?tool=pmcentrez&artid=34701

The National Library of Medicine: PubMed One of the quickest and most comprehensive ways to find academic studies in both English and other languages is to use PubMed, maintained by the National Library of Medicine.6 The advantage of PubMed over previously mentioned sources is that it covers a greater number of domestic and foreign references. It is also free to use. If the publisher has a Web site that offers full text of its journals, PubMed will provide links to that site, as well as to sites offering other related data. User registration, a subscription fee, or some other type of fee may be required to access the full text of articles in some journals. To generate your own bibliography of studies dealing with insulin resistance, simply go to the PubMed Web site at http://www.ncbi.nlm.nih.gov/pubmed. Type “insulin resistance” (or synonyms) into the search box, and click “Go.” The following is the type of output you can expect from PubMed for insulin resistance (hyperlinks lead to article summaries): •

A novel cellular marker of insulin resistance and early atherosclerosis in humans is related to impaired fat cell differentiation and low adiponectin. Author(s): Jansson PA, Pellme F, Hammarstedt A, Sandqvist M, Brekke H, Caidahl K, Forsberg M, Volkmann R, Carvalho E, Funahashi T, Matsuzawa Y, Wiklund O, Yang X, Taskinen MR, Smith U. Source: The Faseb Journal : Official Publication of the Federation of American Societies for Experimental Biology. 2003 August; 17(11): 1434-40. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12890697

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A paradox resolved: the postprandial model of insulin resistance explains why gynoid adiposity appears to be protective. Author(s): McCarty MF. Source: Medical Hypotheses. 2003 August; 61(2): 173-6. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888298

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Abdominal fat distribution and peripheral and hepatic insulin resistance in type 2 diabetes mellitus. Author(s): Miyazaki Y, Glass L, Triplitt C, Wajcberg E, Mandarino LJ, DeFronzo RA. Source: American Journal of Physiology. Endocrinology and Metabolism. 2002 December; 283(6): E1135-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12424102

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PubMed was developed by the National Center for Biotechnology Information (NCBI) at the National Library of Medicine (NLM) at the National Institutes of Health (NIH). The PubMed database was developed in conjunction with publishers of biomedical literature as a search tool for accessing literature citations and linking to full-text journal articles at Web sites of participating publishers. Publishers that participate in PubMed supply NLM with their citations electronically prior to or at the time of publication.

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Abdominal obesity, muscle composition, and insulin resistance in premenopausal women. Author(s): Ross R, Freeman J, Hudson R, Janssen I. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 November; 87(11): 5044-51. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414870

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Acanthosis nigricans is a reliable cutaneous marker of insulin resistance in obese Japanese children. Author(s): Yamazaki H, Ito S, Yoshida H. Source: Pediatrics International : Official Journal of the Japan Pediatric Society. 2003 December; 45(6): 701-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651545

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Acculturation and psychosocial stress show differential relationships to insulin resistance (HOMA) and body fat distribution in two groups of blacks living in the US Virgin Islands. Author(s): Tull ES, Thurland A, LaPorte RE, Chambers EC. Source: Journal of the National Medical Association. 2003 July; 95(7): 560-9. Erratum In: J Natl Med Assoc. 2003 October; 95(10): 1000-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12911254

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Adiponectin, an adipocyte-derived protein, predicts future insulin resistance: twoyear follow-up study in Japanese population. Author(s): Yamamoto Y, Hirose H, Saito I, Nishikai K, Saruta T. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 8790. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715832

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Adipose tissue as an endocrine organ: impact on insulin resistance. Author(s): Jazet IM, Pijl H, Meinders AE. Source: The Netherlands Journal of Medicine. 2003 June; 61(6): 194-212. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12948164

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Alanine aminotransferase levels predict insulin resistance in HIV lipodystrophy. Author(s): Chung RT, Casson DR, Murray G, Song S, Grinspoon S, Hadigan C. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2003 December 15; 34(5): 534-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14657767

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Alterations in high-density lipoprotein metabolism and reverse cholesterol transport in insulin resistance and type 2 diabetes mellitus: role of lipolytic enzymes, lecithin:cholesterol acyltransferase and lipid transfer proteins. Author(s): Borggreve SE, De Vries R, Dullaart RP. Source: European Journal of Clinical Investigation. 2003 December; 33(12): 1051-69. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14636288

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Apolipoprotein E kinetics: influence of insulin resistance and type 2 diabetes. Author(s): Bach-Ngohou K, Ouguerram K, Nazih H, Maugere P, Ripolles-Piquer B, Zair Y, Frenais R, Krempf M, Bard JM. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2002 November; 26(11): 1451-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439646

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Association between the insulin resistance of puberty and the insulin-like growth factor-I/growth hormone axis. Author(s): Moran A, Jacobs DR Jr, Steinberger J, Cohen P, Hong CP, Prineas R, Sinaiko AR. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 October; 87(10): 4817-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12364479

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Association of (-)786T-C mutation of endothelial nitric oxide synthase gene with insulin resistance. Author(s): Ohtoshi K, Yamasaki Y, Gorogawa S, Hayaishi-Okano R, Node K, Matsuhisa M, Kajimoto Y, Hori M. Source: Diabetologia. 2002 November; 45(11): 1594-601. Epub 2002 October 09. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12436344

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Association of glutathione peroxidase activity with insulin resistance and dietary fat intake during normal pregnancy. Author(s): Chen X, Scholl TO, Leskiw MJ, Donaldson MR, Stein TP. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 December; 88(12): 5963-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671197

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Association of high serum ferritin concentration with glucose intolerance and insulin resistance in healthy people. Author(s): Haap M, Fritsche A, Mensing HJ, Haring HU, Stumvoll M. Source: Annals of Internal Medicine. 2003 November 18; 139(10): 869-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14623634

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Association of insulin resistance with depression: cross sectional findings from the British Women's Heart and Health Study. Author(s): Lawlor DA, Smith GD, Ebrahim S; British Women's Heart and Health Study. Source: Bmj (Clinical Research Ed.). 2003 December 13; 327(7428): 1383-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14670883

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Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Author(s): Piatti P, Di Mario C, Monti LD, Fragasso G, Sgura F, Caumo A, Setola E, Lucotti P, Galluccio E, Ronchi C, Origgi A, Zavaroni I, Margonato A, Colombo A. Source: Circulation. 2003 October 28; 108(17): 2074-81. Epub 2003 Oct 06. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14530196

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Association of lipoprotein(a), insulin resistance, and reproductive hormones in a multiethnic cohort of pre- and perimenopausal women (The SWAN Study). Author(s): Sowers M, Crawford SL, Cauley JA, Stein E. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 533-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943872

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Associations between insulin resistance and thrombotic risk factors in high-risk South Asian subjects. Author(s): Kain K, Catto AJ, Grant PJ. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 August; 20(8): 651-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12873293

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AZ 242, a novel PPARalpha/gamma agonist with beneficial effects on insulin resistance and carbohydrate and lipid metabolism in ob/ob mice and obese Zucker rats. Author(s): Ljung B, Bamberg K, Dahllof B, Kjellstedt A, Oakes ND, Ostling J, Svensson L, Camejo G. Source: Journal of Lipid Research. 2002 November; 43(11): 1855-63. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401884

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Battling insulin resistance in elderly obese people with type 2 diabetes: bring on the heavy weights. Author(s): Willey KA, Singh MA. Source: Diabetes Care. 2003 May; 26(5): 1580-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716822

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Beneficial effects of viscous dietary fiber from Konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial. Author(s): Vuksan V, Sievenpiper JL, Owen R, Swilley JA, Spadafora P, Jenkins DJ, Vidgen E, Brighenti F, Josse RG, Leiter LA, Xu Z, Novokmet R. Source: Diabetes Care. 2000 January; 23(1): 9-14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10857960

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Beta-blocking agents in patients with insulin resistance: effects of vasodilating betablockers. Author(s): Jacob S, Balletshofer B, Henriksen EJ, Volk A, Mehnert B, Loblein K, Haring HU, Rett K. Source: Blood Pressure. 1999; 8(5-6): 261-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10803485

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Beta-cell dysfunction and insulin resistance in type 2 diabetes: role of metabolic and genetic abnormalities. Author(s): LeRoith D. Source: The American Journal of Medicine. 2002 October 28; 113 Suppl 6A: 3S-11S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12431757

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beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus. Author(s): Nam JH, Mun JI, Kim SI, Kang SW, Choi KH, Park K, Ahn CW, Cha BS, Song YD, Lim SK, Kim KR, Lee HC, Huh KB. Source: Transplantation. 2001 May 27; 71(10): 1417-23. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11391229

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Beyond type 2 diabetes: the need for a clinically useful way to identify insulin resistance. Author(s): McLaughlin TL, Reaven GM. Source: The American Journal of Medicine. 2003 April 15; 114(6): 501-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727584

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Bezafibrate-induced improvement in glucose uptake and endothelial function in protease inhibitor-associated insulin resistance. Author(s): Nystrom T, Bratt G, Sjoholm A. Source: Journal of Internal Medicine. 2002 December; 252(6): 570-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12472919

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Bioinformatic and experimental tools for identification of single-nucleotide polymorphisms in genes with a potential role for the development of the insulin resistance syndrome. Author(s): Bennet AM, Naslund TI, Morgenstern R, de Faire U. Source: Journal of Internal Medicine. 2001 February; 249(2): 127-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11240843

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Biological variation of homeostasis model assessment-derived insulin resistance in type 2 diabetes. Author(s): Jayagopal V, Kilpatrick ES, Jennings PE, Hepburn DA, Atkin SL. Source: Diabetes Care. 2002 November; 25(11): 2022-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401750

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Birth weight and the insulin resistance syndrome: association of low birth weight with truncal obesity and raised plasminogen activator inhibitor-1 but not with abdominal obesity or plasma lipid disturbances. Author(s): Byberg L, McKeigue PM, Zethelius B, Lithell HO. Source: Diabetologia. 2000 January; 43(1): 54-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10663216

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Birth weight of offspring and insulin resistance in late adulthood: cross sectional survey. Author(s): Lawlor DA, Davey Smith G, Ebrahim S. Source: Bmj (Clinical Research Ed.). 2002 August 17; 325(7360): 359. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12183306

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Birth weight, type 2 diabetes, and insulin resistance in Pima Indian children and young adults. Author(s): Dabelea D, Pettitt DJ, Hanson RL, Imperatore G, Bennett PH, Knowler WC. Source: Diabetes Care. 1999 June; 22(6): 944-50. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10372247

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Blockade of the growth hormone (GH) receptor unmasks rapid GH-releasing peptide6-mediated tissue-specific insulin resistance. Author(s): Muller AF, Janssen JA, Hofland LJ, Lamberts SW, Bidlingmaier M, Strasburger CJ, van der Lely AJ. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 February; 86(2): 590-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11158013

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Body fat distribution and cardiovascular risk in normal weight women. Associations with insulin resistance, lipids and plasma leptin. Author(s): Tai ES, Lau TN, Ho SC, Fok AC, Tan CE. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2000 June; 24(6): 751-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10878682

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Body fat distribution and insulin resistance in healthy Asian Indians and Caucasians. Author(s): Raji A, Seely EW, Arky RA, Simonson DC. Source: The Journal of Clinical Endocrinology and Metabolism. 2001 November; 86(11): 5366-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11701707

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Body mass index is the most important determining factor for the degree of insulin resistance in non-obese type 2 diabetic patients in Korea. Author(s): Chang SA, Kim HS, Yoon KH, Ko SH, Kwon HS, Kim SR, Lee WC, Yoo SJ, Son HS, Cha BY, Lee KW, Son HY, Kang SK. Source: Metabolism: Clinical and Experimental. 2004 February; 53(2): 142-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767863

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Brief review: hypertension in pregnancy : a manifestation of the insulin resistance syndrome? Author(s): Solomon CG, Seely EW. Source: Hypertension. 2001 February; 37(2): 232-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11230277

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Caffeine: a cause of insulin resistance? Author(s): Biaggioni I, Davis SN. Source: Diabetes Care. 2002 February; 25(2): 399-400. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11815519

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Cardiovascular hemodynamics: relationships with insulin resistance in obese children. Author(s): Giordano U, Ciampalini P, Turchetta A, Santilli A, Calzolari F, Crino A, Pompei E, Alpert BS, Calzolari A. Source: Pediatric Cardiology. 2003 November-December [epub Ahead of Print] http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12949696

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Carotid hemodynamic alterations in hypertensive patients with insulin resistance. Author(s): Watanabe S, Okura T, Kitami Y, Hiwada K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 October; 15(10 Pt 1): 851-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12372671

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Caveolin-1-deficient mice show insulin resistance and defective insulin receptor protein expression in adipose tissue. Author(s): Cohen AW, Razani B, Wang XB, Combs TP, Williams TM, Scherer PE, Lisanti MP. Source: American Journal of Physiology. Cell Physiology. 2003 July; 285(1): C222-35. Epub 2003 March 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12660144

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Cellular mechanism of insulin resistance: potential links with inflammation. Author(s): Perseghin G, Petersen K, Shulman GI. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 December; 27 Suppl 3: S6-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704736

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Challenges and opportunities with glycogen synthase kinase-3 inhibitors for insulin resistance and Type 2 diabetes treatment. Author(s): Eldar-Finkelman H, Ilouz R. Source: Expert Opinion on Investigational Drugs. 2003 September; 12(9): 1511-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943495

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Circulating resistin levels are not associated with obesity or insulin resistance in humans and are not regulated by fasting or leptin administration: cross-sectional and interventional studies in normal, insulin-resistant, and diabetic subjects. Author(s): Lee JH, Chan JL, Yiannakouris N, Kontogianni M, Estrada E, Seip R, Orlova C, Mantzoros CS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4848-56. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557464

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Clinical, endocrine and metabolic studies in the kindred of familial partial lipodystrophy--a syndrome of insulin resistance. Author(s): Vaidya RA, Vaidya AD, Talwalkar SC, Mehtalia SD, Shringi MS, Pandey SN, Shah SJ, Godse C, Joshi JV, Sheth J, Kamdar VV. Source: J Assoc Physicians India. 2002 June; 50: 773-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12240840

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Clustering and heritability of insulin resistance in Chinese and Japanese hypertensive families: a Stanford-Asian Pacific Program in Hypertension and Insulin Resistance sibling study. Author(s): Wu KD, Hsiao CF, Ho LT, Sheu WH, Pei D, Chuang LM, Curb D, Chen YD, Tsai HJ, Dzau VJ, Cox D, Tai TY. Source: Hypertens Res. 2002 July; 25(4): 529-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358137

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Combined effects of genetic and environmental factors on insulin resistance associated with reduced fetal growth. Author(s): Jaquet D, Tregouet DA, Godefroy T, Nicaud V, Chevenne D, Tiret L, Czernichow P, Levy-Marchal C. Source: Diabetes. 2002 December; 51(12): 3473-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453902

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Comparison of the associations of apolipoprotein B and low-density lipoprotein cholesterol with other cardiovascular risk factors in the Insulin Resistance Atherosclerosis Study (IRAS). Author(s): Williams K, Sniderman AD, Sattar N, D'Agostino R Jr, Wagenknecht LE, Haffner SM. Source: Circulation. 2003 November 11; 108(19): 2312-6. Epub 2003 October 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14581403

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Contribution of salt intake to insulin resistance associated with hypertension. Author(s): Ogihara T, Asano T, Fujita T. Source: Life Sciences. 2003 June 20; 73(5): 509-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12770608

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Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Author(s): Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S, Miyazaki Y, Kohane I, Costello M, Saccone R, Landaker EJ, Goldfine AB, Mun E, DeFronzo R, Finlayson J, Kahn CR, Mandarino LJ. Source: Proceedings of the National Academy of Sciences of the United States of America. 2003 July 8; 100(14): 8466-71. Epub 2003 June 27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12832613

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Correction of insulin resistance and hyperandrogenism in polycystic ovary syndrome by combined rosiglitazone and clomiphene citrate therapy. Author(s): Shobokshi A, Shaarawy M. Source: Journal of the Society for Gynecologic Investigation. 2003 February; 10(2): 99104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12593999

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Correlation between midthigh low-density muscle and insulin resistance in obese nondiabetic patients in Korea. Author(s): Kim D, Nam S, Ahn C, Kim K, Yoon S, Kim J, Cha B, Lim S, Kim K, Lee H, Huh K. Source: Diabetes Care. 2003 June; 26(6): 1825-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12766117

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Correlations between surrogate measures of insulin resistance and cardiovascular risk factors in obese and overweight patients. Author(s): Lerman I, Villa AR, Rios Torres JM, Tamez LE, Gomez Perez F, del Villar Velasco SL, Rull Rodrigo JA. Source: Journal of Diabetes and Its Complications. 2003 March-April; 17(2): 66-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12614971

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C-reactive protein and insulin resistance in non-obese Japanese type 2 diabetic patients. Author(s): Taniguchi A, Nagasaka S, Fukushima M, Sakai M, Okumura T, Yoshii S, Watanabe T, Ogura M, Yamadori N, Nin K, Kuroe A, Yamada Y, Seino Y, Nakai Y. Source: Metabolism: Clinical and Experimental. 2002 December; 51(12): 1578-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12489071

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C-reactive protein is more strongly related to post-glucose load glucose than to fasting glucose in non-diabetic subjects; the Insulin Resistance Atherosclerosis Study. Author(s): Festa A, D'Agostino R Jr, Tracy RP, Haffner SM. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2002 November; 19(11): 939-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12421431

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Current concepts in insulin resistance, type 2 diabetes mellitus, and the metabolic syndrome. Author(s): Reusch JE. Source: The American Journal of Cardiology. 2002 September 5; 90(5A): 19G-26G. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12231075

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Currently identified genes affecting insulin resistance are not associated with birth weight in the Pima population. Author(s): Lindsay RS, Prochazka M, Baier LJ, Knowler WC, Bogardus C, Hanson RL. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2002 October; 19(10): 882-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358881

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Decreased plasma adiponectin concentrations are closely related to hepatic fat content and hepatic insulin resistance in pioglitazone-treated type 2 diabetic patients. Author(s): Bajaj M, Suraamornkul S, Piper P, Hardies LJ, Glass L, Cersosimo E, Pratipanawatr T, Miyazaki Y, DeFronzo RA. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 2006. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715850

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Defective signaling through Akt-2 and -3 but not Akt-1 in insulin-resistant human skeletal muscle: potential role in insulin resistance. Author(s): Brozinick JT Jr, Roberts BR, Dohm GL. Source: Diabetes. 2003 April; 52(4): 935-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663464

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Detection of insulin resistance and its treatment in adolescents with polycystic ovary syndrome. Author(s): Legro RS. Source: J Pediatr Endocrinol Metab. 2002 December; 15 Suppl 5: 1367-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12510993

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Detection of insulin resistance by simple quantitative insulin sensitivity check index QUICKI for epidemiological assessment and prevention. Author(s): Hrebicek J, Janout V, Malincikova J, Horakova D, Cizek L. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 January; 87(1): 1447. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11788638

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Detection of insulin resistance in Turkish adults: a hospital-based study. Author(s): Gokcel A, Baltali M, Tarim E, Bagis T, Gumurdulu Y, Karakose H, Yalcin F, Akbaba M, Guvener N. Source: Diabetes, Obesity & Metabolism. 2003 March; 5(2): 126-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12630938

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Diabetes and progression of carotid atherosclerosis: the insulin resistance atherosclerosis study. Author(s): Wagenknecht LE, Zaccaro D, Espeland MA, Karter AJ, O'Leary DH, Haffner SM. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 June 1; 23(6): 1035-41. Epub 2003 April 17. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702517

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Dietary habits and their relations to insulin resistance and postprandial lipemia in nonalcoholic steatohepatitis. Author(s): Musso G, Gambino R, De Michieli F, Cassader M, Rizzetto M, Durazzo M, Faga E, Silli B, Pagano G. Source: Hepatology (Baltimore, Md.). 2003 April; 37(4): 909-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12668986

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Differences in LDL oxidizability by glycemic status: the insulin resistance atherosclerosis study. Author(s): Schwenke DC, D'Agostino RB Jr, Goff DC Jr, Karter AJ, Rewers MJ, Wagenknecht LE; Insulin resistance atherosclerosis study. Source: Diabetes Care. 2003 May; 26(5): 1449-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716803

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Differentiation between obesity and insulin resistance in the association with Creactive protein. Author(s): McLaughlin T, Abbasi F, Lamendola C, Liang L, Reaven G, Schaaf P, Reaven P. Source: Circulation. 2002 December 3; 106(23): 2908-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12460870

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Differing aspects of insulin resistance in diabetes complications: the shape of things to come. RD Lawrence Lecture 2000. Author(s): Chaturvedi N. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2002 December; 19(12): 973-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647836

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Digitalis-like factor response to hyperinsulinemia in human pregnancy, a model of insulin resistance. Author(s): Seely EW, Carroll JA, Goodfriend TL, Tao QF, Graves W. Source: Journal of Human Hypertension. 2002 December; 16(12): 851-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12522466

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Distribution of fasting plasma insulin, free fatty acids, and glucose concentrations and of homeostasis model assessment of insulin resistance in a representative sample of Quebec children and adolescents. Author(s): Allard P, Delvin EE, Paradis G, Hanley JA, O'Loughlin J, Lavallee C, Levy E, Lambert M. Source: Clinical Chemistry. 2003 April; 49(4): 644-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651818

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Diurnal triglyceridaemia and insulin resistance in mildly obese subjects with normal fasting plasma lipids. Author(s): Halkes CJ, Van Wijk JP, Ribalta J, Masana L, Castro Cabezas M. Source: Journal of Internal Medicine. 2004 January; 255(1): 74-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687241

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Does glucocorticoid dysregulation contribute to the link between cigarette smoking and insulin resistance? Author(s): Girod JP, Brotman DJ. Source: Journal of the American College of Cardiology. 2003 August 20; 42(4): 771; Author Reply 771-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12932618

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Does insulin resistance cause atherosclerosis in the post-prandial period? Author(s): Kendrick M. Source: Medical Hypotheses. 2003 January; 60(1): 6-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12450763

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Does magnesium dysbalance participate in the development of insulin resistance in early stages of renal disease? Author(s): Sebekova K, Stefikova K, Polakovicova D, Spustova V, Dzurik R. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2002; 51(6): 605-12. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12511185

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Does postprandial storage of triglycerides in endothelial cells contribute to the endothelial dysfunction associated with insulin resistance and fatty diets? Author(s): McCarty MF. Source: Medical Hypotheses. 2003 August; 61(2): 167-72. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12888297

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Does the autonomic nervous system play a role in the development of insulin resistance? A study on heart rate variability in first-degree relatives of Type 2 diabetes patients and control subjects. Author(s): Lindmark S, Wiklund U, Bjerle P, Eriksson JW. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2003 May; 20(5): 399-405. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12752490

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Down-regulation of insulin receptor substrates (IRS)-1 and IRS-2 and Src homologous and collagen-like protein Shc gene expression by insulin in skeletal muscle is not associated with insulin resistance or type 2 diabetes. Author(s): Huang X, Vaag A, Hansson M, Groop L. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 January; 87(1): 2559. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11788655

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Doxazosin, but not amlodipine decreases insulin resistance in patients with chronic renal failure: a prospective, randomized-controlled study. Author(s): Yildiz A, Hursit M, Celik AV, Kayacan SM, Yazici H, Akkaya V, Gurol AO, Karsidag K. Source: Clinical Nephrology. 2002 December; 58(6): 405-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12508961

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Early life origins of insulin resistance and type 2 diabetes in India and other Asian countries. Author(s): Yajnik CS. Source: The Journal of Nutrition. 2004 January; 134(1): 205-10. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704320

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Early postnatal undernutrition in preterm infants and reduced risk of insulin resistance. Author(s): Yeung MY, Smyth JP. Source: Lancet. 2003 June 28; 361(9376): 2248-9; Author Reply 2249. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12842393

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Effect of abdominal obesity on insulin resistance and the components of the metabolic syndrome: evidence supporting obesity as the central feature. Author(s): Turkoglu C, Duman BS, Gunay D, Cagatay P, Ozcan R, Buyukdevrim AS. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 2003 October; 13(5): 699-705. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14627463

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Effect of lifestyle modification on adipokine levels in obese subjects with insulin resistance. Author(s): Monzillo LU, Hamdy O, Horton ES, Ledbury S, Mullooly C, Jarema C, Porter S, Ovalle K, Moussa A, Mantzoros CS. Source: Obesity Research. 2003 September; 11(9): 1048-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972674

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93

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Effect of type 1 diabetes on the gender difference in coronary artery calcification: a role for insulin resistance? The Coronary Artery Calcification in Type 1 Diabetes (CACTI) Study. Author(s): Dabelea D, Kinney G, Snell-Bergeon JK, Hokanson JE, Eckel RH, Ehrlich J, Garg S, Hamman RF, Rewers M; The Coronary Artery Calcification in Type 1 Diabetes Study. Source: Diabetes. 2003 November; 52(11): 2833-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14578303

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Effects of equal weight loss with orlistat and placebo on body fat and serum fatty acid composition and insulin resistance in obese women. Author(s): Tiikkainen M, Bergholm R, Rissanen A, Aro A, Salminen I, Tamminen M, Teramo K, Yki-Jarvinen H. Source: The American Journal of Clinical Nutrition. 2004 January; 79(1): 22-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14684393

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Effects of exercise training on fasting insulin, insulin resistance, insulin-like growth factors, and insulin-like growth factor binding proteins in postmenopausal breast cancer survivors: a randomized controlled trial. Author(s): Fairey AS, Courneya KS, Field CJ, Bell GJ, Jones LW, Mackey JR. Source: Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology. 2003 August; 12(8): 721-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12917202

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Effects of free fatty acids (FFA) on glucose metabolism: significance for insulin resistance and type 2 diabetes. Author(s): Boden G. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2003 May; 111(3): 121-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12784183

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Effects of insulin resistance and insulin secretion on the efficacy of interventions to retard development of type 2 diabetes mellitus: the DA Qing IGT and Diabetes Study. Author(s): Li G, Hu Y, Yang W, Jiang Y, Wang J, Xiao J, Hu Z, Pan X, Howard BV, Bennett PH; DA Qing IGT and Diabetes Study. Source: Diabetes Research and Clinical Practice. 2002 December; 58(3): 193-200. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12413779

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Effects of insulin resistance and obesity on lipoproteins and sensitivity to egg feeding. Author(s): Knopp RH, Retzlaff B, Fish B, Walden C, Wallick S, Anderson M, Aikawa K, Kahn SE. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2003 August 1; 23(8): 143743. Epub 2003 June 19. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12816878

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Effects of ramipril therapy on some components of insulin resistance syndrome in patients with essential hypertension. Author(s): Bojovic L, Micic D. Source: Med Pregl. 2002 July-August; 55(7-8): 286-92. English, Croatian. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434673

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Effects of sex steroids on components of the insulin resistance syndrome in transsexual subjects. Author(s): Elbers JM, Giltay EJ, Teerlink T, Scheffer PG, Asscheman H, Seidell JC, Gooren LJ. Source: Clinical Endocrinology. 2003 May; 58(5): 562-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12699437

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Endothelial nitric oxide synthase polymorphisms are associated with type 2 diabetes and the insulin resistance syndrome. Author(s): Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, Valsecchi G, Lucotti P, Pozza G, Bernardinelli L, Casari G, Piatti P. Source: Diabetes. 2003 May; 52(5): 1270-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716763

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Endothelium-dependent flow-mediated vasodilatation, insulin resistance and the metabolic syndrome in 60-year-old men. Author(s): Wendelhag I, Fagerberg B, Hulthe J, Bokemark L, Wikstrand J. Source: Journal of Internal Medicine. 2002 October; 252(4): 305-13. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12366603

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Essential hypertension in adolescents: association with insulin resistance and with metabolism of homocysteine and vitamins. Author(s): Kahleova R, Palyzova D, Zvara K, Zvarova J, Hrach K, Novakova I, Hyanek J, Bendlova B, Kozich V. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 October; 15(10 Pt 1): 857-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12372672

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Ethnic and racial differences in diabetes care: The Insulin Resistance Atherosclerosis Study. Author(s): Bonds DE, Zaccaro DJ, Karter AJ, Selby JV, Saad M, Goff DC Jr. Source: Diabetes Care. 2003 April; 26(4): 1040-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12663570

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Evaluation of human resistin assays with serum from patients with type 2 diabetes and different degrees of insulin resistance. Author(s): Pfutzner A, Langenfeld M, Kunt T, Lobig M, Forst T. Source: Clin Lab. 2003; 49(11-12): 571-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651328

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Evaluation of insulin resistance in acromegalic patients before and after treatment with somatostatin analogues. Author(s): Ronchi CL, Orsi E, Giavoli C, Cappiello V, Epaminonda P, Beck-Peccoz P, Arosio M. Source: J Endocrinol Invest. 2003 June; 26(6): 533-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12952367

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Evaluation of the synergistic effect of insulin resistance and insulin-like growth factors on the risk of breast carcinoma. Author(s): Malin A, Dai Q, Yu H, Shu XO, Jin F, Gao YT, Zheng W. Source: Cancer. 2004 February 15; 100(4): 694-700. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14770423

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Exercise training and antioxidants: relief from oxidative stress and insulin resistance. Author(s): Henriksen EJ, Saengsirisuwan V. Source: Exercise and Sport Sciences Reviews. 2003 April; 31(2): 79-84. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12715971

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Factor analysis of ethnic variation in the multiple metabolic (insulin resistance) syndrome in three Canadian populations. Author(s): Kue Young T, Chateau D, Zhang M. Source: American Journal of Human Biology : the Official Journal of the Human Biology Council. 2002 September-October; 14(5): 649-58. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12203819

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Factor analysis of metabolic syndrome using directly measured insulin sensitivity: The Insulin Resistance Atherosclerosis Study. Author(s): Hanley AJ, Karter AJ, Festa A, D'Agostino R Jr, Wagenknecht LE, Savage P, Tracy RP, Saad MF, Haffner S; Insulin Resistance Atherosclerosis Study. Source: Diabetes. 2002 August; 51(8): 2642-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145182

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Factor analysis of the metabolic syndrome: obesity vs insulin resistance as the central abnormality. Author(s): Anderson PJ, Critchley JA, Chan JC, Cockram CS, Lee ZS, Thomas GN, Tomlinson B. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2001 December; 25(12): 1782-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11781758

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Factors of insulin resistance syndrome--related phenotypes are linked to genetic locations on chromosomes 6 and 7 in nondiabetic mexican-americans. Author(s): Arya R, Blangero J, Williams K, Almasy L, Dyer TD, Leach RJ, O'Connell P, Stern MP, Duggirala R. Source: Diabetes. 2002 March; 51(3): 841-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11872689

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Familial combined hyperlipidemia and insulin resistance. Author(s): Frohlich J, Sniderman A. Source: Arteriosclerosis, Thrombosis, and Vascular Biology. 2001 December; 21(12): 2100-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11742892

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Fasting plasma ghrelin levels are negatively correlated with insulin resistance and PAI-1, but not with leptin, in obese children and adolescents. Author(s): Ikezaki A, Hosoda H, Ito K, Iwama S, Miura N, Matsuoka H, Kondo C, Kojima M, Kangawa K, Sugihara S. Source: Diabetes. 2002 December; 51(12): 3408-11. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453893

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Fat distribution, lipid accumulation in the liver, and exercise capacity do not explain the insulin resistance in healthy males with a family history for type 2 diabetes. Author(s): Johanson EH, Jansson PA, Lonn L, Matsuzawa Y, Funahashi T, Taskinen MR, Smith U, Axelsen M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 September; 88(9): 4232-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12970292

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Fat versus carbohydrate in insulin resistance, obesity, diabetes and cardiovascular disease. Author(s): Hung T, Sievenpiper JL, Marchie A, Kendall CW, Jenkins DJ. Source: Current Opinion in Clinical Nutrition and Metabolic Care. 2003 March; 6(2): 16576. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12589186

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Fat-induced liver insulin resistance. Author(s): Shah P, Basu A, Rizza R. Source: Curr Diab Rep. 2003 June; 3(3): 214-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12762968

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Fatty acid binding protein-2 gene variants and insulin resistance: gene and geneenvironment interaction effects. Author(s): Weiss EP, Brown MD, Shuldiner AR, Hagberg JM. Source: Physiological Genomics. 2002 September 3; 10(3): 145-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12209017

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Fatty acid-induced insulin resistance: decreased muscle PI3K activation but unchanged Akt phosphorylation. Author(s): Kruszynska YT, Worrall DS, Ofrecio J, Frias JP, Macaraeg G, Olefsky JM. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 January; 87(1): 22634. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11788651

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Fatty liver in type 2 diabetes mellitus: relation to regional adiposity, fatty acids, and insulin resistance. Author(s): Kelley DE, McKolanis TM, Hegazi RA, Kuller LH, Kalhan SC. Source: American Journal of Physiology. Endocrinology and Metabolism. 2003 October; 285(4): E906-16. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12959938

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FFA cause hepatic insulin resistance by inhibiting insulin suppression of glycogenolysis. Author(s): Boden G, Cheung P, Stein TP, Kresge K, Mozzoli M. Source: American Journal of Physiology. Endocrinology and Metabolism. 2002 July; 283(1): E12-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12067837

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First trimester insulin resistance and subsequent preeclampsia: a prospective study. Author(s): Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 April; 87(4): 1563-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11932283

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FOXC2 mRNA Expression and a 5' untranslated region polymorphism of the gene are associated with insulin resistance. Author(s): Ridderstrale M, Carlsson E, Klannemark M, Cederberg A, Kosters C, Tornqvist H, Storgaard H, Vaag A, Enerback S, Groop L. Source: Diabetes. 2002 December; 51(12): 3554-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453913

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Free fatty acid-induced peripheral insulin resistance augments splanchnic glucose uptake in healthy humans. Author(s): Bajaj M, Berria R, Pratipanawatr T, Kashyap S, Pratipanawatr W, Belfort R, Cusi K, Mandarino L, DeFronzo RA. Source: American Journal of Physiology. Endocrinology and Metabolism. 2002 August; 283(2): E346-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12110541

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Free fatty acids in obesity and type 2 diabetes: defining their role in the development of insulin resistance and beta-cell dysfunction. Author(s): Boden G, Shulman GI. Source: European Journal of Clinical Investigation. 2002 June; 32 Suppl 3: 14-23. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12028371

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Free fatty acids, insulin resistance, and pregnancy. Author(s): Sivan E, Boden G. Source: Curr Diab Rep. 2003 August; 3(4): 319-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12866995

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Frequency of the WHO metabolic syndrome in European cohorts, and an alternative definition of an insulin resistance syndrome. Author(s): Balkau B, Charles MA, Drivsholm T, Borch-Johnsen K, Wareham N, Yudkin JS, Morris R, Zavaroni I, van Dam R, Feskins E, Gabriel R, Diet M, Nilsson P, Hedblad B; European Group For The Study Of Insulin Resistance (EGIR). Source: Diabetes & Metabolism. 2002 November; 28(5): 364-76. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12461473

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Fructose, weight gain, and the insulin resistance syndrome. Author(s): Elliott SS, Keim NL, Stern JS, Teff K, Havel PJ. Source: The American Journal of Clinical Nutrition. 2002 November; 76(5): 911-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12399260

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Genetic and structural evaluation of fatty acid transport protein-4 in relation to markers of the insulin resistance syndrome. Author(s): Gertow K, Bellanda M, Eriksson P, Boquist S, Hamsten A, Sunnerhagen M, Fisher RM. Source: The Journal of Clinical Endocrinology and Metabolism. 2004 January; 89(1): 3929. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14715877

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Genetic epidemiology of insulin resistance and visceral adiposity. The IRAS Family Study design and methods. Author(s): Henkin L, Bergman RN, Bowden DW, Ellsworth DL, Haffner SM, Langefeld CD, Mitchell BD, Norris JM, Rewers M, Saad MF, Stamm E, Wagenknecht LE, Rich SS. Source: Annals of Epidemiology. 2003 April; 13(4): 211-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12684185

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Genetic polymorphism PC-1 K121Q and ethnic susceptibility to insulin resistance. Author(s): Abate N, Carulli L, Cabo-Chan A Jr, Chandalia M, Snell PG, Grundy SM. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 December; 88(12): 5927-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671192

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Genetic variants of insulin receptor substrate-1 (IRS-1) in syndromes of severe insulin resistance. Functional analysis of Ala513Pro and Gly1158Glu IRS-1. Author(s): Berger D, Barroso I, Soos M, Yeo G, Schafer AJ, O'Rahilly S, Whitehead JP. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2002 October; 19(10): 804-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12358865

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Genetics of type 2 diabetes and insulin resistance: knowledge from human studies. Author(s): McIntyre EA, Walker M. Source: Clinical Endocrinology. 2002 September; 57(3): 303-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12201821

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Genotype-phenotype correlation in inherited severe insulin resistance. Author(s): Longo N, Wang Y, Smith SA, Langley SD, DiMeglio LA, Giannella-Neto D. Source: Human Molecular Genetics. 2002 June 1; 11(12): 1465-75. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12023989

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Gestational diabetes and insulin resistance: role in short- and long-term implications for mother and fetus. Author(s): Catalano PM, Kirwan JP, Haugel-de Mouzon S, King J. Source: The Journal of Nutrition. 2003 May; 133(5 Suppl 2): 1674S-1683S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12730484

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Getting to the HAART of insulin resistance. Author(s): Nolan D, Mallal S. Source: Aids (London, England). 2001 October 19; 15(15): 2037-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11600834

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Ghrelin levels correlate with insulin levels, insulin resistance, and high-density lipoprotein cholesterol, but not with gender, menopausal status, or cortisol levels in humans. Author(s): Purnell JQ, Weigle DS, Breen P, Cummings DE. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 December; 88(12): 5747-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671163

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Glucocorticoid induced insulin resistance impairs basal but not glucose entrained high-frequency insulin pulsatility in humans. Author(s): Hollingdal M, Juhl CB, Dall R, Sturis J, Veldhuis JD, Schmitz O, Porksen N. Source: Diabetologia. 2002 January; 45(1): 49-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11845223

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Glucose flux is normalized by compensatory hyperinsulinaemia in growth hormoneinduced insulin resistance in healthy subjects, while skeletal muscle protein synthesis remains unchanged. Author(s): Nygren J, Thorell A, Brismar K, Essen P, Wernerman J, McNurlan MA, Garlick PJ, Ljungqvist O. Source: Clinical Science (London, England : 1979). 2002 April; 102(4): 457-64. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11914108

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Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. Author(s): Yildiz BO, Yarali H, Oguz H, Bayraktar M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 May; 88(5): 2031-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12727950

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Glucose metabolism and insulin resistance in women with polycystic ovary syndrome during therapy with oral contraceptives containing cyproterone acetate or desogestrel. Author(s): Cagnacci A, Paoletti AM, Renzi A, Orru M, Pilloni M, Melis GB, Volpe A. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3621-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915645

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Glucose transporters and insulin action--implications for insulin resistance and diabetes mellitus. Author(s): Shepherd PR, Kahn BB. Source: The New England Journal of Medicine. 1999 July 22; 341(4): 248-57. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10413738

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Glucose-to-insulin ratio rather than sex hormone-binding globulin and adiponectin levels is the best predictor of insulin resistance in nonobese women with polycystic ovary syndrome. Author(s): Ducluzeau PH, Cousin P, Malvoisin E, Bornet H, Vidal H, Laville M, Pugeat M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 August; 88(8): 3626-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12915646

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GLUT4 expression in human muscle fibres is not correlated with intracellular triglyceride (TG) content. Is TG a maker or a marker of insulin resistance? Author(s): Gaster M, Ottosen PD, Vach W, Christiansen H, Staehr P, Beck-Nielsen H, Schroder HD. Source: Apmis : Acta Pathologica, Microbiologica, Et Immunologica Scandinavica. 2003 February; 111(2): 338-48. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716391

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Gout, diet, and the insulin resistance syndrome. Author(s): Fam AG. Source: The Journal of Rheumatology. 2002 July; 29(7): 1350-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12136887

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Growth hormone receptor antagonist improves insulin resistance in acromegaly. Author(s): Rose DR, Clemmons DR. Source: Growth Hormone & Igf Research : Official Journal of the Growth Hormone Research Society and the International Igf Research Society. 2002 December; 12(6): 41824. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423627

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Growth hormone replacement therapy induces insulin resistance by activating the glucose-fatty acid cycle. Author(s): Bramnert M, Segerlantz M, Laurila E, Daugaard JR, Manhem P, Groop L. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 April; 88(4): 145563. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12679422

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Growth hormone therapy and its relationship to insulin resistance, glucose intolerance and diabetes mellitus: a review of recent evidence. Author(s): Jeffcoate W. Source: Drug Safety : an International Journal of Medical Toxicology and Drug Experience. 2002; 25(3): 199-212. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11945115

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Hair loss, insulin resistance, and heredity in middle-aged women. A populationbased study. Author(s): Matilainen V, Laakso M, Hirsso P, Koskela P, Rajala U, KeinanenKiukaanniemi S. Source: Journal of Cardiovascular Risk. 2003 June; 10(3): 227-31. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12775957

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Heart rate recovery after exercise is related to the insulin resistance syndrome and heart rate variability in elderly men. Author(s): Lind L, Andren B. Source: American Heart Journal. 2002 October; 144(4): 666-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12360163

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Hepatic steatosis, insulin resistance, and adipose tissue disorders. Author(s): Garg A, Misra A. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 July; 87(7): 3019-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107193

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Heritability of features of the insulin resistance syndrome in a community-based study of healthy families. Author(s): Freeman MS, Mansfield MW, Barrett JH, Grant PJ. Source: Diabetic Medicine : a Journal of the British Diabetic Association. 2002 December; 19(12): 994-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12647839

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High prevalence of insulin resistance and metabolic syndrome in overweight/obese preadolescent Hong Kong Chinese children aged 9-12 years. Author(s): Sung RY, Tong PC, Yu CW, Lau PW, Mok GT, Yam MC, Lam PK, Chan JC. Source: Diabetes Care. 2003 January; 26(1): 250-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502696

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High prevalence of secondary hypertension and insulin resistance in patients with refractory hypertension. Author(s): Martell N, Rodriguez-Cerrillo M, Grobbee DE, Lopez-Eady MD, FernandezPinilla C, Avila M, Fernandez-Cruz A, Luque M. Source: Blood Pressure. 2003; 12(3): 149-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12875476

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High-salt diet enhances insulin signaling and induces insulin resistance in Dahl saltsensitive rats. Author(s): Ogihara T, Asano T, Ando K, Sakoda H, Anai M, Shojima N, Ono H, Onishi Y, Fujishiro M, Abe M, Fukushima Y, Kikuchi M, Fujita T. Source: Hypertension. 2002 July; 40(1): 83-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12105143

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HOMA-estimated insulin resistance is an independent predictor of cardiovascular disease in type 2 diabetic subjects: prospective data from the Verona Diabetes Complications Study. Author(s): Bonora E, Formentini G, Calcaterra F, Lombardi S, Marini F, Zenari L, Saggiani F, Poli M, Perbellini S, Raffaelli A, Cacciatori V, Santi L, Targher G, Bonadonna R, Muggeo M. Source: Diabetes Care. 2002 July; 25(7): 1135-41. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087010

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Homeostasis model assessment of insulin resistance in relation to the incidence of cardiovascular disease: the San Antonio Heart Study. Author(s): Hanley AJ, Williams K, Stern MP, Haffner SM. Source: Diabetes Care. 2002 July; 25(7): 1177-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12087016

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Homeostasis model assessment of insulin resistance, quantitative insulin sensitivity check index, and oral glucose insulin sensitivity index in nonobese, nondiabetic subjects with high-normal blood pressure. Author(s): Kanauchi M, Yamano S, Kanauchi K, Saito Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 July; 88(7): 3444-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12843200

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Homocysteine plasma levels are independently associated with insulin resistance in normal weight, overweight and obese pre-menopausal women. Author(s): De Pergola G, Pannacciulli N, Zamboni M, Minenna A, Brocco G, Sciaraffia M, Bosello, Giorgino R. Source: Diabetes Nutr Metab. 2001 October; 14(5): 253-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11806465

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Hormones and insulin resistance during pregnancy. Author(s): Ryan EA. Source: Lancet. 2003 November 29; 362(9398): 1777-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14654313

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Human insulin resistance: the role of glucocorticoids. Author(s): Reynolds RM, Walker BR. Source: Diabetes, Obesity & Metabolism. 2003 January; 5(1): 5-12. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12542720

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Hyperglycaemic siblings of Type II (non-insulin-dependent) diabetic patients have increased PAI-1, central obesity and insulin resistance compared with their paired normoglycaemic sibling. Author(s): Herlihy OM, Barrow BA, Grant PJ, Levy JC. Source: Diabetologia. 2002 May; 45(5): 635-41. Epub 2002 April 26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107743

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Hyperglycemia and insulin resistance: possible mechanisms. Author(s): Tomas E, Lin YS, Dagher Z, Saha A, Luo Z, Ido Y, Ruderman NB. Source: Annals of the New York Academy of Sciences. 2002 June; 967: 43-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12079834

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Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. Author(s): Mulligan K, Grunfeld C, Tai VW, Algren H, Pang M, Chernoff DN, Lo JC, Schambelan M. Source: Journal of Acquired Immune Deficiency Syndromes (1999). 2000 January 1; 23(1): 35-43. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10708054

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Hypertension and insulin resistance: role of peroxisome proliferator-activated receptor gamma. Author(s): Itoh H, Doi K, Tanaka T, Fukunaga Y, Hosoda K, Inoue G, Nishimura H, Yoshimasa Y, Yamori Y, Nakao K. Source: Clinical and Experimental Pharmacology & Physiology. 1999 July; 26(7): 558-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10405788

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Hypertriglyceridemia is associated with increased insulin resistance in subjects with normal glucose tolerance: evaluation in a large cohort of subjects assessed with the 1999 World Health Organization criteria for the classification of diabetes. Author(s): Moro E, Gallina P, Pais M, Cazzolato G, Alessandrini P, Bittolo-Bon G. Source: Metabolism: Clinical and Experimental. 2003 May; 52(5): 616-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12759893

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Hypoadiponectinemia is associated with insulin resistance, hypertriglyceridemia, and fat redistribution in human immunodeficiency virus-infected patients treated with highly active antiretroviral therapy. Author(s): Addy CL, Gavrila A, Tsiodras S, Brodovicz K, Karchmer AW, Mantzoros CS. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 February; 88(2): 627-36. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12574192

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Hypoadiponectinemia is associated with visceral fat accumulation and insulin resistance in Japanese men with type 2 diabetes mellitus. Author(s): Yatagai T, Nagasaka S, Taniguchi A, Fukushima M, Nakamura T, Kuroe A, Nakai Y, Ishibashi S. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1274-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564678

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IGFBP-1 levels in adult women born small for gestational age suggest insulin resistance in spite of normal BMI. Author(s): Kistner A, Jacobson SH, Celsi G, Vanpee M, Brismar K. Source: Journal of Internal Medicine. 2004 January; 255(1): 82-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687242

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Impact of Prol2Ala variant in the peroxisome proliferator-activated receptor (PPAR) gamma2 on obesity and insulin resistance in Japanese Type 2 diabetic and healthy subjects. Author(s): Kawasaki I, Tahara H, Emoto M, Shoji T, Shioji A, Okuno Y, Inaba M, Nishizawa Y. Source: Osaka City Med J. 2002 June; 48(1): 23-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12375694

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Impaired glucose phosphorylation and transport in skeletal muscle cause insulin resistance in HIV-1-infected patients with lipodystrophy. Author(s): Behrens GM, Boerner AR, Weber K, van den Hoff J, Ockenga J, Brabant G, Schmidt RE. Source: The Journal of Clinical Investigation. 2002 November; 110(9): 1319-27. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12417571

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Inflammation and the IKK beta/I kappa B/NF-kappa B axis in obesity- and dietinduced insulin resistance. Author(s): Shoelson SE, Lee J, Yuan M. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 December; 27 Suppl 3: S49-52. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704745

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Inflammation: the link between insulin resistance, obesity and diabetes. Author(s): Dandona P, Aljada A, Bandyopadhyay A. Source: Trends in Immunology. 2004 January; 25(1): 4-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14698276

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Insights into obesity and insulin resistance from the study of extreme human phenotypes. Author(s): O'Rahilly S. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2002 October; 147(4): 435-41. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370103

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Insulin and insulin resistance: impact on blood pressure and cardiovascular disease. Author(s): Sowers JR, Frohlich ED. Source: The Medical Clinics of North America. 2004 January; 88(1): 63-82. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14871051

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Insulin resistance (HOMA) in relation to plasma cortisol, IGF-I and IGFBP-3. A study in normal short-statured and GH-deficient children. Author(s): Bleicher M, Hogel J, Wudy S, Wabitsch M, Homoki J, Sorgo W, Heinze E. Source: Hormone Research. 2002; 58(5): 229-32. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401942

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Insulin resistance and HIV-related lipoatrophy. Author(s): Mikhail N. Source: Jama : the Journal of the American Medical Association. 2002 October 9; 288(14): 1716; Author Reply 1716. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12365946

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Insulin resistance and lipid profile in women with polycystic appearing ovaries: implications with regard to polycystic ovary syndrome. Author(s): Cenk Sayin N, Gucer F, Balkanli-Kaplan P, Ali Yuce M, Yardim T. Source: Gynecological Endocrinology : the Official Journal of the International Society of Gynecological Endocrinology. 2003 October; 17(5): 387-96. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14710586

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Insulin resistance and tissue repair: a “fato-logical” phenomenon. Author(s): Sanyal AJ. Source: Gastroenterology. 2003 December; 125(6): 1886-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14724842

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Insulin resistance in patients with the mitochondrial tRNA(Leu(UUR)) gene mutation at position 3243. Author(s): Becker R, Laube H, Linn T, Damian MS. Source: Experimental and Clinical Endocrinology & Diabetes : Official Journal, German Society of Endocrinology [and] German Diabetes Association. 2002 September; 110(6): 291-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373633

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Insulin resistance is associated with chronic hepatitis C and virus infection fibrosis progression. Author(s): Hui JM, Sud A, Farrell GC, Bandara P, Byth K, Kench JG, McCaughan GW, George J. Source: Gastroenterology. 2003 December; 125(6): 1695-704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14724822

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Insulin resistance is associated with increased serum levels of glycosylphosphatidylinositol-specific phospholipase D. Author(s): Kurtz TA, Fineberg NS, Considine RV, Deeg MA. Source: Metabolism: Clinical and Experimental. 2004 February; 53(2): 138-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14767861

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Insulin resistance syndrome. Author(s): Fonseca VA, Kendall DM, Sobel BE; Partners Against Insulin Resistance (PAIR) Advisory Panel. Source: Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists. 2003 November-December; 9(6): 567-9; Author Reply 569. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14753181

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Insulin resistance syndrome: a potent culprit in cardiovascular disease. Author(s): Coulston AM, Peragallo-Dittko V. Source: Journal of the American Dietetic Association. 2004 February; 104(2): 176-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14760563

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Insulin resistance, diabetes, and atherosclerosis: thiazolidinediones as therapeutic interventions. Author(s): Raji A, Plutzky J. Source: Current Cardiology Reports. 2002 November; 4(6): 514-21. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12379175

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Insulin resistance, heart disease and inflammation. Identifying the 'at-risk' patient: the earlier the better? The role of inflammatory markers. Author(s): Koenig W. Source: Int J Clin Pract Suppl. 2002 October; (132): 23-30. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12425360

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Insulin resistance, impaired postprandial lipid metabolism and abdominal obesity. A deadly triad. Author(s): Frayn KN. Source: Medical Principles and Practice : International Journal of the Kuwait University, Health Science Centre. 2002; 11 Suppl 2: 31-40. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12444308

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Insulin resistance: a metabolic link between depressive disorder and atherosclerotic vascular diseases. Author(s): Ramasubbu R. Source: Medical Hypotheses. 2002 November; 59(5): 537-51. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12376076

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Juvenile acanthosis nigricans and insulin resistance. Author(s): Hermanns-Le T, Hermanns JF, Pierard GE. Source: Pediatric Dermatology. 2002 January-February; 19(1): 12-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11860562

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K121Q PC-1 gene polymorphism is not associated with insulin resistance in a Spanish population. Author(s): Gonzalez-Sanchez JL, Martinez-Larrad MT, Fernandez-Perez C, Kubaszek A, Laakso M, Serrano-Rios M. Source: Obesity Research. 2003 May; 11(5): 603-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12740448

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Knockout models are useful tools to dissect the pathophysiology and genetics of insulin resistance. Author(s): Mauvais-Jarvis F, Kulkarni RN, Kahn CR. Source: Clinical Endocrinology. 2002 July; 57(1): 1-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12100063

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Lack of association of insulin resistance and carotid intimal medial thickness in nondiabetic Asian Indian subjects. Author(s): Snehalatha C, Vijay V, Suresh Mohan R, Satyavani K, Sivasankari S, Megha T, Radhika S, Ramachandran A. Source: Diabetes/Metabolism Research and Reviews. 2001 November-December; 17(6): 444-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11757080

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Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study. The Hoorn Study. Author(s): Ruige JB, Dekker JM, Blum WF, Stehouwer CD, Nijpels G, Mooy J, Kostense PJ, Bouter LM, Heine RJ. Source: Diabetes Care. 1999 July; 22(7): 1097-104. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10388974

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Leptin levels in type 2 diabetes: associations with measures of insulin resistance and insulin secretion. Author(s): Wauters M, Considine RV, Yudkin JS, Peiffer F, De Leeuw I, Van Gaal LF. Source: Hormone and Metabolic Research. Hormon- Und Stoffwechselforschung. Hormones Et Metabolisme. 2003 February; 35(2): 92-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12734788

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Leukocyte angiotensin II levels inpatients with essential hypertension:relation to insulin resistance. Author(s): Fukuda N, Nakayama M, Jian T, Satoh C, Nakayama T, Soma M, Izumi Y, Kanmatsuse K. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2003 February; 16(2): 129-34. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12559679

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Life course influences on insulin resistance: findings from the British Women's Heart and Health Study. Author(s): Lawlor DA, Davey Smith G, Ebrahim S. Source: Diabetes Care. 2003 January; 26(1): 97-103. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12502664

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Lipodystrophy, insulin resistance, diabetes mellitus, dyslipidemia, and cardiovascular disease in human immunodeficiency virus infection. Author(s): Tanwani LK, Mokshagundam SL. Source: Southern Medical Journal. 2003 February; 96(2): 180-8; Quiz 189. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12630645

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Lipoprotein abnormalities in human genetic CD36 deficiency associated with insulin resistance and abnormal fatty acid metabolism. Author(s): Kuwasako T, Hirano K, Sakai N, Ishigami M, Hiraoka H, Yakub MJ, Yamauchi-Takihara K, Yamashita S, Matsuzawa Y. Source: Diabetes Care. 2003 May; 26(5): 1647-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12716848

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Lipoprotein disorders associated with type 2 diabetes mellitus and insulin resistance. Author(s): Haffner SM. Source: The American Journal of Cardiology. 2002 October 17; 90(8A): 55I-61I. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12419481

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Lipoprotein lipase is a gene for insulin resistance in Mexican Americans. Author(s): Goodarzi MO, Guo X, Taylor KD, Quinones MJ, Saad MF, Yang H, Hsueh WA, Rotter JI. Source: Diabetes. 2004 January; 53(1): 214-20. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14693718

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Liver-fat accumulation and insulin resistance in obese women with previous gestational diabetes. Author(s): Tiikkainen M, Tamminen M, Hakkinen AM, Bergholm R, Vehkavaara S, Halavaara J, Teramo K, Rissanen A, Yki-Jarvinen H. Source: Obesity Research. 2002 September; 10(9): 859-67. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226133

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Longitudinal changes in risk variables of insulin resistance syndrome from childhood to young adulthood in offspring of parents with type 2 diabetes: the Bogalusa Heart Study. Author(s): Srinivasan SR, Frontini MG, Berenson GS; Bogalusa Heart Study. Source: Metabolism: Clinical and Experimental. 2003 April; 52(4): 443-50; Discussion 451-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12701056

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Long-term association of cardiovascular risk factors with impaired insulin secretion and insulin resistance. Author(s): Kekalainen P, Sarlund H, Laakso M. Source: Metabolism: Clinical and Experimental. 2000 October; 49(10): 1247-54. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11079811

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Long-term cardiovascular effects of insulin sensitizer troglitazone on non-diabetic individuals with insulin resistance: double blind, prospective randomized study. Author(s): Stakos DA, Schuster DP, Sparks EA, Wooley CF, Osei K, Boudoulas H. Source: J Cardiol. 2003 April; 41(4): 183-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12728539

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Low adipocyte-derived plasma protein adiponectin concentrations are associated with the metabolic syndrome and small dense low-density lipoprotein particles: atherosclerosis and insulin resistance study. Author(s): Hulthe J, Hulten LM, Fagerberg B. Source: Metabolism: Clinical and Experimental. 2003 December; 52(12): 1612-4. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14669165

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Low birth weight and insulin resistance: can capillary recruitment predict hypertension development? Author(s): Virdis A, Schiffrin EL. Source: Journal of Hypertension. 2002 October; 20(10): 1933-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12359965

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Low ghrelin concentrations in nonalcoholic fatty liver disease are related to insulin resistance. Author(s): Marchesini G, Pagotto U, Bugianesi E, De Iasio R, Manini R, Vanni E, Pasquali R, Melchionda N, Rizzetto M. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 December; 88(12): 5674-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14671152

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Low nutrient intake and early growth for later insulin resistance in adolescents born preterm. Author(s): Singhal A, Fewtrell M, Cole TJ, Lucas A. Source: Lancet. 2003 March 29; 361(9363): 1089-97. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12672313

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Low plasma ghrelin is associated with insulin resistance, hypertension, and the prevalence of type 2 diabetes. Author(s): Poykko SM, Kellokoski E, Horkko S, Kauma H, Kesaniemi YA, Ukkola O. Source: Diabetes. 2003 October; 52(10): 2546-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514639

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Low-dose flutamide-metformin therapy reverses insulin resistance and reduces fat mass in nonobese adolescents with ovarian hyperandrogenism. Author(s): Ibanez L, Ong K, Ferrer A, Amin R, Dunger D, de Zegher F. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 June; 88(6): 2600-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12788862

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Lung function, insulin resistance and incidence of cardiovascular disease: a longitudinal cohort study. Author(s): Engstrom G, Hedblad B, Nilsson P, Wollmer P, Berglund G, Janzon L. Source: Journal of Internal Medicine. 2003 May; 253(5): 574-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12702035

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Management of diabetes mellitus and insulin resistance in patients with cardiovascular disease. Author(s): Fonseca VA. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 50J-60J. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957327

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Markers of insulin resistance in day and shift workers aged 30-59 years. Author(s): Nagaya T, Yoshida H, Takahashi H, Kawai M. Source: International Archives of Occupational and Environmental Health. 2002 October; 75(8): 562-8. Epub 2002 August 14. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12373318

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Measuring insulin resistance: a task worth doing. But how? Author(s): Haymond MW. Source: Pediatric Diabetes. 2003 September; 4(3): 115-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14655268

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Mechanisms and strategies for insulin resistance in acquired immune deficiency syndrome. Author(s): Grinspoon S. Source: Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America. 2003; 37 Suppl 2: S85-90. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12942379

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Meeting notes from the 2nd International AIDS Society Conference on HIV Pathogenesis and Treatment. Metabolic update: better defining lipodystrophy and treating insulin resistance. Author(s): Currier J. Source: Aids Clin Care. 2003 September; 15(9): 79-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14669724

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Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis. Author(s): Chalasani N, Deeg MA, Persohn S, Crabb DW. Source: The American Journal of Gastroenterology. 2003 August; 98(8): 1849-55. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12907343

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Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. Author(s): Vgontzas AN, Bixler EO, Chrousos GP. Source: Journal of Internal Medicine. 2003 July; 254(1): 32-44. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12823641

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Methods for quantifying insulin resistance in human immunodeficiency viruspositive patients. Author(s): Chu JW, Abbasi F, Beatty GW, Khalili M, Koch J, Rosen A, Schmidt JM, Stansell JD, Reaven GM. Source: Metabolism: Clinical and Experimental. 2003 July; 52(7): 858-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12870161

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Microcirculation in insulin resistance and diabetes: more than just a complication. Author(s): Wiernsperger NF, Bouskela E. Source: Diabetes & Metabolism. 2003 September; 29(4 Pt 2): 6S77-87. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502104

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Modulators of insulin action and their role in insulin resistance. Author(s): Pirola L, Johnston AM, Van Obberghen E. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 December; 27 Suppl 3: S61-4. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704748

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Molecular mechanism of insulin resistance and obesity. Author(s): Kadowaki T, Hara K, Yamauchi T, Terauchi Y, Tobe K, Nagai R. Source: Experimental Biology and Medicine (Maywood, N.J.). 2003 November; 228(10): 1111-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14610248

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Molecular mechanisms of inflammation in obesity-linked insulin resistance. Author(s): Marette A. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2003 December; 27 Suppl 3: S46-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14704744

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Muscle uridine diphosphate-hexosamines do not decrease despite correction of hyperglycemia-induced insulin resistance in type 2 diabetes. Author(s): Pouwels MJ, Span PN, Tack CJ, Olthaar AJ, Sweep CG, van Engelen BG, de Jong JG, Lutterman JA, Hermus AR. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 November; 87(11): 5179-84. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414889

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NAD (P) H oxidase p22 phox C242T polymorphism affects LDL particle size and insulin resistance in Japanese subjects. Author(s): Hayaishi-Okano R, Yamasaki Y, Ohtoshi K, Yasuda T, Katakami N, Hirano T, Yoshino G, Kajimoto Y, Hori M. Source: J Atheroscler Thromb. 2002; 9(4): 200-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12226552

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Neighborhood characteristics and components of the insulin resistance syndrome in young adults: the coronary artery risk development in young adults (CARDIA) study. Author(s): Diez Roux AV, Jacobs DR, Kiefe CI; Coronary Artery Risk Developoment in Young Adults (CARDIA) Study. Source: Diabetes Care. 2002 November; 25(11): 1976-82. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401742

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Neither homeostasis model assessment nor quantitative insulin sensitivity check index can predict insulin resistance in elderly patients with poorly controlled type 2 diabetes mellitus. Author(s): Katsuki A, Sumida Y, Urakawa H, Gabazza EC, Murashima S, Morioka K, Kitagawa N, Tanaka T, Araki-Sasaki R, Hori Y, Nakatani K, Yano Y, Adachi Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 November; 87(11): 5332-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12414910

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New concepts in insulin resistance of pregnancy and gestational diabetes: long-term implications for mother and offspring. Author(s): Barbour LA. Source: Journal of Obstetrics and Gynaecology : the Journal of the Institute of Obstetrics and Gynaecology. 2003 September; 23(5): 545-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12963518

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New paradigm for the mechanism and treatment of insulin resistance. Author(s): Lautt WW. Source: Proc West Pharmacol Soc. 2002; 45: 223-4. Review. No Abstract Available. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12434584

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Nicotinic acid-induced insulin resistance is related to increased circulating fatty acids and fat oxidation but not muscle lipid content. Author(s): Poynten AM, Gan SK, Kriketos AD, O'Sullivan A, Kelly JJ, Ellis BA, Chisholm DJ, Campbell LV. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 699-704. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12800094

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Nonalcoholic steatohepatitis and insulin resistance: interface between gastroenterologists and endocrinologists. Author(s): Scheen AJ, Luyckx FH. Source: Acta Clin Belg. 2003 March-April; 58(2): 81-91. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12836490

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Nut consumption, body weight and insulin resistance. Author(s): Garcia-Lorda P, Megias Rangil I, Salas-Salvado J. Source: European Journal of Clinical Nutrition. 2003 September; 57 Suppl 1: S8-11. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12947444

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Nutrient-induced insulin resistance. Author(s): Proietto J, Filippis A, Nakhla C, Clark S. Source: Molecular and Cellular Endocrinology. 1999 May 25; 151(1-2): 143-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10411329

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Nutrition, growth, and body size in relation to insulin resistance and type 2 diabetes. Author(s): Yajnik CS. Source: Curr Diab Rep. 2003 April; 3(2): 108-14. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12728636

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Obesity, hypertension, and insulin resistance. Author(s): Bloomgarden ZT. Source: Diabetes Care. 2002 November; 25(11): 2088-97. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12401761

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Obesity, insulin resistance, and other clinicopathological correlates of pediatric nonalcoholic fatty liver disease. Author(s): Schwimmer JB, Deutsch R, Rauch JB, Behling C, Newbury R, Lavine JE. Source: The Journal of Pediatrics. 2003 October; 143(4): 500-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14571229

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Obesity, insulin resistance, diabetes, and cardiovascular risk in children: an American Heart Association scientific statement from the Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young) and the Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Author(s): Steinberger J, Daniels SR; American Heart Association Atherosclerosis, Hypertension, and Obesity in the Young Committee (Council on Cardiovascular Disease in the Young); American Heart Association Diabetes Committee (Council on Nutrition, Physical Activity, and Metabolism). Source: Circulation. 2003 March 18; 107(10): 1448-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12642369

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Olanzapine induces insulin resistance: results from a prospective study. Author(s): Ebenbichler CF, Laimer M, Eder U, Mangweth B, Weiss E, Hofer A, Hummer M, Kemmler G, Lechleitner M, Patsch JR, Fleischhacker WW. Source: The Journal of Clinical Psychiatry. 2003 December; 64(12): 1436-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14728104

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Oleic acid from cooking oils is associated with lower insulin resistance in the general population (Pizarra study). Author(s): Soriguer F, Esteva I, Rojo-Martinez G, Ruiz de Adana MS, Dobarganes MC, Garcia-Almeida JM, Tinahones F, Beltran M, Gonzalez-Romero S, Olveira G, GomezZumaquero JM. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2004 January; 150(1): 33-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14713277

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Ovariectomy leads to increased insulin resistance in human apolipoprotein B transgenic mice lacking brown adipose tissue. Author(s): Siri PW, Ginsberg HN. Source: Metabolism: Clinical and Experimental. 2003 June; 52(6): 659-61. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12800087

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Overexpression of human apolipoprotein A-II in transgenic mice does not increase their susceptibility to insulin resistance and obesity. Author(s): Escola-Gil JC, Blanco-Vaca F, Julve J. Source: Diabetologia. 2002 April; 45(4): 600-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12032642

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Overweight, waist circumference, age, gender, and insulin resistance as risk factors for hyperleptinemia. Author(s): Mendoza-Nunez VM, Garcia-Sanchez A, Sanchez-Rodriguez M, GalvanDuarte RE, Fonseca-Yerena ME. Source: Obesity Research. 2002 April; 10(4): 253-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11943833

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Oxidative stress is associated with adiposity and insulin resistance in men. Author(s): Urakawa H, Katsuki A, Sumida Y, Gabazza EC, Murashima S, Morioka K, Maruyama N, Kitagawa N, Tanaka T, Hori Y, Nakatani K, Yano Y, Adachi Y. Source: The Journal of Clinical Endocrinology and Metabolism. 2003 October; 88(10): 4673-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14557439

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Oxidative stress markers in Korean subjects with insulin resistance syndrome. Author(s): Lee KU. Source: Diabetes Research and Clinical Practice. 2001 December; 54 Suppl 2: S29-33. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11733106

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Plasma adiponectin in overweight, nondiabetic individuals with or without insulin resistance. Author(s): Shand BI, Scott RS, Elder PA, George PM. Source: Diabetes, Obesity & Metabolism. 2003 September; 5(5): 349-53. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12940874

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Plasma ghrelin, body fat, insulin resistance, and smoking in clinically healthy men: the atherosclerosis and insulin resistance study. Author(s): Fagerberg B, Hulten LM, Hulthe J. Source: Metabolism: Clinical and Experimental. 2003 November; 52(11): 1460-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14624407

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Plasma resistin, adiponectin and leptin levels in lean and obese subjects: correlations with insulin resistance. Author(s): Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ. Source: European Journal of Endocrinology / European Federation of Endocrine Societies. 2003 October; 149(4): 331-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14514348

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Plasminogen activator inhibitor-1, inflammation, obesity, insulin resistance and vascular risk. Author(s): Juhan-Vague I, Alessi MC, Mavri A, Morange PE. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 July; 1(7): 1575-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871293

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Platelet count is independently associated with insulin resistance in non-obese Japanese type 2 diabetic patients. Author(s): Taniguchi A, Fukushima M, Seino Y, Sakai M, Yoshii S, Nagasaka S, Yamauchi I, Okumura T, Nin K, Tokuyama K, Yamadori N, Ogura M, Kuroe A, Nakai Y. Source: Metabolism: Clinical and Experimental. 2003 October; 52(10): 1246-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14564674

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Polycystic ovarian syndrome and insulin resistance in white and Mexican American women. Author(s): Gokcel A, Bagis T, Zeyneloglu HB. Source: American Journal of Obstetrics and Gynecology. 2003 June; 188(6): 1661; Author Reply 1661-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12825010

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Polycystic ovarian syndrome and insulin resistance in white and Mexican American women: a comparison of two distinct populations. Author(s): Kauffman RP, Baker VM, Dimarino P, Gimpel T, Castracane VD. Source: American Journal of Obstetrics and Gynecology. 2002 November; 187(5): 1362-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439532

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Polycystic ovary syndrome (PCOS), insulin resistance and insulin-like growth factors (IGfs)/IGF-binding proteins (IGFBPs). Author(s): Wang HS, Wang TH. Source: Chang Gung Med J. 2003 August; 26(8): 540-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14609034

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Possible relationship between insulin resistance and remnant-like lipoprotein particles in coronary endothelial dysfunction. Author(s): Inoue T, Uchida T, Kamishirado H, Sakuma M, Sakai Y, Takayanagi K, Hayashi T, Morooka S. Source: Clin Cardiol. 2002 November; 25(11): 532-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12430784

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Prediabetes in obese youth: a syndrome of impaired glucose tolerance, severe insulin resistance, and altered myocellular and abdominal fat partitioning. Author(s): Weiss R, Dufour S, Taksali SE, Tamborlane WV, Petersen KF, Bonadonna RC, Boselli L, Barbetta G, Allen K, Rife F, Savoye M, Dziura J, Sherwin R, Shulman GI, Caprio S. Source: Lancet. 2003 September 20; 362(9388): 951-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14511928

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Reducing insulin resistance with metformin: the evidence today. Author(s): Giannarelli R, Aragona M, Coppelli A, Del Prato S. Source: Diabetes & Metabolism. 2003 September; 29(4 Pt 2): 6S28-35. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502098

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Relation of insulin resistance and body composition to left ventricular mass in children. Author(s): Steinberger J, Jacobs DR, Moran A, Hong CP, Rocchini AP, Prineas RJ, Sinaiko AR. Source: The American Journal of Cardiology. 2002 November 15; 90(10): 1177-80. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12423731

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Relation of leptin to insulin resistance syndrome in children. Author(s): Steinberger J, Steffen L, Jacobs DR Jr, Moran A, Hong CP, Sinaiko AR. Source: Obesity Research. 2003 September; 11(9): 1124-30. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12972683

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Relationship between insulin resistance and accumulation of coronary risk factors. Author(s): Ohnishi H, Saitoh S, Ura N, Takagi S, Obara F, Akasaka H, Oimatsu H, Shimamoto K. Source: Diabetes, Obesity & Metabolism. 2002 November; 4(6): 388-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12406036

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Relationship between insulin resistance and gonadotropin dissociation in obese and nonobese women with polycystic ovary syndrome. Author(s): Moran C, Garcia-Hernandez E, Barahona E, Gonzalez S, Bermudez JA. Source: Fertility and Sterility. 2003 December; 80(6): 1466-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14667885

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Relationships of the systolic blood pressure response during exercise with insulin resistance, obesity, and endurance fitness in men with type 2 diabetes mellitus. Author(s): Kumagai S, Kai Y, Hanada H, Uezono K, Sasaki H. Source: Metabolism: Clinical and Experimental. 2002 October; 51(10): 1247-52. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370842

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Relative contribution of iron burden, HFE mutations, and insulin resistance to fibrosis in nonalcoholic fatty liver. Author(s): Bugianesi E, Manzini P, D'Antico S, Vanni E, Longo F, Leone N, Massarenti P, Piga A, Marchesini G, Rizzetto M. Source: Hepatology (Baltimore, Md.). 2004 January; 39(1): 179-87. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14752836

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Rituximab therapy for the type B syndrome of severe insulin resistance. Author(s): Coll AP, Thomas S, Mufti GJ. Source: The New England Journal of Medicine. 2004 January 15; 350(3): 310-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14724317

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Role of endothelial dysfunction in insulin resistance. Author(s): Hsueh WA, Quinones MJ. Source: The American Journal of Cardiology. 2003 August 18; 92(4A): 10J-17J. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12957322

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Role of lipases, lecithin:cholesterol acyltransferase and cholesteryl ester transfer protein in abnormal high density lipoprotein metabolism in insulin resistance and type 2 diabetes mellitus. Author(s): de Vries R, Borggreve SE, Dullaart RP. Source: Clin Lab. 2003; 49(11-12): 601-13. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14651331

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Salicylic acid reverses phorbol 12-myristate-13-acetate (PMA)- and tumor necrosis factor alpha (TNFalpha)-induced insulin receptor substrate 1 (IRS1) serine 307 phosphorylation and insulin resistance in human embryonic kidney 293 (HEK293) cells. Author(s): Jiang G, Dallas-Yang Q, Liu F, Moller DE, Zhang BB. Source: The Journal of Biological Chemistry. 2003 January 3; 278(1): 180-6. Epub 2002 October 29. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12409308

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Serum corticosteroid-binding globulin concentration and insulin resistance syndrome: a population study. Author(s): Fernandez-Real JM, Pugeat M, Grasa M, Broch M, Vendrell J, Brun J, Ricart W. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 October; 87(10): 4686-90. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12364459

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Sex steroid hormones, upper body obesity, and insulin resistance. Author(s): Abate N, Haffner SM, Garg A, Peshock RM, Grundy SM. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 October; 87(10): 4522-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12364429

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Skeletal muscle triglyceride: marker or mediator of obesity-induced insulin resistance in type 2 diabetes mellitus? Author(s): Goodpaster BH, Kelley DE. Source: Curr Diab Rep. 2002 June; 2(3): 216-22. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12643176

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Sleep-disordered breathing, glucose intolerance, and insulin resistance. Author(s): Punjabi NM, Ahmed MM, Polotsky VY, Beamer BA, O'Donnell CP. Source: Respiratory Physiology & Neurobiology. 2003 July 16; 136(2-3): 167-78. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12853008

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Socioeconomic position in childhood and adulthood and insulin resistance: cross sectional survey using data from British women's heart and health study. Author(s): Lawlor DA, Ebrahim S, Davey Smith G; British women's heart and health study. Source: Bmj (Clinical Research Ed.). 2002 October 12; 325(7368): 805. Erratum In: Bmj. 2003 March 1; 326(7387): 488. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12376440

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Stress-induced hemodynamic responses are associated with insulin resistance in mild hypertensives. Author(s): Nazzaro P, Ciancio L, Vulpis V, Triggiani R, Schirosi G, Pirrelli A. Source: American Journal of Hypertension : Journal of the American Society of Hypertension. 2002 October; 15(10 Pt 1): 865-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12372673

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Supplementation with conjugated linoleic acid causes isomer-dependent oxidative stress and elevated C-reactive protein: a potential link to fatty acid-induced insulin resistance. Author(s): Riserus U, Basu S, Jovinge S, Fredrikson GN, Arnlov J, Vessby B. Source: Circulation. 2002 October 8; 106(15): 1925-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12370214

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Surveillance of insulin resistance in children. Author(s): Pereira MA, Ludwig DS. Source: Clinical Chemistry. 2003 April; 49(4): 540-1. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12651804

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Sustained benefits of metformin therapy on markers of cardiovascular risk in human immunodeficiency virus-infected patients with fat redistribution and insulin resistance. Author(s): Hadigan C, Rabe J, Grinspoon S. Source: The Journal of Clinical Endocrinology and Metabolism. 2002 October; 87(10): 4611-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12364443

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The dysmetabolic syndrome, insulin resistance and increased cardiovascular (CV) morbidity and mortality in type 2 diabetes: aetiological factors in the development of CV complications. Author(s): Eschwege E. Source: Diabetes & Metabolism. 2003 September; 29(4 Pt 2): 6S19-27. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502097

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The effects of sibutramine and orlistat on the ultrasonographic findings, insulin resistance and liver enzyme levels in obese patients with non-alcoholic steatohepatitis. Author(s): Sabuncu T, Nazligul Y, Karaoglanoglu M, Ucar E, Kilic FB. Source: Rom J Gastroenterol. 2003 September; 12(3): 189-92. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14502318

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The impact of impaired insulin release and insulin resistance on glucose intolerance after renal transplantation. Author(s): Hjelmesaeth J, Hagen M, Hartmann A, Midtvedt K, Egeland T, Jenssen T. Source: Clinical Transplantation. 2002 December; 16(6): 389-96. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12437616

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The metabolic syndrome, insulin resistance and cardiovascular disease. Author(s): Ascott-Evans B. Source: Cardiovasc J S Afr. 2002 July-August; 13(4): 187-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12389061

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The relation of insulin resistance syndromes to risk of cardiovascular disease. Author(s): Nesto RW. Source: Reviews in Cardiovascular Medicine. 2003; 4 Suppl 6: S11-8. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14668699

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The relationship between insulin resistance and cardiovascular risk factors in overweight/obese non-diabetic Asian adults: the 1992 Singapore National Health Survey. Author(s): Lim SC, Tan BY, Chew SK, Tan CE. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2002 November; 26(11): 1511-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12439654

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The roles of insulin resistance, hyperinsulinemia, and thiazolidinediones in cardiovascular disease. Author(s): Uwaifo GI, Ratner RE. Source: The American Journal of Medicine. 2003 December 8; 115 Suppl 8A: 12S-19S. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14678860

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Therapeutic approach in insulin resistance with acanthosis nigricans. Author(s): Tankova T, Koev D, Dakovska L, Kirilov G. Source: Int J Clin Pract. 2002 October; 56(8): 578-81. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12425366

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Tumor necrosis factor-alpha-induced insulin resistance may mediate the hepatitis C virus-diabetes association. Author(s): Knobler H, Zhornicky T, Sandler A, Haran N, Ashur Y, Schattner A. Source: The American Journal of Gastroenterology. 2003 December; 98(12): 2751-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14687828

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Type 2 diabetes, cardiovascular risk, and the link to insulin resistance. Author(s): Stolar MW, Chilton RJ. Source: Clinical Therapeutics. 2003; 25 Suppl B: B4-31. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14553864

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Understanding the pathogenesis and treatment of insulin resistance and type 2 diabetes mellitus: what can we learn from transgenic and knockout mice? Author(s): Mauvais-Jarvis F, Kahn CR. Source: Diabetes & Metabolism. 2000 December; 26(6): 433-48. Review. Erratum In: Diabetes Metab 2001 April; 27(2 Pt 1): 176. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11173714

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Understanding type 2 diabetes mellitus and associated cardiovascular disease: linked by insulin resistance. Author(s): Tennyson GE. Source: Am J Manag Care. 2002 October; 8(16 Suppl): S450-9. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12408408

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Unexpected inverse relationship between insulin resistance and serum homocysteine in healthy subjects. Author(s): Rosolova H, Simon J, Mayer O Jr, Racek J, Dierze T, Jacobsen DW. Source: Physiological Research / Academia Scientiarum Bohemoslovaca. 2002; 51(1): 938. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12071296

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Unraveling the mysteries of syndrome X. As the number of Americans with insulin resistance grows, pharmacists can help patients prevent the onset of type 2 diabetes and cardiovascular disease. Author(s): Campbell RK. Source: J Am Pharm Assoc (Wash Dc). 2003 September-October; 43(5 Suppl 1): S32-3. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14626524

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Unraveling the riddle of insulin resistance. Author(s): Goldfine ID. Source: The Journal of Laboratory and Clinical Medicine. 1999 August; 134(2): 100-2. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10444021

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Upper abdominal obesity, insulin resistance and breast cancer risk. Author(s): Stoll BA. Source: International Journal of Obesity and Related Metabolic Disorders : Journal of the International Association for the Study of Obesity. 2002 June; 26(6): 747-53. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12037643

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Usefulness of plasma glucose and insulin concentrations in identifying patients with insulin resistance. Author(s): Tuan CY, Abbasi F, Lamendola C, McLaughlin T, Reaven G. Source: The American Journal of Cardiology. 2003 September 1; 92(5): 606-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12943888

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Utility of a surrogate measure of insulin resistance in American Indians: the Strong Heart Study. Author(s): Resnick HE, Bergman RN, Henderson JA, Nez-Henderson P, Howard BV. Source: Ethn Dis. 2002 Fall; 12(4): 523-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12477138

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Variables of the insulin resistance syndrome are associated with reduced arterial distensibility in healthy non-diabetic middle-aged women. Author(s): van Popele NM, Westendorp IC, Bots ML, Reneman RS, Hoeks AP, Hofman A, Grobbee DE, Witteman JC. Source: Diabetologia. 2000 May; 43(5): 665-72. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10855542

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Variants in the aromatase gene and on the Y-chromosome are not associated with adult height or insulin resistance in a UK population. Author(s): Weedon MN, Turner M, Knight B, Clark P, Hattersley AT, Frayling TM. Source: Clinical Endocrinology. 2003 August; 59(2): 175-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12864794

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Variants in the calpain-10 gene predispose to insulin resistance and elevated free fatty acid levels. Author(s): Orho-Melander M, Klannemark M, Svensson MK, Ridderstrale M, Lindgren CM, Groop L. Source: Diabetes. 2002 August; 51(8): 2658-64. Erratum In: Diabetes. 2003 May; 52(5): 1306. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12145185

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Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians. Author(s): Rasmussen SK, Urhammer SA, Berglund L, Jensen JN, Hansen L, Echwald SM, Borch-Johnsen K, Horikawa Y, Mashima H, Lithell H, Cox NJ, Hansen T, Bell GI, Pedersen O. Source: Diabetes. 2002 December; 51(12): 3561-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12453914

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Vascular function, insulin resistance and fatty acids. Author(s): Steinberg HO, Baron AD. Source: Diabetologia. 2002 May; 45(5): 623-34. Epub 2002 April 04. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12107742

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Venesection therapy of insulin resistance-associated hepatic iron overload. Author(s): Guillygomarc'h A, Mendler MH, Moirand R, Laine F, Quentin V, David V, Brissot P, Deugnier Y. Source: Journal of Hepatology. 2001 September; 35(3): 344-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11592595

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Visceral adipose tissue and markers of the insulin resistance syndrome in obese black and white teenagers. Author(s): Owens S, Gutin B, Barbeau P, Litaker M, Allison J, Humphries M, Okuyama T, Le NA. Source: Obesity Research. 2000 July; 8(4): 287-93. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10933304

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Visceral fat accumulation contributes to insulin resistance, small-sized low-density lipoprotein, and progression of coronary artery disease in middle-aged non-obese Japanese men. Author(s): Kobayashi H, Nakamura T, Miyaoka K, Nishida M, Funahashi T, Yamashita S, Matsuzawa Y. Source: Japanese Circulation Journal. 2001 March; 65(3): 193-9. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11266194

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Visceral fat and insulin resistance--causative or correlative? Author(s): Frayn KN. Source: The British Journal of Nutrition. 2000 March; 83 Suppl 1: S71-7. Review. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10889795

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Visceral obesity and insulin resistance are associated with plasma aldosterone levels in women. Author(s): Goodfriend TL, Kelley DE, Goodpaster BH, Winters SJ. Source: Obesity Research. 1999 July; 7(4): 355-62. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10440591

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Waist circumference predicts insulin resistance in offspring of diabetic patients. Author(s): Kuo CS, Hwu CM, Chiang SC, Hsiao LC, Weih MJ, Kao WY, Lee SH, Kwok CF, Ho LT. Source: Diabetes Nutr Metab. 2002 April; 15(2): 101-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12059091

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Weak and non-independent association between plasma TAFI antigen levels and the insulin resistance syndrome. Author(s): Aubert H, Frere C, Aillaud MF, Morange PE, Juhan-Vague I, Alessi MC. Source: Journal of Thrombosis and Haemostasis : Jth. 2003 April; 1(4): 791-7. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12871417

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Weight gain and insulin resistance during nicotine replacement therapy. Author(s): Assali AR, Beigel Y, Schreibman R, Shafer Z, Fainaru M. Source: Clin Cardiol. 1999 May; 22(5): 357-60. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=10326169

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Weight loss after Swedish Adjustable Gastric Banding: relationships to insulin resistance and metabolic syndrome. Author(s): Gazzaruso C, Giordanetti S, La Manna A, Celsa M, De Amici E, Turpini C, Catona A, Fratino P. Source: Obesity Surgery : the Official Journal of the American Society for Bariatric Surgery and of the Obesity Surgery Society of Australia and New Zealand. 2002 December; 12(6): 841-5. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12568192

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Weight loss-induced plasticity of glucose transport and phosphorylation in the insulin resistance of obesity and type 2 diabetes. Author(s): Williams KV, Bertoldo A, Kinahan P, Cobelli C, Kelley DE. Source: Diabetes. 2003 July; 52(7): 1619-26. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=12829624

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What is the contribution of differences in three measures of tumor necrosis factoralpha activity to insulin resistance in healthy volunteers? Author(s): Zavaroni I, Numeroso F, Dongiovanni P, Ardigo D, Valenti L, Fracanzani A, Valtuena S, Delsignore R, Fargion S, Reaven GM. Source: Metabolism: Clinical and Experimental. 2003 December; 52(12): 1593-6. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14669161

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Where does insulin resistance in lipodystrophic HIV-1-positive subjects come from? Author(s): Schmidt HH. Source: Aids (London, England). 2001 November 9; 15(16): 2187-8. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11684939

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White blood cell count and insulin resistance in patients with coronary artery disease. Author(s): Piedrola G, Novo E, Escobar F, Garcia-Robles R. Source: Annales D'endocrinologie. 2001 February; 62(1 Pt 1): 7-10. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=11240402

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Whole-grain intake and insulin sensitivity: the Insulin Resistance Atherosclerosis Study. Author(s): Liese AD, Roach AK, Sparks KC, Marquart L, D'Agostino RB Jr, Mayer-Davis EJ. Source: The American Journal of Clinical Nutrition. 2003 November; 78(5): 965-71. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=A bstract&list_uids=14594783

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CHAPTER 2. NUTRITION AND INSULIN RESISTANCE Overview In this chapter, we will show you how to find studies dedicated specifically to nutrition and insulin resistance.

Finding Nutrition Studies on Insulin Resistance The National Institutes of Health’s Office of Dietary Supplements (ODS) offers a searchable bibliographic database called the IBIDS (International Bibliographic Information on Dietary Supplements; National Institutes of Health, Building 31, Room 1B29, 31 Center Drive, MSC 2086, Bethesda, Maryland 20892-2086, Tel: 301-435-2920, Fax: 301-480-1845, E-mail: [email protected]). The IBIDS contains over 460,000 scientific citations and summaries about dietary supplements and nutrition as well as references to published international, scientific literature on dietary supplements such as vitamins, minerals, and botanicals.7 The IBIDS includes references and citations to both human and animal research studies. As a service of the ODS, access to the IBIDS database is available free of charge at the following Web address: http://ods.od.nih.gov/databases/ibids.html. After entering the search area, you have three choices: (1) IBIDS Consumer Database, (2) Full IBIDS Database, or (3) Peer Reviewed Citations Only. Now that you have selected a database, click on the “Advanced” tab. An advanced search allows you to retrieve up to 100 fully explained references in a comprehensive format. Type “insulin resistance” (or synonyms) into the search box, and click “Go.” To narrow the search, you can also select the “Title” field.

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Adapted from http://ods.od.nih.gov. IBIDS is produced by the Office of Dietary Supplements (ODS) at the National Institutes of Health to assist the public, healthcare providers, educators, and researchers in locating credible, scientific information on dietary supplements. IBIDS was developed and will be maintained through an interagency partnership with the Food and Nutrition Information Center of the National Agricultural Library, U.S. Department of Agriculture.

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The following is a typical result when searching for recently indexed consumer information on insulin resistance: •

Effect of maternal diabetes on the pattern of selected insulin resistance syndrome parameters in normal glucose tolerant subjects to two Algonquin Indian communities in Quebec. Author(s): Centre de Recherche Hotel-Dieu de Montreal, Montreal, Quebec, Canada. Source: Ekoe, J.M. Thomas, F. Balkau, B. Eschwege, E. Delisle, H. Diabetes-care (USA). (August 1996). volume 19(8) page 822-826.

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Fatty acid composition of skeletal muscle membrane phospholipids, insulin resistance and obesity. Author(s): The Center for Genetics, Nutrition and Health, Washington, DC. Source: Simopoulos, A.P. Nutrition-today (USA). (February 1994). volume 29(1) page 1216.

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Fatty acids and insulin resistance. Author(s): Temple University Hospital, Philadelphia, PA. Source: Boden, G. Diabetes-care (USA). (April 1996). volume 19(4) page 394-395.

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Pasta-makes-you-fat furor raises question of insulin resistance. Source: Hudnall, M. Environmental-nutrition (USA). (May 1995). volume 18(5) page 1, 4.

Additional consumer oriented references include: •

Beneficial effects of viscous dietary fiber from Konjac-mannan in subjects with the insulin resistance syndrome: results of a controlled metabolic trial. Author(s): Department of Nutritional Sciences, St. Michael's Hospital, University of Toronto, Canada. [email protected] Source: Vuksan, V Sievenpiper, J L Owen, R Swilley, J A Spadafora, P Jenkins, D J Vidgen, E Brighenti, F Josse, R G Leiter, L A Xu, Z Novokmet, R Diabetes-Care. 2000 January; 23(1): 9-14 0149-5992

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Dyslipidemia of central obesity and insulin resistance. Source: Brunzell, J.D. Hokanson, J.E. Diabetes-care. Alexandria, Va. : American Diabetes Association, Inc. April 1999. volume 22 (suppl.3) page C10-C13. 0149-5992

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Fasting plasma homocysteine levels in the insulin resistance syndrome: the Framingham offspring study. Author(s): General Medicine Division and Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114, USA. [email protected] Source: Meigs, J B Jacques, P F Selhub, J Singer, D E Nathan, D M Rifai, N D'Agostino, R B Sr Wilson, P W Diabetes-Care. 2001 August; 24(8): 1403-10 0149-5992

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Homeostasis model assessment as a clinical index of insulin resistance in type 2 diabetic patients treated with sulfonylureas. Author(s): Second Department of Internal Medicine, Osaka City University Medical School, Japan. Source: Emoto, M Nishizawa, Y Maekawa, K Hiura, Y Kanda, H Kawagishi, T Shoji, T Okuno, Y Morii, H Diabetes-Care. 1999 May; 22(5): 818-22 0149-5992

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Impaired incretin response after a mixed meal is associated with insulin resistance in nondiabetic men. Author(s): Department of Public Health and Clinical Medicine, Umea University Hospital, 901 85 Umea, Sweden. [email protected]

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Source: Rask, E Olsson, T Soderberg, S Johnson, O Seckl, J Holst, J J Ahren, B DiabetesCare. 2001 September; 24(9): 1640-5 0149-5992 •

Insulin resistance and insulin secretory dysfunction are independent predictors of worsening of glucose tolerance during each stage of type 2 diabetes development. Author(s): Clinical Diabetes and Nutrition Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Phoenix, Arizona 85016, USA. [email protected] Source: Weyer, C Tataranni, P A Bogardus, C Pratley, R E Diabetes-Care. 2001 January; 24(1): 89-94 0149-5992

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Insulin resistance in burns and trauma. Author(s): Massachusetts General Hospital, USA. Source: Carter, E A Nutr-Revolume 1998 January; 56(1 Pt 2): S170-6 0029-6643

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Is fasting leptin associated with insulin resistance among nondiabetic individuals? The Miami Community Health Study. Author(s): Department of Social and Preventive Medicine, University of Buffalo, NY 14214, USA. [email protected] Source: Donahue, R P Prineas, R J Donahue, R D Zimmet, P Bean, J A De Courten, M Collier, G Goldberg, R B Skyler, J S Schneiderman, N Diabetes-Care. 1999 July; 22(7): 1092-6 0149-5992

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Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study: the Hoorn Study. Source: Ruige, J.B. Mooy, J. Dekker, J.M. Kostense, P.J. Blum, W.F. Bouter, L.M. Stehouwer, C.D.A. Heine, R.J. Nipels, G. Diabetes-care. Alexandria, Va. : American Diabetes Association, Inc. July 1999. volume 22 (7) page 1097-1104. 0149-5992

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Lifestyle changes may reverse development of the insulin resistance syndrome: the Oslo Diet and Exercise Study: a randomized trial. Source: Torjesen, P.A. Birkeland, K.I. Anderssen, S.A. Hijermann, I. Holme, I. Urdal, P. Diabetes-care (USA). (January 1997). volume 20(1) page 26-31. metabolic disorders insulin diet physical activity body weight 0149-5992

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Obese premenopausal African-American women with normal and impaired glucose tolerance have a similar degree of insulin resistance but differ in beta-cell function. Author(s): National Institutes of Health, Bethesda, Maryland, USA. [email protected] Source: Sumner, A E Farmer, N M Cochran, C S Sebring, N G Vanevski, K Reynolds, J C PremkuMarch, A Boston, R C Diabetes-Care. 2001 November; 24(11): 1978-83 0149-5992

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Obesity, diabetes, and insulin resistance: implications from molecular biology, epidemiology, and experimental studies in humans and animals. Synopsis of the American Diabetes Association's 29th Research Symposium and Satellite Conference of the 7th International Congress on Obesity, Boston, Massachusetts. Source: Hansen, B C Diabetes-Care. 1995 June; 18(6): A2-9 0149-5992

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Polymorphism of the tumor necrosis factor-alpha receptor 2 gene is associated with obesity, leptin levels, and insulin resistance in young subjects and diet-treated type 2 diabetic patients. Author(s): Diabetes Unit, Endocrinology and Nutrition, University Hospital of Girona Dr. Josep Trueta, Barcelona, Spain. [email protected] Source: Fernandez Real, J M Vendrell, J Ricart, W Broch, M Gutierrez, C Casamitjana, R Oriola, J Richart, C Diabetes-Care. 2000 June; 23(6): 831-7 0149-5992

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Prevalences of type 2 diabetes, the insulin resistance syndrome, and coronary heart disease in an elderly, biethnic population. Author(s): Department of Medicine, University of New Mexico School of Medicine, Albuquerque, USA. [email protected] Source: Lindeman, R D Romero, L J Hundley, R Allen, A S Liang, H C Baumgartner, R N Koehler, K M Schade, D S Garry, P J Diabetes-Care. 1998 June; 21(6): 959-66 0149-5992

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Relationship between several surrogate estimates of insulin resistance and quantification of insulin-mediated glucose disposal in 490 healthy nondiabetic volunteers. Author(s): Stanford University School of Medicine, California, USA. Source: Yeni Komshian, H Carantoni, M Abbasi, F Reaven, G M Diabetes-Care. 2000 February; 23(2): 171-5 0149-5992

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Successful treatment with plasmapheresis, cyclophosphamide, and cyclosporin A in type B syndrome of insulin resistance. Case report. Author(s): Department of Medicine, Umea University Hospital, Sweden. [email protected] Source: Eriksson, J W Bremell, T Eliasson, B Fowelin, J Fredriksson, L Yu, Z W DiabetesCare. 1998 August; 21(8): 1217-20 0149-5992

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The 32nd annual meeting of the European Association for the Study of Diabetes. Leptin, insulin resistance, intrauterine malnutrition, sulfonylureas, oral agents alone and with insulin, and new pharmacological approaches to type 2 diabetes. Source: Bloomgarden, Z T Diabetes-Care. 1997 August; 20(8): 1334-7 0149-5992

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The insulin resistance epidemic in India: fetal origins, later lifestyle, or both? Author(s): Diabetes Unit, King Edward Memorial Hospital & Research Center, Rasta Peth, Pune, India. Source: Yajnik, C S Nutr-Revolume 2001 January; 59(1 Pt 1): 1-9 0029-6643

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Treatment with dietary trans10cis12 conjugated linoleic acid causes isomer-specific insulin resistance in obese men with the metabolic syndrome. Author(s): Department of Public Health and Caring Sciences/Geriatrics, Uppsala University, Uppsala, Sweden. [email protected] Source: Riserus, U Arner, P BrisMarch, K Vessby, B Diabetes-Care. 2002 September; 25(9): 1516-21 0149-5992

The following information is typical of that found when using the “Full IBIDS Database” to search for “insulin resistance” (or a synonym): •

Acarbose improves indirectly both insulin resistance and secretion in obese type 2 diabetic patients. Author(s): Division of Therapeutic Education for Chronic Diseases, University Hospital Geneva, Switzerland. Source: Delgado, H Lehmann, T Bobbioni Harsch, E Ybarra, J Golay, A Diabetes-Metab. 2002 June; 28(3): 195-200 1262-3636

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Clinical course of the syndrome of autoantibodies to the insulin receptor (type B insulin resistance): a 28-year perspective. Author(s): Diabetes Branch, National Institute of Diabetes, Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, Maryland 20892-1829, USA. Source: Arioglu, Elif Andewelt, Alexa Diabo, Crystal Bell, Melissa Taylor, Simeon I Gorden, Phillip Medicine-(Baltimore). 2002 March; 81(2): 87-100 0025-7974

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Components of the insulin resistance syndrome in seven-year-old children: relations with birth weight and the polyunsaturated fatty acid content of umbilical cord plasma phospholipids. Author(s): Department of Human Biology, Maastricht University, Maastricht, The Netherlands. Source: Rump, P Popp Snijders, C Heine, R J Hornstra, G Diabetologia. 2002 March; 45(3): 349-55 0012-186X

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D-chiro-inositol in insulin action and insulin resistance-old-fashioned biochemistry still at work. Author(s): Insmed Pharmaceuticals, Inc, Richmond, VA 23219, USA. Source: Larner, J IUBMB-Life. 2001 March; 51(3): 139-48 1521-6543

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D-chiro-inositol--its functional role in insulin action and its deficit in insulin resistance. Author(s): Department of Pharmacology, University of Virginia School of Medicine, Charlottesville 22908, USA. [email protected] Source: Larner, J Int-J-Exp-Diabetes-Res. 2002; 3(1): 47-60 1560-4284

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Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Author(s): Department of Medicine, Division of Endocrinology, University of Toronto, Canada M5G 2C4. [email protected] Source: Lewis, Gary F Carpentier, Andre Adeli, Khosrow Giacca, Adria EndocrRevolume 2002 April; 23(2): 201-29 0163-769X

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Effects of gemfibrozil on insulin resistance to fat metabolism in subjects with type 2 diabetes and hypertriglyceridaemia. Author(s): Diabetes Resource Centre and Department of Clinical Biochemistry, University Hospitals Birmingham, UK. [email protected] Source: Whitelaw, D C Smith, J M Nattrass, M Diabetes-Obes-Metab. 2002 May; 4(3): 187-94 1462-8902

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Effects of omapatrilat on blood pressure and insulin sensitivity in an animal model of insulin resistance. Author(s): Departamento de Endocrinologia y Metabolismo, Unidad de Investigacion Experimental, Instituto Nacional de la Nutricion, Mexico City, Mexico. [email protected] Source: Aguilar Salinas, C A Arellano, S A Villanueva Sanchez, O Magos, G A Guillen Pineda, L E Rodriguez, R Gomez Perez, F J Blood-Press. 2001; 10(3): 164-9 0803-7051

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Free fatty acids-the link between obesity and insulin resistance. Author(s): Division of Endocrinology/Diabetes/Metabolism and the General Clinical Research Center, Temple University School of Medicine, Philadelphia, Pennsylvania 19140, USA. Source: Boden, G Endocr-Pract. 2001 Jan-February; 7(1): 44-51 1530-891X

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Insulin resistance and upper-normal glucose levels in hypertension: a review. Author(s): Nova Southeastern University, HPD, Florida, USA, and Center for the Detection and Treatment of Silent Cardiovascular Risk Factors (SIL-DETECT), Central University of Venezuela, Caracas, Venezuela. [email protected] Source: Cubeddu, L X Hoffmann, I S J-Hum-Hypertens. 2002 March; 16 Suppl 1: S52-5 0950-9240

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Insulin resistance in type 2 diabetes: role of fatty acids. Author(s): Karolinska Institute, Huddinge Hospital, Huddinge, Sweden. [email protected] Source: Arner, P Diabetes-Metab-Res-Revolume 2002 Mar-April; 18 Suppl 2: S5-9 15207552

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Mechanisms of muscle insulin resistance in obese individuals. Source: Dohm, G.L. Int-j-sports-med-exerc-nutr. Champaign, IL : Human Kinetics, c2000-. December 2001. volume 11 (suppl.) page S64-S70. 1526-484X

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Metabolic characterization of insulin resistance syndrome feature loci in three brown Norway-derived congenic strains. Author(s): Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic. Source: Seda, O Sedova, L Kazdova, L Krenova, D Kren, V Folia-Biol-(Praha). 2002; 48(3): 81-8 0015-5500

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Perinatal growth failure: the road to obesity, insulin resistance and cardiovascular disease in adults. Author(s): Department of Paediatrics, Addenbrookes Hospital Box 116, Cambridge, CB2 2QQ, UK. Source: Ong, Ken K Dunger, David B Best-Pract-Res-Clin-Endocrinol-Metab. 2002 June; 16(2): 191-207 1521-690X

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Pharmacological treatment of insulin resistance in obesity. Author(s): AstraZeneca R & D, Molndal S 431 83, Sweden. [email protected] Source: Camejo, G Ljung, B Oakes, N Nutr-Metab-Cardiovasc-Dis. 2001 August; 11(4): 275-84 0939-4753

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Polycystic ovaries, obesity and insulin resistance in women with epilepsy. A comparative study of carbamazepine and valproic acid in 105 women. Author(s): Department of Neurology, University Hospital Innsbruck, Anichstrasse 35, Austria. [email protected] Source: Luef, G Abraham, I Haslinger, M Trinka, E Seppi, K Unterberger, I Alge, A Windisch, J Lechleitner, M Bauer, G J-Neurol. 2002 July; 249(7): 835-41 0340-5354

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PPARgamma2 pro12Ala polymorphism and insulin resistance in Japanese hypertensive patients. Author(s): Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan. Source: Yamamoto, J Kageyama, S Nemoto, M Sasaki, T Sakurai, T Ishibashi, K Mimura, A Yokota, K Tajima, N Hypertens-Res. 2002 January; 25(1): 25-9 0916-9636

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Psammomys obesus and the albino rat--two different models of nutritional insulin resistance, representing two different types of human populations. Author(s): Diabetes Research Unit, Hadassah University Hospital, Jerusalem, Israel. [email protected] Source: Kalman, R Ziv, E Shafrir, E Bar On, H Perez, R Lab-Anim. 2001 October; 35(4): 346-52 0023-6772

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Federal Resources on Nutrition In addition to the IBIDS, the United States Department of Health and Human Services (HHS) and the United States Department of Agriculture (USDA) provide many sources of information on general nutrition and health. Recommended resources include: •

healthfinder®, HHS’s gateway to health information, including diet and nutrition: http://www.healthfinder.gov/scripts/SearchContext.asp?topic=238&page=0

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The United States Department of Agriculture’s Web site dedicated to nutrition information: www.nutrition.gov

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The Food and Drug Administration’s Web site for federal food safety information: www.foodsafety.gov

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The National Action Plan on Overweight and Obesity sponsored by the United States Surgeon General: http://www.surgeongeneral.gov/topics/obesity/

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The Center for Food Safety and Applied Nutrition has an Internet site sponsored by the Food and Drug Administration and the Department of Health and Human Services: http://vm.cfsan.fda.gov/

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Center for Nutrition Policy and Promotion sponsored by the United States Department of Agriculture: http://www.usda.gov/cnpp/

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Food and Nutrition Information Center, National Agricultural Library sponsored by the United States Department of Agriculture: http://www.nal.usda.gov/fnic/

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Food and Nutrition Service sponsored by the United States Department of Agriculture: http://www.fns.usda.gov/fns/

Additional Web Resources A number of additional Web sites offer encyclopedic information covering food and nutrition. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=174&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/med_nutrition.html

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Google: http://directory.google.com/Top/Health/Nutrition/

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Healthnotes: http://www.healthnotes.com/

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Open Directory Project: http://dmoz.org/Health/Nutrition/

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Yahoo.com: http://dir.yahoo.com/Health/Nutrition/

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WebMDHealth: http://my.webmd.com/nutrition

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WholeHealthMD.com: http://www.wholehealthmd.com/reflib/0,1529,00.html

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The following is a specific Web list relating to insulin resistance; please note that any particular subject below may indicate either a therapeutic use, or a contraindication (potential danger), and does not reflect an official recommendation: •

Vitamins Vitamin A Source: Prima Communications, Inc.www.personalhealthzone.com Vitamin E Source: Healthnotes, Inc.; www.healthnotes.com

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Minerals Calcium Source: Healthnotes, Inc.; www.healthnotes.com Chromium Source: Healthnotes, Inc.; www.healthnotes.com HMG-CoA Reductase Inhibitors (Statins) Source: Integrative Medicine Communications; www.drkoop.com Iron Source: Healthnotes, Inc.; www.healthnotes.com Magnesium Source: Healthnotes, Inc.; www.healthnotes.com Zinc Source: Healthnotes, Inc.; www.healthnotes.com

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Food and Diet Low-Purine Diet Source: Healthnotes, Inc.; www.healthnotes.com Low-Salt Diet Source: Healthnotes, Inc.; www.healthnotes.com Nutritional Yeast Source: Integrative Medicine Communications; www.drkoop.com Weight Loss and Obesity Source: Healthnotes, Inc.; www.healthnotes.com

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CHAPTER 3. DISSERTATIONS ON INSULIN RESISTANCE Overview In this chapter, we will give you a bibliography on recent dissertations relating to insulin resistance. We will also provide you with information on how to use the Internet to stay current on dissertations. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical dissertations that use the generic term “insulin resistance” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on insulin resistance, we have not necessarily excluded non-medical dissertations in this bibliography.

Dissertations on Insulin Resistance ProQuest Digital Dissertations, the largest archive of academic dissertations available, is located at the following Web address: http://wwwlib.umi.com/dissertations. From this archive, we have compiled the following list covering dissertations devoted to insulin resistance. You will see that the information provided includes the dissertation’s title, its author, and the institution with which the author is associated. The following covers recent dissertations found when using this search procedure: •

Effects of Hyperinsulinemia, Insulin Sensitivity, and Other Factors Associated with the Insulin Resistance Syndrome on Colorectal Epithelial Proliferation and Carcinogenesis in Rats by Tran, Thien Tram; PhD from University of Toronto (Canada), 2003, 238 pages http://wwwlib.umi.com/dissertations/fullcit/NQ78428

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High Glucose and Glucosamine-Induced Insulin Resistance in 3t3-l1 Adipocytes by Nelson, Bryce Allen; PhD from Medical University of South Carolina, 2003, 208 pages http://wwwlib.umi.com/dissertations/fullcit/3105741

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Regulation of Fatty Acid Metabolism: Role of Leptin, Exercise and Insulin Resistance by Atkinson, Laura Lee; PhD from University of Alberta (Canada), 2003, 249 pages http://wwwlib.umi.com/dissertations/fullcit/NQ82079

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The Relationship between Depression and Risk Factors for Insulin Resistance While Controlling for Stress and Social Support: Secondary Data Analysis of the Nhanes I by Gangwisch, James Edward; PhD from Columbia University, 2003, 277 pages http://wwwlib.umi.com/dissertations/fullcit/3088332

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The Role of Suppressor of Cytokine Signaling-3 in Interleukin-6 Dependent Insulin Resistance by Senn, Joseph James; PhD from The University of Rochester, 2003, 151 pages http://wwwlib.umi.com/dissertations/fullcit/3092243

Keeping Current Ask the medical librarian at your library if it has full and unlimited access to the ProQuest Digital Dissertations database. From the library, you should be able to do more complete searches via http://wwwlib.umi.com/dissertations.

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CHAPTER 4. CLINICAL TRIALS AND INSULIN RESISTANCE Overview In this chapter, we will show you how to keep informed of the latest clinical trials concerning insulin resistance.

Recent Trials on Insulin Resistance The following is a list of recent trials dedicated to insulin resistance.8 Further information on a trial is available at the Web site indicated. •

Bypass Angioplasty Revascularization Investigation in Type 2 Diabetics (BARI 2D) Condition(s): Coronary Disease; Cardiovascular Diseases; Heart Diseases; Insulin Resistance; Diabetes Mellitus; Diabetes Mellitus, non-insulin dependent Study Status: This study is currently recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI); National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The BARI 2D trial is a multicenter study that uses a 2x2 factorial design, with 2800 patients being assigned at random to initial elective revascularization with aggressive medical therapy or aggressive medical therapy alone with equal probability, and simultaneously being assigned at random to an insulin providing or insulin sensitizing strategy of glycemic control (with a target value for HbA1c of <7.0% for all patients). SPECIFIC AIMS A. Primary Aim The primary aim of the BARI 2D trial is to test the following two hypotheses of treatment efficacy in 2800 patients with Type 2 diabetes mellitus and documented stable CAD, in the setting of uniform glycemic control and intensive management of all other risk factors including dyslipidemia, hypertension, smoking, and obesity: 1. Coronary Revascularization Hypothesis: a strategy of initial elective revascularization of choice (surgical or catheter-based) combined with aggressive medical therapy results in lower 5-year mortality compared to a strategy of aggressive medical therapy alone; 2. Method of Glycemic Control Hypothesis: with a target HbA1c level of <7.0%, a strategy of hyperglycemia management directed at insulin sensitization results in lower 5-year mortality compared

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These are listed at www.ClinicalTrials.gov.

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to a strategy of insulin provision. B. Secondary Aims The secondary aims of the BARI 2D trial include: a) comparing the death, myocardial infarction or stroke combined endpoint event rate between the revascularization versus medical therapy groups and between the insulin sensitization versus insulin provision groups; b) comparing rates of myocardial infarction, other ischemic events, angina and quality of life associated with each revascularization and hyperglycemia management strategy; c) evaluating the relative economic costs associated with the trial treatment strategies, d) exploring the effect of glycemic control strategy on the progression and mechanism of vasculopathy including changes in PAI-1 gene expression. Phase(s): Phase III Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006305 •

Effects of Oral Glucosamine on Insulin and Blood Vessel Activity in Normal and Obese People Condition(s): Obesity; Insulin Resistance Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: This study will examine whether glucosamine affects the way the body responds to insulin. Insulin is a hormone that causes the body to use glucose (sugar). Insulin does not work as well in overweight people, causing a condition called insulin resistance. Insulin also increases the flow of blood into muscle by opening inactive blood vessels. This study will test whether glucosamine, a nutritional supplement that many people take to treat arthritis, can cause or worsen insulin resistance or change how blood vessels react to insulin in normal weight and overweight people. Healthy normal weight and overweight volunteers between 21 and 65 years of age may be eligible for this study. Candidates will be screened with a brief physical examination, medical history, and blood and urine tests. After screening, participants will have three additional outpatient clinic visits for the following procedures: Visit 1 - Glucose clamp test to measure the body's response to insulin: For this procedure, a needle is placed in a vein of each arm, one for drawing blood samples, and one for infusing glucose and a potassium solution. The glucose is infused continuously during this 4-hour test and blood is drawn frequently to monitor glucose and insulin levels. After the test, blood glucose levels are monitored for another 2 hours to make sure they remain at an adequate level to prevent hypoglycemia (low blood sugar). - Blood flow measurement: Blood flow in the brachial artery of the arm is measured to assess how many capillaries (very small blood vessels) are being used to supply nutrients and oxygen to the muscle in the forearm. This test is done at the same time as the glucose clamp test. Blood flow is measured using a technique called contrast ultrasound. A small amount of contrast agent consisting of gas-filled bubbles the size of red blood cells is infused over 10 minutes through one of the catheters placed in the vein for the glucose clamp test. The contrast agent is infused twice, once at the beginning of the glucose clamp test and once at the end of the test. The contrast material creates a signal in response to ultrasound that provides information about the distribution of capillaries in the forearm. - Assignment to medication group: Participants are randomly assigned to take either glucosamine or placebo three times a day by mouth for 6 weeks. At the end of the 6 weeks, no study drug is taken for 1 week, and then participants "cross-over" medications, those who took glucosamine for the first 6 weeks take placebo

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for the next 6 weeks and vice versa. Visits 2 and 3 For these visits, the glucose clamp test and blood flow measurements are repeated. Visit 2 is scheduled at the end of the first 6week treatment period, and Visit 3 is scheduled at the end of the second 6-week treatment period. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00065377 •

Genetic Studies of Insulin and Diabetes Condition(s): Diabetes Mellitus; Insulin Resistance Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: The study will allow researchers to obtain blood, plasma, DNA, and RNA for genetic studies of insulin. There will be a focus on the causes of insulin resistance and diabetes mellitus. Insulin is a hormone found in the body that controls the level of sugar in the blood. Insulin resistance refers to conditions like diabetes when insulin does not work properly. In this study researchers would like to compare patients with diabetes and other forms of insulin resistance to normal individuals. The study will investigate how insulin attaches to cells. Researchers will take 4 to 6 ounces (100-150 ml) of blood from adult patients and may request up to 12 ounces (one unit) of blood if necessary. Skin samples may be taken for a biopsy if further genetic testing is necessary. In addition some patients may be asked not to eat for up to 72 hours prior to testing. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00001987

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Ginkgo Biloba Extract and the Insulin Resistance Syndrome Condition(s): Type 2 diabetes mellitus Study Status: This study is currently recruiting patients. Sponsor(s): National Center for Complementary and Alternative Medicine (NCCAM) Purpose - Excerpt: The purpose of this study is to examine whether the ingestion of the herbal dietary supplement Ginkgo biloba extract has any effect on the efficacy of three classes of diabetic medications - (Glucotrol, Glucophage and Actose). Additionally, the study will examine the effect of Ginkgo biloba extract on pancreatic insulin production in non-diabetic subjects between the ages of 20 and 75 years old. Phase(s): Phase I; Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00032474

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Insulin Resistance and Insulin Secretion Condition(s): Diabetes Mellitus, Type 2

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Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This is a pilot study to examine the prevalence of metabolic risk factors (impaired insulin release and impaired insulin sensitivity) for type 2 diabetes mellitus in children and adults from a population that is at high risk for this disease. We hypothesize that at least one of these pre-diabetic traits will be evident in a large proportion of relatives of known type 2 diabetic children as compared to a control group of subjects without a family history of type 2 diabetes. By isolating these traits, it will be possible to determine the relative contributions of genes and environment to each trait and to identify those at risk for subsequent development of type 2 diabetes by virtue of having one trait. Ultimately, those individuals at risk, especially those with impaired insulin release, would hopefully benefit from intervention to prevent the weight gain that will 'unmask' their underlying pancreatic dysfunction and thus prevent or retard the development of type 2 diabetes. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00073294 •

Metformin to Treat Obesity in Children with Insulin Resistance Condition(s): Hyperinsulinemia; Obesity Study Status: This study is currently recruiting patients. Sponsor(s): National Institute of Child Health and Human Development (NICHD) Purpose - Excerpt: This study will examine the safety and effectiveness of the medicine metformin to help overweight children control their food intake, weight, insulin, cholesterol, and triglyceride (blood fat) levels. Obesity and high insulin levels can lead to high blood pressure, diabetes, high cholesterol and triglyceride levels and heart disease. Metformin-approved by the Food and Drug Administration to treat adults with type 2 diabetes mellitus-helps lower insulin levels and may control weight gain in adults. Overweight children 6 to 11 years old who are in general good health may be eligible for this study. Children will be studied at the National Institutes of Health in Bethesda, Maryland, and at the Phoenix Indian Medical Center and the Gila River Reservation in the Phoenix, Arizona area. Candidates will have a medical history and physical examination and fasting blood test, and will provide a 7-day record of their food intake as part of the screening process. Those enrolled will be randomly assigned to receive either metformin or placebo (a look-alike tablet with no active medicine) twice a day for a six month period. After the 6 month study period, all children will be offered the opportunity to take metformin for another 6 months. Participants will be hospitalized for 2-3 days for the following procedures: history and physical examination; fasting blood test; several urine collections; X-ray studies to determine bone age and amount of body fat and muscle; magnetic resonance imaging (MRI) scan to measure body fat; "hyperglycemic clamp study" to evaluate insulin resistance; food intake testing; nutrition consultation; resting metabolic rate; and a "doubly labeled water" test. For the hyperglycemic clamp study, a catheter (thin flexible tube) is inserted into a vein in each arm. A sugar solution is given through one tube and blood samples are drawn every 5 minutes through the other to measure insulin. For the food intake testing, the child is asked about his or her hunger level, then given various foods he or she may choose to eat, then questioned again at various intervals both during and after finishing eating about his or her hunger level. The doubly labeled water study involves

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drinking "heavy water" (water which is enriched to have special kinds of hydrogen and oxygen). Urine specimens are collected 2, 3 and 4 hours after drinking the water. The child also drinks a special milk shake called a Scandishake and repeats the calorie intake and hunger study. (Two food intake studies are done on separate days.) One week after the heavy water test, additional urine samples are collected one week later. After completing the tests, the child will begin treatment with metformin or placebo, plus a daily vitamin tablet. Participants will be followed once a month with a brief history and physical examination, including a blood test. After 6 months, all of the tests described above will be repeated. All children who complete the second round of tests-both those who took metformin and those who took placebo-will be offered metformin for an additional 6 months and will be seen once a month for follow-up evaluations. Parents will not be told which children received metformin and which received placebo until all children in the study complete the first 6 months of the trial. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005669 •

Study of Recombinant Human Insulin-Like Growth Factor I in Patients with Severe Insulin Resistance Condition(s): Insulin Resistance; Hyperglycemia Study Status: This study is currently recruiting patients. Sponsor(s): FDA Office of Orphan Products Development; Beth Israel Deaconess Medical Center Purpose - Excerpt: Objectives: I. Determine the efficacy and toxic effects of recombinant human insulin-like growth factor I (rhIGF-I) on carbohydrate tolerance, insulin action, insulin secretion, hyperandrogenism, and hyperlipidemia in patients with severe insulin resistance who have failed other therapies. II. Determine the dose and time response of rhIGF-I on carbohydrate homeostasis and secondary abnormalities in this patient population. III. Determine the effect of rhIGF-I on insulin clearance, the regulation of insulin-like growth factor binding protein 1, the regulation of sex hormone binding globulin, and hypothalamic pituitary gonadal axis in this patient population. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004419

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Epidemiology of Stress and the Metabolic Syndrome Condition(s): Cardiovascular Diseases; Heart Diseases; Obesity; Hypertension; Hyperinsulinism; Insulin Resistance; Metabolic Syndrome X Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To examine the effects of psychological stress on the metabolic syndrome. Study Type: Observational Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00073775 •

Genetics of the Metabolic Syndrome in Japanese Americans Condition(s): Cardiovascular Diseases; Coronary Disease; Heart Diseases; Insulin Resistance; Diabetes Mellitus, non-insulin dependent; Diabetes Mellitus; Metabolic Syndrome X Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To investigate the genetic influence of candidate gene polymorphisms on risk factors for the metabolic insulin resistance syndrome in Japanese American sibships and kindreds. The original grant in 1994 had as its objective to understand the genetic epidemiology of coronary heart disease (CHD) risk factors in Japanese- American families with probands living in Seattle, Washington. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005374

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Genomewide Search for Loci Underlying Metabolic Syndrome Condition(s): Metabolic Syndrome X; Cardiovascular Diseases; Heart Diseases; Obesity; Hypertension; Hyperinsulinism; Insulin Resistance Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To identify the genes involved in the metabolic syndrome. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00074451

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Influence of Insulin on BP Change During Adolescence Condition(s): Cardiovascular Diseases; Hypertension; Obesity; Insulin Resistance; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To define the relation of insulin resistance during childhood and adolescence to the development of the insulin resistance syndrome in young adulthood. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00007098

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Insulin Resistance Atherosclerosis Study (IRAS) Condition(s): Cardiovascular Diseases; Atherosclerosis; Diabetes Mellitus; Heart Diseases; Obesity; Insulin Resistance

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Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a multicenter study of the relationship between insulin resistance and cardiovascular disease (CVD) and its risk factors in a tri-ethnic (AfricanAmerican, Hispanic, and non-Hispanic white) population aged 40 to 69 years at baseline. Also, to identify the genetic determinants of insulin resistance and visceral adiposity. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005135 •

Prenatal Nutrition and Adult Disease Condition(s): Cardiovascular Diseases; Heart Diseases; Diabetes Mellitus; Diabetes Mellitus, non-insulin dependent; Insulin Resistance; Obesity; Hypertension Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine whether maternal undernutrition in pregnancy is associated with differences between siblings for cardiovascular risk factors in adulthood. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00024583

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VA HDL Intervention Trial (VA-HIT) Ancillary Study Data Analysis Condition(s): Coronary Disease; Heart Diseases; Cardiovascular Diseases; Carotid Artery Diseases; Diabetes Mellitus, non-insulin dependent; Hypertension; Insulin Resistance; Obesity; Diabetes Mellitus Study Status: This study is no longer recruiting patients. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To evaluate additional cardiovascular risk factors using data from the VA HDL Intervention Trial (VA-HIT). Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00035711

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A clinical trial to prevent the complications of insulin resistance (including type-2 diabetes) Condition(s): Insulin Resistance; Diabetes Mellitus Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR) Purpose - Excerpt: The goal of this study is to aggressively treat insulin resistance and its clinical manifestations when they first appear in childhood, and to prevent the subsequent progression towards impaired glucose tolerance and type-2 diabetes. In the

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process of this clinical trial, we will learn more about the early manifestations of insulin resistance, its treatment, and its relationship to obesity and type-2 diabetes through parallel in-vivo and in-vitro studies. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00015626 •

Central Obesity and Disease Risk in Japanese Americans Condition(s): Cardiovascular Diseases; Heart Diseases; Atherosclerosis; Hypertension; Obesity; Diabetes Mellitus, non-insulin dependent; Hyperinsulinism; Insulin Resistance; Coronary Arteriosclerosis; Diabetes Mellitus; Metabolic Syndrome X Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To conduct a longitudinal study of central obesity and related risk factors found to be associated with hypertension and atherosclerotic cardiovascular disease (ASCVD) in a previously-examined cross-sectional cohort of second-generation Japanese Americans and in a newly-recruited cohort of third generation Japanese Americans. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005365

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Diet, Insulin Resistance, and Cardiovascular Risk Condition(s): Cardiovascular Diseases; Heart Diseases; Insulin Resistance; Hyperinsulinism; Diabetes Mellitus, non-insulin dependent; Diabetes Mellitus Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To elucidate dietary factors that elevate risk for cardiovascular disease (CVD) in conjunction with insulin resistance. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005530

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Insulin and Biogenic Amines in Cardiovascular Disease Condition(s): Cardiovascular Diseases; Hypertension; Heart Diseases; Obesity; Myocardial Infarction; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the role played by insulin and biogenic amines in obesity-related hypertension and cardiovascular disease. Study Type: Observational

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Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005194 •

Insulin Resistance and Blood Pressure Regulation in Blacks Condition(s): Cardiovascular Diseases; Hypertension; Heart Diseases; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To determine the role of insulin resistance in peripheral vascular dynamics, sodium sensitivity, and blood pressure regulation in a young representative Black population and in a group of young Blacks at high risk for hypertension. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005164

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Insulin, Androgen, and Risk in African-American Women Condition(s): Cardiovascular Diseases; Diabetes Mellitus; Hypertension; Heart Diseases; Hyperinsulinism; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To distinguish whether the observed gender differences in plasma insulin and insulin resistance reflect biologic differences, or whether the gender differences in insulinemia are determined by greater adiposity in women. Also, to determine if the hyperinsulinemia per se contributes to excess risk for cardiovascular disease in African American women. Finally, since higher androgenicity is linked with cardiovascular risk in women, to determine if the risk factors associated with hyperinsulinemia are modulated by sex hormones. Study Type: Observational Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00005380

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Leptin to Treat Severe Insulin Resistance - Pilot Study Condition(s): Syndrome Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: This pilot study will evaluate the safety and effectiveness of leptin therapy in two children with severe insulin resistance syndrome. Patients with this condition often have high blood sugar levels and may have hormone imbalances, a constant feeling of warmth, fertility problems, large appetite, and enlarged liver due to fat accumulation. Leptin is a hormone produced by fat cells. It influences appetite, affects levels of reproductive hormones, and possibly manages how the body reacts to insufficient food. Certain people with severe insulin resistance syndromes have decreased amounts of fat tissue and make little or no leptin. A 13-year-old male and an 11-year-old female with severe insulin resistance will participate in this study. They will have the following tests and procedures before beginning 4 months of leptin

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therapy: - Insulin tolerance test - measures blood sugar levels after intravenous (IV) administration of insulin. Blood samples are collected through the IV tube at various intervals during the 1-hour test. - Ultrasound of the liver and, if abnormalities are found, possibly liver biopsies. - Fasting blood tests - to measure blood count, blood lipids, and various hormones and assess liver function. - Resting metabolic rate - to measure the amount of oxygen breathed at rest in order to calculate how many calories are required to maintain resting body functions. - Magnetic resonance imaging of the liver and other organs, and of muscle and fat. - Pelvic ultrasound in female patient - to detect ovarian cysts. - Estimation of body fat - measurements of height, weight, waist, hip size, and skin folds over the arms and abdomen to estimate body fat content. - Oral glucose tolerance test - measures blood sugar and insulin levels. The patient drinks a very sweet drink containing glucose (sugar), after which blood samples are collected through an IV tube in an arm vein at various intervals during the 3-hour test. - Intravenous glucose tolerance test - measures tissue response to insulin and glucose after glucose injection and insulin infusion. Blood is collected over 3 hours to measure insulin and glucose levels. - Appetite level and food intake - to measure hunger level and caloric intake. Patients are questioned about their hunger level, given a variety of foods they may choose to eat and questioned again at various intervals about hunger level. On another day, patients are given breakfast (usually a milkshake) and when they want to eat again, the appetite level and caloric intake study is repeated. - Hormone function tests - the function of three hormones influenced by leptin (corticotropin-releasing hormone, thyrotropin-releasing hormone and luteinizing hormone-releasing hormone) are assessed. The hormones are injected intravenously and then blood samples are drawn. Questionnaire - patients complete a questionnaire about their activities and how they feel. - 24-hour urine collections - to measure specific hormones, proteins and sugars excreted in the urine. When the above tests are completed, leptin therapy will start. The drug is injected under the skin twice a day for 4 months. Patients will record their symptoms weekly throughout the study. Those with diabetes will measure their blood glucose levels daily before each meal and at bedtime. Follow-up visits at 1, 2 and 4 months after therapy will include a physical examination, blood tests and a meeting with a dietitian. At the 4-month visit, the tests done at the beginning of the study will be repeated. Phase(s): Phase II; MedlinePlus consumer health information Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00027456 •

Lipoprotein Metabolism in Hypertensive African-Americans Condition(s): Cardiovascular Diseases; Heart Diseases; Hyperinsulinism; Hypertension; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Heart, Lung, and Blood Institute (NHLBI) Purpose - Excerpt: To study relationships among lipoprotein metabolism, hypertension, and hyperinsulinemia-insulin resistance in African American males and females. The study was part of a Collaborative Project on Minority Health which investigated the mechanisms by which insulin contributes to cardiovascular disease. Study Type: Observational Contact(s): see Web site below

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Web Site: http://clinicaltrials.gov/ct/show/NCT00005709 •

Phase II Study of the Effect of Leuprolide Acetate and Spironolactone on Insulin Resistance in Hyperandrogenic Women with Polycystic Ovarian Disease or Hyperandrogenism Insulin Resistance Acanthosis Nigricans Syndrome Condition(s): Acanthosis Nigricans; Polycystic Ovary Syndrome Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); Baylor College of Medicine Purpose - Excerpt: Objectives: I. Evaluate insulin resistance in thin and obese hyperandrogenic women with polycystic ovarian disease or hyperandrogenism insulin resistance acanthosis nigricans syndrome and in thin and obese controls, using an estimation of tissue sensitivity to insulin. II. Evaluate the effect of androgen suppression with leuprolide acetate and spironolactone on insulin secretion and resistance. Phase(s): Phase II Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00004311

•

Rosiglitazone and exercise training: effects on HIV-infected people with insulin resistance, hypertriglyceridemia, and adipose tissue maldistribution Condition(s): HIV Infections; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Center for Research Resources (NCRR); The Campbell Foundation Purpose - Excerpt: Several complications have become prevalent in people living with HIV/AIDS, including increased blood sugar, increased blood fats and cholesterol, and fat tissue redistribution. The causes of these complications are not well understood and effective treatments have not been identified. We propose to test the efficacy and safety of 2 treatments for these complications in people living with HIV/AIDS: aerobic, weight lifting exercise training, and a new insulin-sensitizing agent called rosiglitazone (Avandia). Exercise and rosiglitazone have been effective and moderately safe when used in HIV-seronegative people with diabetes, but a specific trial is needed to test efficacy and safety in people living with HIV/AIDS. Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00025753

•

Underlying abnormalities in fat and muscle leading to Lipodystrophy Syndrome Condition(s): HIV Infections; Lipodystrophy; Insulin Resistance Study Status: This study is completed. Sponsor(s): National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Purpose - Excerpt: With the advent of highly active anti-retroviral therapy(HAART), patients with HIV disease are developing a series of metabolic abnormalities including peripheral fat wasting, increase in truncal fat, high serum triglyceride levels, insulin(a hormone that controls blood sugar) resistance with an increased incidence of Type 2

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Diabetes Mellitus and elevated blood pressure. The premise of this study is that abnormalities in the ability of fat and muscle tissue to respond to the hormone insulin may be the cause of the diabetes mellitus, high serum triglyceride levels and abnormal fat distribution. The purpose of the study is to assess how insulin resistant patients with HIV disease are and if their fat and muscle tissue are responding abnormally to insulin. This is done by administering insulin and taking small tissue samples of fat and muscle from the upper thigh and assessing how good insulin acts in these tissues. Patients with HIV disease will be admitted into the study after undergoing a screening medical history and examination. Once patients qualify, they will have their insulin resistance measured as well as the response of their fat and muscle to insulin; blood levels of glucose (sugar), cholesterol and triglycerides will be measured; body fat will be assessed using radiological tests; a detailed medical history will be obtained to assess risk factors for developing this syndrome. Patients who are found to be insulin resistant will be offered a trial of an insulin sensitizing agent, called Avandia, for 6-12 weeks. It is hoped that the Avandia will restore the body's ability to respond normally to insulin (as it does in patients with Diabetes) and perhaps improve the fat abnormalities as well. All the same measures will be performed at the end of the course of Avandia as were done at baseline. Patients who are not insulin resistant will be asked to come back yearly to assess whether they develop insulin resistance over time. This study will continue to recruit patients over the next 3 years. Phase(s): Phase I Study Type: Interventional Contact(s): see Web site below Web Site: http://clinicaltrials.gov/ct/show/NCT00006185

Keeping Current on Clinical Trials The U.S. National Institutes of Health, through the National Library of Medicine, has developed ClinicalTrials.gov to provide current information about clinical research across the broadest number of diseases and conditions. The site was launched in February 2000 and currently contains approximately 5,700 clinical studies in over 59,000 locations worldwide, with most studies being conducted in the United States. ClinicalTrials.gov receives about 2 million hits per month and hosts approximately 5,400 visitors daily. To access this database, simply go to the Web site at http://www.clinicaltrials.gov/ and search by “insulin resistance” (or synonyms). While ClinicalTrials.gov is the most comprehensive listing of NIH-supported clinical trials available, not all trials are in the database. The database is updated regularly, so clinical trials are continually being added. The following is a list of specialty databases affiliated with the National Institutes of Health that offer additional information on trials: •

For clinical studies at the Warren Grant Magnuson Clinical Center located in Bethesda, Maryland, visit their Web site: http://clinicalstudies.info.nih.gov/

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For clinical studies conducted at the Bayview Campus in Baltimore, Maryland, visit their Web site: http://www.jhbmc.jhu.edu/studies/index.html

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For cancer trials, visit the National Cancer Institute: http://cancertrials.nci.nih.gov/

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For eye-related trials, visit and search the Web page of the National Eye Institute: http://www.nei.nih.gov/neitrials/index.htm

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For heart, lung and blood trials, visit the Web page of the National Heart, Lung and Blood Institute: http://www.nhlbi.nih.gov/studies/index.htm

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For trials on aging, visit and search the Web site of the National Institute on Aging: http://www.grc.nia.nih.gov/studies/index.htm

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For rare diseases, visit and search the Web site sponsored by the Office of Rare Diseases: http://ord.aspensys.com/asp/resources/rsch_trials.asp

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For alcoholism, visit the National Institute on Alcohol Abuse and Alcoholism: http://www.niaaa.nih.gov/intramural/Web_dicbr_hp/particip.htm

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For trials on infectious, immune, and allergic diseases, visit the site of the National Institute of Allergy and Infectious Diseases: http://www.niaid.nih.gov/clintrials/

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For trials on arthritis, musculoskeletal and skin diseases, visit newly revised site of the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health: http://www.niams.nih.gov/hi/studies/index.htm

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For hearing-related trials, visit the National Institute on Deafness and Other Communication Disorders: http://www.nidcd.nih.gov/health/clinical/index.htm

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For trials on diseases of the digestive system and kidneys, and diabetes, visit the National Institute of Diabetes and Digestive and Kidney Diseases: http://www.niddk.nih.gov/patient/patient.htm

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For drug abuse trials, visit and search the Web site sponsored by the National Institute on Drug Abuse: http://www.nida.nih.gov/CTN/Index.htm

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For trials on mental disorders, visit and search the Web site of the National Institute of Mental Health: http://www.nimh.nih.gov/studies/index.cfm

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For trials on neurological disorders and stroke, visit and search the Web site sponsored by the National Institute of Neurological Disorders and Stroke of the NIH: http://www.ninds.nih.gov/funding/funding_opportunities.htm#Clinical_Trials

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CHAPTER 5. PATENTS ON INSULIN RESISTANCE Overview Patents can be physical innovations (e.g. chemicals, pharmaceuticals, medical equipment) or processes (e.g. treatments or diagnostic procedures). The United States Patent and Trademark Office defines a patent as a grant of a property right to the inventor, issued by the Patent and Trademark Office.9 Patents, therefore, are intellectual property. For the United States, the term of a new patent is 20 years from the date when the patent application was filed. If the inventor wishes to receive economic benefits, it is likely that the invention will become commercially available within 20 years of the initial filing. It is important to understand, therefore, that an inventor’s patent does not indicate that a product or service is or will be commercially available. The patent implies only that the inventor has “the right to exclude others from making, using, offering for sale, or selling” the invention in the United States. While this relates to U.S. patents, similar rules govern foreign patents. In this chapter, we show you how to locate information on patents and their inventors. If you find a patent that is particularly interesting to you, contact the inventor or the assignee for further information. IMPORTANT NOTE: When following the search strategy described below, you may discover non-medical patents that use the generic term “insulin resistance” (or a synonym) in their titles. To accurately reflect the results that you might find while conducting research on insulin resistance, we have not necessarily excluded nonmedical patents in this bibliography.

Patents on Insulin Resistance By performing a patent search focusing on insulin resistance, you can obtain information such as the title of the invention, the names of the inventor(s), the assignee(s) or the company that owns or controls the patent, a short abstract that summarizes the patent, and a few excerpts from the description of the patent. The abstract of a patent tends to be more technical in nature, while the description is often written for the public. Full patent descriptions contain much more information than is presented here (e.g. claims, references, figures, diagrams, etc.). We will tell you how to obtain this information later in the chapter. 9Adapted

from the United States Patent and Trademark Office: http://www.uspto.gov/web/offices/pac/doc/general/whatis.htm.

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The following is an example of the type of information that you can expect to obtain from a patent search on insulin resistance: •

3-aryl-2-hydroxypropionic acid derivative I Inventor(s): Andersson; Kjell (Fjar.ang.s, SE) Assignee(s): Astrazeneca AB (sodertalje, Se) Patent Number: 6,660,879 Date filed: January 4, 2002 Abstract: A novel 3-aryl-2-hydroxypropionic acid derivative, a process and intermediate for its manufacture, pharmaceutical preparations containing it and the use of the compound in clinical conditions associated with insulin resistance. Excerpt(s): The present invention releates to a novel 3-aryl-2-hydroxypropionic acid derivative, to a process and intermediate for preparing such a compound, having the utility in clinical conditions associated with insulin resistance, to methods for its therapeutic use and to pharmaceutical compositions containing it. Insulin resistance, defined as reduced sensitivity to the actions of insulin in the whole body or individual tissues such as skeletal muscle, myocardium, fat and liver prevail in many individuals with or without diabetes mellitus. The insulin resistance syndrome, IRS, refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, possibly non insulin dependent diabetes mellitus (NIDDM); arterial hypertension; central (visceral) obesity; dyslipidemia observed as deranged lipoprotein levels typically characterized by elevated VLDL (very low density lipoproteins) and reduced HDL (high density lipoproteins) concentrations and reduced fibrinolysis. Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In non-insulin dependent diabetes mellitus these atherosclerosis related conditions cause up to 80% of all deaths. Web site: http://www.delphion.com/details?pn=US06660879__

•

Antidiabetic formulation and method Inventor(s): Piper; Beth Anne (Hopewell, NJ) Assignee(s): Bristol-myers Squibb Co. (princeton, Nj) Patent Number: 6,586,438 Date filed: November 3, 1999 Abstract: A low dose antidiabetic pharmaceutical formulation is provided, especially adapted for treating Type II diabetes in drug naive patients, which includes a combination of metformin (employed in a reduced amount (less than 800 mg metformin per day) compared to that employed in generally accepted medical practice) and at least one other antidiabetic agent such as a sulfonyl urea, for example, glyburide, which combination provides at least about substantially equivalent efficacy in treating diabetes in drug naive patients, as do antidiabetic formulations containing metformin employed in dosages prescribed in generally accepted medical practice for first line therapy in treating diabetes, but with substantially reduced side effects, such as hypoglycemia and/or gastrointestinal distress. A method for treating diabetes in drug naive human patients is also provided employing the above formulation to reduce insulin resistance

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and/or post-prandial glucose excursion and/or hemoglobin 1Ac, and/or increase postprandial insulin, thereby treating the diabetes. Excerpt(s): The present invention relates to a low dose pharmaceutical formulation for treating type 2 diabetes in drug naive patients, which includes metformin (preferably employed in reduced amounts compared to that employed in generally accepted medical practice) and another antidiabetic agent such as a sulfonyl urea, for example, glyburide, which formulation has at least substantially equivalent efficacy in treating type 2 diabetes as compared to prior art antidiabetic formulations containing metformin, but with substantially reduced side effects, and to a method for treating diabetes employing such formulations. The biguanide antihyperglycemic agent metformin disclosed in U.S. Pat. No. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage.RTM.), Bristol-Myers Squibb Company). The diagnosis and management of type 2 diabetes mellitus is rapidly undergoing progressive changes. It is now widely accepted that glycemic control makes a difference. The goal of diabetes therapy today is to achieve and maintain as near normal glycemia as possible to prevent the long-term microvascular and macrovascular complications of an elevated blood glucose. The diagnosis of diabetes has undergone significant changes as evidenced by the new ADA diagnostic and classification guidelines. Oral therapeutic options for the treatment of type 2 diabetes mellitus, until recently, have been severely limited. Prior to 1995, sulfonyl ureas had been the mainstay of oral diabetes agents in the United States. Sulfonyl ureas target one mechanism of hyperglycemia by augmenting insulin secretion from the beta cell. Since 1995, three new classes of agents have been added to the antidiabetes armamentarium for the management of hyperglycemia. Metformin, a biguanide, targets additional mechanisms of hyperglycemia by inhibiting hepatic glucose production and enhancing peripheral glucose uptake and thereby reduce insulin resistance; thiazolidinediones such as troglitazone, rosiglitazone and pioglitazone decrease peripheral insulin resistance; and alpha-glucosidase inhibitors such as acarbose and miglitol help control postprandial glucose excursion by delaying absorption of dietary carbohydrate. These agents are all indicated as monotherapy and some are indicated for use in combination therapy, generally, after monotherapy has been found to be inadequate. Web site: http://www.delphion.com/details?pn=US06586438__ •

Biguanide and sulfonylurea formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus Inventor(s): Pearson; Don C. (Lakewood, WA), Richardson; Kenneth T. (Anchorage, AK) Assignee(s): Chrono RX Llc (anchorage, Ak) Patent Number: 6,693,094 Date filed: March 7, 2002 Abstract: The invention describes formulations that include either metformin, sulfonylurea or a biguanide-sulfonylurea combination as one active ingredient in addition to specific, other active ingredients. The compositions and dosage forms of the invention are clinically useful as methods for increasing the effectiveness, efficiency and safety of the included biguanide (metformin) and/or sulfonylurea in the prevention and treatment of insulin resistance and diabetes mellitus. The carefully chosen additional active ingredients of the invention are designed in a modular fashion to prevent and rectify adverse events associated with insulin resistance syndrome and diabetes mellitus, and those adverse incidences associated with the concurrent use of metformin

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and/or the sulfonylureas. When clinically administered, the invention will provide therapeutic levels of metformin and of a sulfonylurea, alone or in combination, and broaden their usefulness. The invention will retard the progression of insulin resistance to type 2 diabetes, and reduce the serious microvascular and macrovascular complications commonly associated with insulin resistance syndrome and diabetes mellitus. Excerpt(s): This invention is in the field of pharmacology, and relates to multicomponent formulations, which contain metformin, a sulfonylurea or a combination of both, in concert with one or more other active ingredients, for use in the pharmacological treatment of insulin resistance and type 2 diabetes mellitus. Insulin resistance and non-insulin-dependent diabetes are prevalent in up to 35% of the population depending upon the age and nature of the subset. In the United States alone, 16 million people have type 2 diabetes and 13 million have impaired glucose tolerance. In fact type 2 diabetes has reached epidemic proportions worldwide. By 2025, an estimated 300 million people will have diabetes, most of who will inhabit China, India, and the United States. Because of an aging and increasingly sedentary, obese population with changing, unhealthy diets, insulin resistance is also increasing alarmingly (it is already two to three times more prevalent than type 2 diabetes). This apparent increase in the prevalence of insulin resistance and type 2 diabetes occurs in all ethnic populations, but especially in those that have migrated from their native lands to more urbanized and westernized regions of the world. Insulin resistance and type 2 diabetes exist not merely as part of the aging process, but also as a process that advances aging. Diabetes affects metabolism in totality: carbohydrate, lipid and protein. Its causes and its management are very, very complex and strikingly nonlinear. Web site: http://www.delphion.com/details?pn=US06693094__ •

Compositions comprising D-chiro inositol and sulfonylureas and methods of treatment thereof Inventor(s): Allan; Geoffrey (Richmond, VA), Sleevi; Mark (Midlothian, VA) Assignee(s): Insmed, Incorporated (glen Allen, Va) Patent Number: 6,492,339 Date filed: October 26, 2001 Abstract: The present invention provides compositions comprising synergistically effective amounts of D-chiro-inositol and sulfonylureas. The present invention also provides methods to treat a subject with insulin resistance comprising administration of D-chiro-inositol and sulfonylurea, either as concurrent single agents or as a combined composition. In particular the methods of the present invention are useful in maintaining pancreatic beta cell function/viability and thus delay diabetes progression. The methods and compositions of the present invention are particularly efficacious in treating insulin resistant subjects with a fasting blood glucose level of less than or equal to 180 mg/dL. Excerpt(s): The present invention provides methods to treat a subject with insulin resistance comprising administration of D-chiro-inositol and sulfonylurea, either as concurrent single agents or as a combined composition. The present invention also provides compositions comprising therapeutically effective amounts of D-chiro-inositol and sulfonylureas. The present invention also provides methods to treat a subject with insulin resistance comprising administration of D-chiro-inositol and sulfonylurea,

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either as concurrent single agents or as a combined composition. In particular, the methods of the present invention are useful in maintaining pancreatic beta cell function/viability and thus, delay diabetes progression. The methods and compositions of the present invention are particularly efficacious in treating insulin resistant subjects with a fasting blood glucose level of less than or equal to 180 mg/dL. Non-insulin dependent diabetes (NIDDM, or type 2 diabetes) is a worldwide health problem. According to the World Health Organization, an estimated 30 million people worldwide had diabetes in 1985. This number increased to 135 million people by 1995 and the WHO predicts a rise to 300 million people by 2025. The insidious nature of type 2 diabetes progression and medical complications that arise from hyperglycemia extract a heavy toll on the individual, healthcare resources, and society. As such, there is a continuing need for new therapeutic agents and therapeutic regimens that prevent diabetes, prevent or delay the progression of diabetes, or prevent or delay diabetic complications. It is generally desirable to treat a subject with diabetes or at risk of developing diabetes in ways that reestablish or maintain the balance between insulin secretion and insulin sensitivity. It is highly desirable to employ methods that avoid administration of exogenous insulin. Therefore a regimen of diet and exercise is primarily used to attempt to establish more physiologic glycemic control. Sadly, however, pharmacological intervention becomes necessary. The current "second line" of therapies includes administration of pharmacological agents including sulfonylureas (e.g. GLUCOTROL.RTM.), biguanides (e.g. metformin), and PPAR gamma agonists (e.g. rosiglitazone) alone or in combination, which are used to increase endogenous insulin production, decrease hepatic glucose output, and increase periperial insulin sensitivity (Kobayashi, Diabetes Obes. Metab., 1(Suppl 1): S32-S40 (1999); Brown et al., J. Natl. Med. Assoc., 91(7): 389-395 (1999)). Sulfonylureas are compounds that stimulate insulin secretion from beta cells in islet tissue of the pancreas and are currently the most frequently prescribed oral hypoglycemic drugs. Increased insulin secretion by sulfonylureas may lead to hypoglycemia (Imura, N. Engl. J. Med., 338: 908-909 (1998)). Unfortunately, prolonged use of sulfonylureas results in unfavorable side effects, particularly desensitization and/or apoptosis of the beta cells resulting in decreased insulin production. The effect is particularly manifest in subjects who have more severe insulin resistance in conjunction with less insulin (Kobayashi, Diabetes Obes. Metab., 1(Suppl 1): S32-S40 (1999); Kolterman et al., Diabetes Care, 7(Suppl 1): 81-89 (1984)). Biguanides are compounds that decrease hepatic glucose output, and thus aid in controlling hyperglycemia. PPAR gamma agonists are insulin-sensitizing compounds that increase the cell's ability to respond to smaller quantities of insulin. Eventually these therapies fail and exogenous insulin is required to maintain a balance of glucose metabolism. Web site: http://www.delphion.com/details?pn=US06492339__ •

Crytalline form of (s)-2 ethoxy)phenyl]propanoic acid

ethoxy

-3-[4-(2-{4-

methanesulfonyloxyphenyl}

Inventor(s): Boije; Maria (Molndal, SE), Horvath; Karol (Sodertalje, SE), Inghardt; Tord (Molndal, SE) Assignee(s): Astrazeneca AB (sodertalje, Se) Patent Number: 6,531,622 Date filed: June 3, 2002

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Abstract: The present invention relates to a novel crystalline form of the compound (S)2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl}ethoxy)phenyl]propanoic acid, shown by formula (I), or a pharmaceutically-acceptable salt thereof, and solvates thereof. The invention also concerns methods of treating one or more metabolic disease conditions, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for use in one or more of said conditions. The invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof. Excerpt(s): or a pharmaceutically-acceptable salt thereof, and solvates thereof. The invention also concerns methods of treating one or more metabolic disease conditions, particularly those associated with Insulin Resistance Syndrome, and the use of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, in the manufacture of a medicament for therapeutic use in one or more of said metabolic diseases. The invention further concerns pharmaceutical compositions containing a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof, as active ingredient, as well as processes for the manufacture of a crystalline form of the compound, or a pharmaceutically-acceptable salt thereof, or a solvate thereof. In the formulation of drug compositions, it is important for the drug substance to be in a form in which it can be conveniently handled and processed. This is of importance, not only from the point of view of obtaining a commercially viable manufacturing process, but also from the point of subsequent manufacture of pharmaceutical formulations comprising the active compound. Web site: http://www.delphion.com/details?pn=US06531622__ •

Ligands of nuclear receptor Inventor(s): Ando; Kunio (Kanagawa, JP), Magae; Junji (Ibaraki, JP), Tamura; Gakuzo (Tokyo, JP), Uchida; Takafumi (Kanagawa, JP) Assignee(s): Nuclear Receptor Research, Ltd. (kanagawa, Jp) Patent Number: 6,605,639 Date filed: June 14, 2001 Abstract: It has been newly found out that ascochlorin, which is a publicly known fatsoluble antibiotic, and its homologues serve as a ligand of retinoid X receptor and react in vivo with the amino group of serum protein to form Schiff bases without showing any side effect of retinoid. Ascochlorin and its homologues are usable in treating and/or preventing a disease or condition which can be relieved by the retinoid X receptor ligand-dependent gene transcriptional regulation (for example, diseases caused by the expression of insulin resistance, hypertension, cerebrovascular diseases, rheumatoid arthritis, autoimmune disease, Ca metabolic disorder, complication of diabetes, arteriosclerosis, etc.). Moreover, they can inhibit denaturation and/or necrosis of pancreatic Langerhans islet.beta.-cells and, therefore, are usable in making these cells to sustain the insulin productivity. Excerpt(s): This invention relates to ligands of retinoid X receptor and pharmaceutical compositions for treating and/or preventing diseases which can be alleviated by the

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retinoid X receptor ligand (RXRL)-dependent transcriptional regulation of certain genetic information. Diseases to be treated and/or prevented by use of the pharmaceutical compositions according to the present invention involve life-style related diseases. From the viewpoint of treating the life-style related diseases, there is an urgent need to develop drugs for use in the treatment of various vascular lesions causative of the onset of the life-style related diseases. Ischemic heart disease, which is prevalent when vascular lesions are present, is also referred to as coronary sclerosis. It is thought that around fifty percent of all deaths in the world are attributable this disease. Ischemic heart disease is the leading cause of death in most developed countries, and the second biggest cause of death in Japan. In addition it is estimated that the incidence of ischemic heart disease will rapidly increase in developing countries also. Major causes of ischemic heart disease, appear to include genetic factors, eating habits, stress, diabetes and hypertension. It is known that ischemic heart disease is closely related to life-style including diet. Hyperlipemia and hyperinsulinemia, which are induced by the excessive intake of high caloric diets, promote sedimentation of low density lipoproteins which are rich in cholesterol on the arterial wall. Degeneration of sedimented low density lipoproteins causes damage to the arterial wall; and leukocytes react to the damage in the arterial wall and infiltrate it to repair the lesion, resulting in chronic inflammation. Thus the mechanism of arteriosclerosis is understood to be as follows: In response to damage of arterial wall, leukocytes, which attempt to repair the damage, cause excessive inflammation which has the effect of thickening the arterial wall, resulting in a sclerosing lesion. Typical examples of known drugs for preventing ischemic heart disease are hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors. These HMG-CoA reductase inhibitors, which inhibit the biosynthesis of mevalonic acid as a rate-determining step in the biosynthesis of cholesterol, reduce the amount of cholesterol synthesized in the liver and thus lower the cholesterol content in the low density lipoprotein which is synthesized in the liver and released into the serum. That is to say, the main function of these drugs resides in inhibiting the biosynthesis of cholesterol and lowering the cholesterol content in the serum, thereby reducing the low density lipoprotein incorporated from the serum into the arterial wall depending on the concentration. Namely, these drugs exert a merely indirect and preventive effect. These HMG-CoA reductase inhibitors exhibit no effect on the sclerosing lesions associated with chronic inflammation which thickens the arterial wall in which macrophages and lymphocytes participate. Thus, it is impossible to achieve any direct therapeutic effect for healing chronic inflammation of an artery. An ideal remedy and/or preventive treatment for arteriosclerosis is a drug which shows an effect of lowering serum cholesterol level and, at the same time, a therapeutic and/or preventive effect on chronic inflammation induced by the sedimentation of cholesterol on the arterial wall. It is expected that such a drug, if any, would serve as an ideal remedy and/or preventive treatment for ischemic heart disease. Web site: http://www.delphion.com/details?pn=US06605639__ •

Ligands, including antibodies, showing reactivity against endocrine cells Inventor(s): Matossian-Rogers; Arpi (376 Finchley Road, London, NW3 7AJ, GB) Assignee(s): None Reported Patent Number: 6,689,359 Date filed: January 20, 2000

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Abstract: The invention provides monoclonal and polyclonal antibodies recognising molecules on secretory cells of various tissue targets of autoimmune disease allowing a unifying method of preventing and treating autoimmune diseases and other conditions where hormonal dysregulation, hyperinsulinaemia and insulin resistance are involved. It also provides a method for detecting similar antibodies in human sera or other body fluids which can be used in the development of diagnostic kits. Treatment methods arising from this invention comprise the administration of preparations of the antibodies, their target molecules and vectors containing coding sequences of the antibodies and their target molecules. Excerpt(s): This invention describes the development of unique autoantibodies which are the cause of several autoimmune and other diseases. It provides diagnostic and prophylactic uses for such antibodies in monoclonal and polyclonal form and also for the molecules recognised by the antibodies. More specifically, the invention provides for the use of these antibodies and the molecules they recognise as specific inhibitors of the development of autoantibodies with the same specificity in children and adults. These antibodies and target molecules are claimed to be of diagnostic, prophylactic and treatment use in a wide variety of autoimmune and other diseases. However, most of the background to the invention will focus on diabetes, not by way of limitation but by way of illustration or example. Diseases associated with autoimmune phenomena can be classified within a spectrum ranging from conditions involving destructive lesions of a single organ or those in which organ or tissue damage is widely disseminated. At the organ-specific end of the spectrum, the organs most commonly affected are the thyroid, adrenal glands, stomach and islets of Langerhans (which contain the insulin producing cells) in the pancreas, while at the non-organ specific pole, rheumatological or systemic (e.g. systemic lupus erythematosus) disorders predominate. Autoimmune diseases are, in rare cases, connected with fulminant viral infections which can also result in organ destruction. In autoimmunity, the damaging process is slow and sometimes it takes years before the disease becomes manifest. The following are organ-specific autoimmune diseases which result from autoimmune phenomena involving breakdown in immunological tolerance to self antigens. Web site: http://www.delphion.com/details?pn=US06689359__ •

Method for identifying compounds for treatment of insulin resistance Inventor(s): Shoelson; Steven (Natick, MA) Assignee(s): Joslin Diabetes Center, Inc. (boston, Ma) Patent Number: 6,468,755 Date filed: August 10, 2000 Abstract: The invention features a method of identifying, evaluating or making a compound or agent, e.g., a candidate compound or agent, for treatment of a disorder characterized by insulin resistance. The method includes evaluating the ability of a compound or agent to interact with, e.g., bind, IKK-.beta., to thereby identify a compound or agent for the treatment of a disorder characterized by insulin resistance. The invention also features compounds for treating insulin resistance identified by such methods, and methods of treating a subject having a disorder characterized by insulin resistance by administering such agents. Excerpt(s): The present invention is based, in part, on the discovery that aspirin reverses insulin resistance in liver and fat cells, e.g., by targeting IKK-.beta. Thus, IKK-.beta. was

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discovered as a target for identifying compounds for the treatment of disorders associated with insulin resistance. Accordingly, in one aspect, the invention features a method of identifying, evaluating or making a compound or agent, e.g., a candidate compound or agent, for treatment of a disorder characterized by insulin resistance. The method includes evaluating the ability of a compound or agent to interact with, e.g., bind, IKK-.beta., to thereby identify a compound or agent for the treatment of a disorder characterized by insulin resistance. In a preferred embodiment, the disorder is diabetes, e.g., Type I or Type II diabetes, obesity, polycystic ovarian disease or syndrome X. Web site: http://www.delphion.com/details?pn=US06468755__ •

Method for treatment of insulin resistance in obesity and diabetes Inventor(s): Brennan; Miles B. (Denver, CO), Hochgeschwender; Ute (Oklahoma City, OK) Assignee(s): Oklajoma Medical Research Foundation (oklahoma City, Ok) Patent Number: 6,689,938 Date filed: September 13, 2001 Abstract: Disclosed is a method to identify compounds useful for reducing insulin resistance in a patient, and particularly a patient that has insulin resistance associated with obesity and/or type II diabetes. Also disclosed is a method of reducing insulin resistance in a patient by administering a compound identified using the method of the invention, and particularly, by administering an antagonist of melanocortin stimulating hormone (MSH) biological activity. Excerpt(s): The present invention relates to a non-human animal model for obesity and uses of such an animal for studying and developing methods for identifying compounds for use in the regulation of insulin resistance in obesity and type II diabetes, as well as a method of treating insulin resistance in obesity and type II diabetes by administration of such compounds. Diabetes, and conditions related thereto, are major health concerns throughout the world, and, particularly in the United States, contribute to morbidity and mortality. Non-insulin dependent diabetes mellitus (NIDDM), also known as type II diabetes, is the major form of diabetes in developed countries. While a large number of environmental and genetic factors contribute to the risk of NIDDM in the United States, prolonged obesity is by far the largest risk factor. The molecular basis of this association, however, is not fully understood. As a consequence, efficient means of therapeutical intervention are lacking. Before the development of diabetes, many obese patients develop a peripheral resistance to the actions of insulin. The molecular basis of insulinresistance in obesity has been the subject of intensive study, by nonetheless remains elusive. Insights into components and mechanisms of the link between obesity and insulin resistance have been gained from mouse models of obesity which display obesity-induced insulin resistance. The molecular basis of the various mouse obesity models covers a range of mechanisms; nonetheless these all develop diabetes, either before or after the onset of obesity. Web site: http://www.delphion.com/details?pn=US06689938__

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Method of treating insulin resistance Inventor(s): Kolesova; Olga Evgenievna (ul. 2-aya Peschanaya, 6-82, Moscow, 125252, RU), Pomytkin; Igor Anatolievich (Shkolny bulv., 1B-35 Chernogolovka, Noginsky r-on, 142432 Moskovskaya obl., RU), Ukhanova; Tatiyana Jurievna (ul. 2-aya Peschanaya, 682, Moscow, 125252, RU) Assignee(s): None Reported Patent Number: 6,521,665 Date filed: August 29, 2001 Abstract: The invention relates to methods of treating insulin resistance in mammals, preferably in humans, which methods comprise administering to a mammal in need thereof an effective amounts of succinic acid or a pharmaceutically acceptable salts thereof. Excerpt(s): The present invention is in the field of medicine, particularly in the treatment of states of insulin resistance that can result from disorders such as dibetes mellitus and its chronic complications such as retinopathy, polyneuropathy, nephropathy, angiopathy; gestational diabetes mellitus; impaired glucose tolerance; obesity; aging; atherosclerosis; syndrome X; cardiovascular disease; AIDS; cancer; wasting/cachecxia; sepsis; trauma associated with burns; malnutrition; lupus and other autoimmune diseases; endocrine diseases; hyperuricemia; hyperlipidemia; dyslipidemia; polycystic ovary syndrome; or complications arising from athletic activity. Succinic acid is the physiologically occurring substrate of succinate dehydrogenase in mammals that play a role in cellular respiration and energy metabolism. Insulin resistance is a condition in which the tissues of the body fail to respond normally to insulin. DeFronzo, R. A. J. Cardiomuscular Pharmacology 20 (Suppl. 11): S1-S16 (1992). The insulin resistance manifesting itself in pathologically elevated endogenous insulin and glucose levels and predisposes to the development of a cluster of abnormalities, including some degree of impaired glucose tolerance, an increase in plasma triglycerides and low density lipoprotein cholesterol (LDL) levels, a decrease in high-density lipoprotein cholesterol (HDL) levels, high blood pressure, hyperuricemia, a decrease in plasma fibrinolytic activity, an increase in cardiovascular disease and atherosclerosis. Reaven, G. M. Physiol-Rev. 75(3): 473-86 (1995). The decompensated insulin resistance is widely believed to be an underlying cause of non-insulin dependent diabetes mellitus. Web site: http://www.delphion.com/details?pn=US06521665__

•

Methods and computer program products for determining risk of developing type 2 diabetes and other insulin resistance related disorders Inventor(s): Bennett; Dennis W. (Shorewood, WI), Otvos; James D. (Apex, NC) Assignee(s): Liposcience, Inc. (raleigh, Nc), North Carolina State University (raleigh, Nc) Patent Number: 6,518,069 Date filed: April 19, 2000 Abstract: Methods for assessing the risk of developing Type 2 diabetes and other related disorders include obtaining an NMR derived reference spectrum for a known glucose concentration sample and storing this information as a reference standard. A patient blood sample is collected and NMR derived patient spectrums for the blood sample are obtained. The two NMR data sets (the reference and the patient) are compared and a

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glucose concentration is determined for the patient sample. The glucose concentration can be evaluated with a blood sample undergoing lipoprotein cholesterol evaluation. The NMR based test can be used to concurrently provide a glucose concentration and lipoprotein constituent values based on a single testing event. The disclosure also includes a multi-purpose test, i.e., a test which concurrently provides lipoprotein screening and coronary heart disease risk evaluation along with a diabetes screening and risk assessment for developing Type 2 diabetes. A method for assessing diabetes includes identifying the presence of diabetic dyslipidemia based on the values of predetermined NMR measured lipoprotein constituents. Excerpt(s): The present invention relates to methods and computer program products for determining whether subjects are at risk for developing Type 2 diabetes and other insulin resistance disorders. Type 2 diabetes, sometimes referred to as adult-onset or non-insulin dependent diabetes mellitus (NIDDM), affects approximately 15 million people in the United States alone. Additionally, approximately 21 million Americans have impaired glucose tolerance or "borderline diabetes" (characterized by high blood sugar levels not high enough to be considered diabetic). Both Type 2 diabetes and borderline diabetes are related to insulin resistance, a condition where the body fails to respond normally to insulin. Insulin resistance is associated with other health problems, including high blood pressure and heart disease. If unchecked, insulin resistance may actually develop into Type 2 diabetes. Type 2 diabetes is associated with a two- to fourfold excess risk of coronary heart disease, and diabetic patients are at an increased risk for morbidity and mortality associated with cardiovascular disease. Type 2 diabetes has been traditionally diagnosed by the detection of elevated levels of glucose (sugar) in the blood (hyperglycemia). While hyperglycemia is a strong indicator of diabetes, it is a very late stage development in the chain of events that lead from insulin resistance to full-blown diabetes. Accordingly, it would be desirable to have a way of identifying whether or not a subject is at risk for developing Type 2 diabetes (i.e., is predisposed to the condition) prior to the development of the classic symptoms, such as hyperglycemia. Earlier detection of indicators of the disease (e.g., detection of an increase in glucose levels prior to the levels reaching an elevation high enough to be considered hyperglycemia) may lead to more effective treatment of the disease, if not actual prevention of the onset of the disease. Web site: http://www.delphion.com/details?pn=US06518069__ •

Modulation of the sulfonylurea receptor and calcium in adipocytes for treatment of obesity/diabetes Inventor(s): Moustaid-Moussa; Naima (Knoxville, TN), Wilkison; William O. (Bahama, NC), Zemel; Michael B. (Knoxville, TN) Assignee(s): Artecel Science, Inc. (durham, Nc) Patent Number: 6,569,633 Date filed: June 12, 2000 Abstract: The invention provides methods for identifying compounds and compositions useful in the regulation of weight, the treatment of obesity, diabetes and other insulin resistance-related disorders hypertension, cardiovascular disease and the like. The methods comprise the use of adipocytes and predipocytes in assays and screens for compounds or compositions of interest. The present invention recognizes the presence of the sulfonylurea receptor in adipocytes and its utility in identifying compounds and in treating obesity and other insulin resistance-related disorders.In addition to assaying

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for agonists and antagonists of the sulfonylurea receptor, the methods of the invention also provide for identifying novel calcium channels or other calcium regulatory channels that are selectively expressed in human adipocytes as compared to human preadipocytes and for screening adipocytes for compounds that selectively antagonize calcium. These compounds may be used in the treatment of obesity and diabetes and other insulin resistance-related disorders. Excerpt(s): This invention relates to methods of identification of the sulfonylurea receptor in human adipocytes and other adipocyte-selective calcium channels and calcium mobilization antagonists and use of these factors for treatment of obesity, diabetes, and insulin-resistance related syndromes. Mice with dominant mutations at the agouti locus, including lethal yellow (A.sup.y) and viable yellow (A.sup.vy) are characterized by obesity, insulin resistance, and yellow coat color. The mouse agouti gene normally regulates differential pigment production in hair-bulb melanocytes. Each melanocyte in the hair bulb switches between the production of eumelanin (black) and phaeomelanin (yellow), producing the wild-type mouse coat color of a black hair with a subapical band of yellow. Agouti mutations disrupt this switching process and form a dominance hierarchy in which the dominant alleles produce a yellow coat and the recessive alleles produce a black coat. Although agouti is normally expressed in neonatal skin, dominant agouti mutations are characterized by ectopic overexpression of agouti throughout life. This is due to mutations in the promoter/regulatory region rather than in protein-coding domain. Transgenic mice designed to express the agouti coding portion in a ubiquitous manner also develop a syndrome of obesity, hyperinsulinemia, hyperglycemia and yellow coat color, similar to A.sup.vy mutation, demonstrating that ectopic overexpression of the agouti gene is directly responsible for pleiotropic effects associated with dominant agouti mutations. However, the mechanism linking this pigmentation gene to obesity has not yet been identified. Web site: http://www.delphion.com/details?pn=US06569633__ •

N-[2-hydroxy-3-(1-piperidinyl)propoxy]pyridine-1-oxide-3-carboximidoyl and its use in the treatment of insulin resistance

chloride

Inventor(s): Barabas; Mihaly (Budapest, HU), Biro; Katalin (Budapest, HU), Csakai; Zita (Kunszentmiklos, HU), Kardos; Mihalyne (Veszprem, HU), Komaromi; Andras (Veszprem, HU), Koranyi; Laszlo (Budapest, HU), Kurthy; Maria (Balatonfured, HU), Marvanyos; Ede (Budapest, HU), Mogyorosi; Tamas (Kazincbarcika, HU), Nagy; Karoly (Budapest, HU), Nagy; Melinda (Veszprem, HU), Nagy; Zoltan (Budapest, HU), Szilbereky; Jeno (Budapest, HU), Torok; Magdolna (Mateszalka, HU), Urogdi; Laszlo (Budapest, HU) Assignee(s): Biorex Kutato ES Fejleszto RT (veszprem-szabadsagpuszta, Hu) Patent Number: 6,649,628 Date filed: December 18, 2001 Abstract: N-[2-hydroxy-3-(1-piperidinyl)-propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, and the addition salts thereof, pharmaceutical compositions containing the same, methods of treating pathological insulin resistance, methods of treating pathological insulin resistance and pathological conditions associated therewith, and methods of treating pathological insulin resistance by simultaneously treating diabetes-induced chronic complications, especially retinopathy, neuropathy and nephropathy, and/or by simultaneously increasing pathologically decreased peripheral neuroregeneration caused by diabetes.

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Excerpt(s): An O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, its application in the treatment of insulin resistance, and the pharmaceutical preparation containing this derivative as effective agent. The invention relates to an O(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivative, the pharmaceutical use thereof and the pharmaceutical products containing this derivative as active ingredient. Namely, the invention relates to N-[2-hydroxy-3-(1-piperidinyl)propoxy]-pyridine-1-oxide-3-carboximidoyl chloride, its stereoisomers, as well as their acid addition salts. Furthermore, the invention also relates to the use of these compounds in the treatment of insulin resistance and the pharmaceutical products containing these derivatives as active ingredient. O-(3-piperidino-2-hydroxy-1-propyl) hydroxymic acid halide derivatives are already known from European Patent Specification No. 0 417 210 B1. According to this patent specification, these compounds exhibit a selective beta blocking effect and are thus suitable for the treatment of diabetic angiopathy, more specifically, of diabetic retinopathy and nephropathy. Web site: http://www.delphion.com/details?pn=US06649628__ •

Pharmaceutical compositions and methods for the treatment of arteriosclerosis Inventor(s): Fujiwara; Toshihiko (Ebina, JP), Maeda; Naoyuki (Zushi, JP), Sada; Toshio (Tokyo, JP), Tsujita; Yoshio (Ichikawa, JP) Assignee(s): Sankyo Company, Limited (tokyo, Jp) Patent Number: 6,610,682 Date filed: August 21, 2001 Abstract: A pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents exhibits excellent arteriosclerotic progress inhibitory effects, and is useful as a drug, particularly as a drug for the prevention or treatment of arteriosclerosis. The invention also provides a method for the treatment or prophylaxis of arteriosclerosis by administering in combination (i) at least one of said angiotensin II receptor antagonists or angiotensin converting enzyme inhibitors and (ii) one or more insulin resistance improving agents to a mammal suffering from or susceptible to arteriosclerosis. The invention also provides kits containing at least a first container which comprises at least one angiotensin II receptor antagonists and/or angiotensin converting enzyme inhibitor and a second container which contains at least one insulin resistance improving agent. Excerpt(s): The present invention relates to a pharmaceutical composition comprising as its active ingredients one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents (particularly a pharmaceutical composition for prevention or treatment of arteriosclerosis), a kit including a first container comprising one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and a second container comprising one or more insulin resistance improving agents for preparing a pharmaceutical composition (particularly a composition for prevention or treatment of arteriosclerosis), and a method which comprises administering in combination effective amounts of one or more drugs selected from the group consisting of angiotensin II receptor antagonists and angiotensin converting enzyme inhibitors, and one or more insulin resistance improving agents to warm-blooded animals for

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preventing or treating diseases (particularly arteriosclerosis). The occurrence of atherosclerosis is increasing with the adoption of Western-style diet and the growth of the aged population. This disease is the main cause of such disorders as myocardial infarction, cerebral infarction and cerebral apoplexy, and there is a need for its effective prevention and treatment. Examples of risk factors which cause atherosclerosis include hyperlipemia (particularly hypercholesterolemia), hypertension and saccharometabolism disorders based on insulin resistance. In addition, there are many cases in which these risk factors occur in the form of complications (Syndrome X), and are considered to be mutually interrelated Diabetes, 37, 1595-1607 (1988). Efforts have been made for the purpose of preventing and treating atherosclerosis by suppression of various risk factors such as hyperlipemia, hypertension and insulin resistance. Although HMG-CoA reductase inhibitors like pravastatin improve hyperlipemia, their inhibitory activity on arteriosclerosis in a case of administration alone is not enough, Biochim. Biophys. Acta, 960, 294-302 (1988). In addition, even insulin resistance improving agents like troglitazone do not exhibit sufficient atherosclerosis inhibitory activity in a case of administration alone (Japanese Patent Application (Kokai) No. Hei 7-41423). Web site: http://www.delphion.com/details?pn=US06610682__ •

Polymorphic human PC-1 sequences associated with insulin resistance Inventor(s): Frittitta; Lucia A. (Catania, IT), Goldfine; Ira (San Francisco, CA), Pizzuti; Antonio (San Giovanni Rotondo, IT), Trischitta; Vincenzo (San Giovanni Rotondo, IT), Vigneri; Riccardo (Catania, IT) Assignee(s): Instituto DI Ricovero E Cura a Carattere Scientifico (foggia, It), The Regents of the University of California (oakland, Ca) Patent Number: 6,465,185 Date filed: November 18, 1999 Abstract: A novel polymorphism in the human PC-1 gene is characterized, which is associated with an increased predisposition to developing insulin resistance. The polymorphism affects heterozygous and homozygous carriers of the allele. The subject nucleic acids and fragments thereof, encoded polypeptides, and antibodies specific for the polymorphic amino acid sequence are useful in determining a genetic predisposition to insulin resistance. The encoded protein is useful in drug screening for compositions that affect the activity of PC-1 and insulin receptor activity or expression. Excerpt(s): Insulin resistance occurs in 25% of non-diabetic, non-obese, apparently healthy individuals, and predisposes them to both diabetes and coronary artery disease. Diabetes mellitus is a major health problem in the United States affecting approximately 7% of the population. The most common form of diabetes mellitus is non-insulindependent diabetes mellitus (NIDDM or type II diabetes). Hyperglycemia in type II diabetes is the result of both resistance to insulin in muscle and other key insulin target tissues, and decreased beta cell insulin secretion. Longitudinal studies of individuals with a strong family history of diabetes indicate that the insulin resistance precedes the secretory abnormalities. Prior to developing diabetes these individuals compensate for their insulin resistance by secreting extra insulin. Diabetes results when the compensatory hyperinsulinemia fails. The secretory deficiency of pancreatic beta cells then plays a major role in the severity of the diabetes. Reaven (1988) Diabetes 37:1595607 were the first to have investigated insulin resistant, non-diabetic, healthy individuals from the general population who are non-obese. Strikingly, they observed

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that 25% of them have insulin resistance that is of a similar magnitude to that seen in type II diabetes patients. These individuals compensate by having insulin levels that are 3-4 times higher than normal. These elevated insulin levels are sufficient to maintain normoglycemia. Others have also confirmed that a large proportion of the non-diabetic population is insulin resistant. These insulin resistant, non-diabetic individuals have a much higher risk for developing type II diabetes than insulin sensitive subjects. However, even without developing hyperglycemia and diabetes, these insulin resistant individuals pay a significant price in terms of general health. Insulin resistance results in an increased risk for having elevated plasma triglycerides (TG), lower high density lipoproteins (HDL), and high blood pressure, a cluster of abnormalities that have been termed by different investigators as either Syndrome X, the insulin resistance syndrome, or the metabolic syndrome. It is believed that either the hyperinsulinemia, insulin resistance, or both play a direct role in causing these abnormalities. Data from ethnic, family, and longitudinal studies suggest that a major component of resistance is inherited. Web site: http://www.delphion.com/details?pn=US06465185__ •

Protein kinase C antagonist related to insulin receptor Inventor(s): Olefsky; Jerrold M. (Solana Beach, CA), Pillay; Tahir S. (San Diego, CA) Assignee(s): The Regents of the University of California (oakland, Ca) Patent Number: 6,511,811 Date filed: June 7, 1995 Abstract: Methods and compositions are provided for the treatment of insulin-resistance through the inhibition of protein kinase C-mediated phosphorylation of the amino acid residue Ser.sub.1270 of the insulin receptor. Methods for testing candidate compounds suitable for inhibition of serine-phosphorylation by protein kinase C are also provided. Excerpt(s): This invention relates to methods and compositions for the treatment of insulin resistance. Insulin resistance is associated with several disease conditions including non-insulin dependent diabetes mellitus (NIDDM), obesity, hypertension, and cardiovascular disease. The most well-studies of these conditions is NIDDM. NIDDM, also termed maturity-onset diabetes or type II diabetes to differentiate it from insulindependent diabetes mellitus (IDDM, also termed type I or juvenile diabetes), usually occurs in middle-aged obese people and accounts for 80% to 90% of diagnosed diabetes. In addition to insulin resistance, NIDDM is associated with normal to elevated levels of insulin, hyperglycemia, increased levels of very low density lipoproteins (VLDL), and decreased muscle uptake of glucose. NIDDM is often associated with hypertriglyceridemia. Ketoacidosis, characteristic of IDDM, is not associated with NIDDM except when the patient is subjected to extreme stress (e.g., septic shock or myocardial infarction). NIDDM patients tend to develop many of the same complications associated with IDDM including nerve, eye, kidney, and coronary artery disease. Mounting scientific evidence suggests that NIDDM results from a combination of two components: 1) a hereditary, genetic component (Rotter et al. In:: Rifkin et al., Diabetes Mellitus: Theory and Practice., New York, Elsevier, 1990, pp. 378-413); and 2) an acquired component (Seely et al. In: Moller, Ed. Insulin Resistance and Its Clinical Disorders. England, John Wile & Sons, Ltd., 1993, pp. 187-252; Olefsky In: Efendic, et al. Eds. New Concepts in the Pathogenesis of NIDDM. New York, Plenum Publishing Corp., 1993; Olefsky, In: DeGroot, et al., Eds. DeGroot Textbook of Endocrinology., 3rd Ed., Philadelphia, W. B. Saunders and Co., 1994). The genetic component of NIDDM is

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responsible for the first stage of the disease, termed the "prediabetic" state. The prediabetic state is characterized by hyperinsulinemia and "primary" insulin resistance. Insulin responsiveness in the prediabetic state is sufficient to maintain normal glucose tolerance (NGT) or at least impaired glucose tolerance (IGT). Web site: http://www.delphion.com/details?pn=US06511811__ •

Regulators of PPAR.delta. (.beta.) and their use in the treatment of obesity and insulin resistance Inventor(s): Hariharan; Narayanan (Richboro, PA) Assignee(s): Bristol-myers Squibb Company (princeton, Nj) Patent Number: 6,677,298 Date filed: July 19, 2001 Abstract: Obesity is a common clinical problem in most developed nations and is also rapidly becoming a major health concern in developing nations. Overweight individuals frequently suffer from several metabolic disorders such as insulin resistance, type 2 diabetes and dyslipidemia. This invention discloses proof of principle for the role PPAR.delta. (also known as.beta.) plays in the development of diet-induced obesity. In accordance with the present invention, a new method for treating obesity, insulin resistance and hyperlipidemia through administration of a pharmaceutical composition containing a chemical agent that antagonizes the function of PPAR.delta.(.beta.) protein, decreases PPAR.delta.(.beta.) gene expression and or transactivation of PPAR.delta.(.beta.) target gene expression is disclosed. This invention also proposes that obese, insulin resistant hyperlipidemic patients can be effectively treated with a combination of a PPAR.delta.(.beta.) antagonist with either an anti-diabetic agent or a lipid-lowering agent (or both). Excerpt(s): The present invention relates to a method for treating obesity, insulin resistance and dyslipidemia in mammals including humans through inhibition of PPAR.delta.(.beta.). This invention also relates to methods of screening for chemical entities that act to regulate PPAR.delta.(.beta.) activity. The invention further relates to a method of treatment of obese, insulin resistant and hyperlipidemic patients with one or more combinations of a PPAR.delta.(.beta.) antagonist, an anti-diabetic agent and a lipid-lowering agent. In mammals, including humans, adipocytes (fat cells) store excess energy in the form of triglycerides at times of nutritional excess (see Lowell, Cell, 99:239242, 1999). During starvation, triglycerides are degraded to fatty acids in adipocytes in order to supplement nutritional and energy requirements. However, excess adiposity achieved either through recruitment of progenitor cells (pre-adipocytes) to become adipocytes (differentiation) and/or through expansion of the pre-existing adipocytes (hypertrophy), is associated with obesity (see Lowell, Cell, 99:239-242, 1999). Hypertrophied adipocytes have been demonstrated to produce excessive amounts of cytokines such as TNF.alpha.(which in turn act to reduce insulin receptor activity and/or response to insulin signaling in skeletal muscle and adipocytes, two major glucose utilizing tissues (see Hotamisligil, et al., Science, 259:87-90, 1993; Lowell, Cell, 99:239-242, 1999). This results in insulin resistance, reduced glucose uptake, and in some individuals type 2 diabetes. Obese individuals with insulin resistance and type 2 diabetes also frequently suffer from hyperlipidemia, atherosclerosis and cardiovascular diseases (see Rosenbaum et al., New. Eng. J. Med. 337:396-407, 1997). Web site: http://www.delphion.com/details?pn=US06677298__

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Remedies for diseases caused by insulin resistance Inventor(s): Asano; Tomoichiro (Tokyo, JP), Kanda; Akira (Tokyo, JP), Kubo; Hideo (Tokyo, JP), Yazaki; Yoshio (Tokyo, JP) Assignee(s): Daiichi Pharmaceutical Co., Ltd. (tokyo, Jp) Patent Number: 6,498,139 Date filed: March 29, 2000 Abstract: The present invention provides methods of inhibiting or sequestering 14-3-3 protein from binding to the insulin receptor substrate -1 or -2 by administering a substance which inhibits the interaction of these two proteins. Excerpt(s): The present application is a 371 of PCT/JP98/04293 filed Sep. 25, 1998. The present invention relates to a drug, particularly a remedy for diseases caused by insulin resistance, such as diabetes, as well as to a screening method for the remedy. Insulin is a hormone which regulates the concentration of blood sugar and blood lipid through the promotion of glucose and lipid intake into cells and utilization and storage of them. Insulin resistance indicates the condition in which insulin does not act normally on cells, and this condition causes elevation of the concentration of blood sugar or blood lipid. Examples of diseases caused by insulin resistance include diabetes, diabetic microangiopathies (diabetic nephropathy, diabetic neuropathy, and diabetic retinopathy), impaired glucose tolerance, hyperinsulinemia, hyperlipemia, arteriosclerosis, hypertension, obesity, ischemic heart diseases, ischemic brain disorders, and peripheral arterial embolism (Tamio Teramoto, et al., (1995) Biomedicine & Therapeutics 29, 8-96). The cause of insulin resistance has not yet been fully elucidated, and causal therapy thereof has not been developed. Web site: http://www.delphion.com/details?pn=US06498139__

Patent Applications on Insulin Resistance As of December 2000, U.S. patent applications are open to public viewing.10 Applications are patent requests which have yet to be granted. (The process to achieve a patent can take several years.) The following patent applications have been filed since December 2000 relating to insulin resistance: •

11-BETA-HYDROXYSTEROID DEHYDROGENASE 1 INHIBITORS USEFUL FOR THE TREATMENT OF DIABETES, OBESITY AND DYSLIPIDEMIA Inventor(s): Balkovec, James M.; (Martinsville, NJ), Olson, Steven H.; (Metuchen, NJ), Zhu, Yuping; (Scotch Plains, NJ) Correspondence: Merck And CO Inc; P O Box 2000; Rahway; NJ; 070650907 Patent Application Number: 20040048912 Date filed: June 9, 2003 Abstract: Compounds having Formula I, including pharmaceutically acceptable salts, hydrates and solvates thereof: 1are selective inhibitors of the 11.beta.-HSD1 enzyme. The compounds are useful for the treatment of diabetes, such as noninsulin-dependent

10

This has been a common practice outside the United States prior to December 2000.

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diabetes (NIDDM), hyperglycemia, obesity, insulin resistance, dylsipidemia, hyperlipidemia, hypertension, Syndrome X, and other symptoms associated with NIDDM. Excerpt(s): The present invention is related to U.S. provisional application Serial No. 60/387,385, filed Jun. 10, 2002, the contents of which are hereby incorporated by reference. The present invention relates to inhibitors of the enzyme 11-betahydroxysteroid dehydrogenase Type I (11.beta.-HSD-1 or HSD-1), and methods of treatment using such compounds. The compounds are useful for the treatment of diabetes, such as non-insulin dependent type 2 diabetes mellitus (NIDDM), insulin resistance, obesity, lipid disorders and other diseases and conditions. Diabetes is caused by multiple factors and is most simply characterized by elevated levels of plasma glucose (hyperglycemia) in the fasting state. There are two generally recognized forms of diabetes: type I diabetes, or insulin-dependent diabetes mellitus (IDDM), in which patients produce little or no insulin, the hormone which regulates glucose utilization, and type 2 diabetes, or noninsulin-dependent diabetes mellitus (NIDDM), wherein patients produce insulin and even exhibit hyperinsulinemia (plasma insulin levels that are the same or even elevated in comparison with non-diabetic subjects), while at the same time demonstrating hyperglycemia. Type 1 diabetes is typically treated with exogenous insulin administered via injection. However, type 2 diabetics often develop "insulin resistance", such that the effect of insulin in stimulating glucose and lipid metabolism in the main insulin-sensitive tissues, namely, muscle, liver and adipose tissues, is diminished. Patients who are insulin resistant but not diabetic have elevated insulin levels that compensate for their insulin resistance, so that serum glucose levels are not elevated. In patients with NIDDM, the plasma insulin levels, even when they are elevated, are insufficient to overcome the pronounced insulin resistance, resulting in hyperglycemia. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

2-substituted thiazolidinones as beta-3 adrenergic receptor agonists Inventor(s): Hu, Baihua; (Audubon, PA) Correspondence: Wyeth; Patent Law Group; Five Giralda Farms; Madison; NJ; 07940; US Patent Application Number: 20030176412 Date filed: May 19, 2003 Abstract: This invention provides compounds of Formula I having the structure 1wherein:A, X, Y, Z, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, and R.sub.6 are as defined hereinbefore or a pharmaceutically acceptable salt thereof, which are useful in treating or inhibiting metabolic disorders related to insulin resistance or hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination; and are particularly useful in the treatment or inhibition of type II diabetes. Excerpt(s): This application is a divisional of U.S. application Ser. No. 10/132,483, filed Apr. 25, 2002, pending, which is a divisional of U.S. application Ser. No. 09/904,157, filed Jul. 12, 2001, now U.S. Pat. No. 6,410,734. The '157 application claims the benefit of U.S. Provisional Application No. 60/218,724, filed Jul. 17, 2000. This invention relates to 2-substituted thiazolidinone derivatives which are.beta.sub.3 adrenergic receptor agonists useful for the treatment of metabolic disorders related to insulin resistance or

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hyperglycemia (typically associated with obesity or glucose intolerance), atherosclerosis, gastrointestinal disorders, neurogenetic inflammation, and frequent urination, and are particularly useful in the treatment or inhibition of type II diabetes. The subdivision of.beta. adrenergic receptors (.beta.-AR) into.beta.sub.1- and.beta.sub.2-AR has led to the development of.beta.sub.1- and.beta.sub.2-antagonists and/or agonists which have been useful for the treatment of cardiovascular disease and asthma. The recent discovery of "atypical" receptors, later called.beta.sub.3-AR, has led to the development of.beta.sub.3AR agnoists which may be potentially useful as antiobesity and antidiabetic agents. For recent reviews on.beta.sub.3-AR agnoists , see: 1. A. D. Strosberg, Annu. Rev. Pharmacol. Toxicol. 1997, 37,421; 2. A. E. Weber, Ann. Rep. Med. Chem. 1998, 33, 193; 3. C. P. Kordik and A. B. Reitz, J. Med. Chem. 1999, 42, 181; 4. C. Weyer, J. F. Gautier and E. Danforth, Diabetes and Metabolism, 1999, 25, 11. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors Inventor(s): Du Bois, Daisy Joe; (Palo Alto, CA) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030195361 Date filed: February 14, 2003 Abstract: This invention relates to compounds of Formula I 1or stereoisomers, pharmaceutically acceptable salts or prod rugs thereof or a pharmaceutically acceptable salts of the prodrugs. This invention also relates to pharmaceutical compositions comprising a compound of Formula I, and to methods of treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia. Excerpt(s): This invention relates to bicyclic pyrrolyl amides and pharmaceutical compositions comprising bicyclic pyrrolyl amides. This invention also relates to the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, and tissue ischemia, particularly myocardial ischemia, using the bicyclic pyrrolyl amides. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory. The use of insulin requires multiple daily doses, usually by self injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed.

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Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Combination therapy using a dual PPAR-a/PPAR-y activator and a GLP-1 derivative for the treatment of metabolic syndrome and related diseases and disorders Inventor(s): Bury, Paul Stanley; (Kobenhavn, DK), Jeppesen, Lone; (Virum, DK), Mogensen, John Patrick; (Herlev, DK), Pettersson, Ingrid; (Frederiksberg, DK), Sauerberg, Per; (Farum, DK) Correspondence: Reza Green, ESQ.; Novo Nordisk Pharmaceuticals, INC.; 100 College Road West; Princeton; NJ; 08540; US Patent Application Number: 20030199451 Date filed: May 20, 2003 Abstract: The present invention relates to a pharmaceutical composition comprising a dual Peroxisome Proliferator-Activated Receptor-alpha/Peroxisome ProliferatorActivated Receptor-gama activator (PPAR-.alpha./PPAR-.gamma.- ) and a Glucagon Like Peptide-1 (GLP-1) derivative for treating, preventing and reducing the risk of developing Type 2 diabetes, insulin resistance, dyslipidemia, obesity, hypertension and other related diseases and disorders. Excerpt(s): This application is a continuation of application Ser. No. 09/771,217, having a filing date of Jan. 26, 2001, now issued U.S. Pat. No. ______, the contents of which are herein incorporated by reference in its entirety. The present invention relates to a pharmaceutical composition comprising a dual Peroxisome Proliferator-Activated Receptor-alpha/Peroxisome Proliferator-Activated Receptor-gama activator (PPAR.alpha./PPAR-.gamma.) and a Glucagon Like Peptide-1 (GLP-1) derivative for treating, preventing and reducing the risk of developing Type 2 diabetes, insulin resistance, dyslipidemia, obesity, hypertension and other related diseases and disorders. Coronary artery disease (CAD) is the major cause of death in Type 2 diabetic and metabolic syndrome patients (i.e. patients that fall within the `deadly quartet` category of impaired glucose tolerance, insulin resistance, hypertriglyceridaemia and/or obesity). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Compositions and methods for diagnosing and treating diabetes, insulin resistance and dyslipidemia Inventor(s): Gustafson, Thomas A.; (Danville, CA), Lavan, Brian; (San Francisco, CA), Moodie, Shonna; (San Francisco, CA), Waters, Steve; (San Ramon, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030186871 Date filed: December 16, 2002 Abstract: The present invention provides compositions and methods for diagnosing and treating diabetes, insulin resistance and dyslipidemia. In particular, the invention provides methods of identifying modulators of AKR1C as well as methods of diagnosing diabetes by measuring the levels of AKR1C or 9.alpha., 11.beta.PGF.sub.2.alpha. in a patient.

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Excerpt(s): This application claims priority to U.S. Provisional Patent Application No. 60/341,451, filed Dec. 17, 2001, which is incorporated in its entirety for any and all purposes. This invention relates to methods of diagnosing and treating diabetes. Diabetes mellitus can be divided into two clinical syndromes, Type 1 and Type 2 diabetes mellitus. Type 1, or insulin-dependent diabetes mellitus (IDDM), is a chronic autoimmune disease characterized by the extensive loss of beta cells in the pancreatic Islets of Langerhans, which produce insulin. As these cells are progressively destroyed, the amount of secreted insulin decreases, eventually leading to hyperglycemia (abnormally high level of glucose in the blood) when the amount of secreted insulin drops below the level required for euglycemia (normal blood glucose level). Although the exact trigger for this immune response is not known, patients with IDDM have high levels of antibodies against pancreatic beta cells. However, not all patients with high levels of these antibodies develop IDDM. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Cyclic sulfamide derivatives and methods of use Inventor(s): Coppola, Gary Mark; (Budd Lake, NJ), Davies, John William; (Montclair, NJ), Jewell, Charles Francis; (Sudbury, MA), Li, Yu-Chin; (Edison, NJ), Sperbeck, Donald Mark; (Berkeley Heights, NJ), Stams, Travis Matthew; (Belle Mead, NJ), Topiol, Sidney Wolf; (Fair Lawn, NJ), Vlattas, Isidoros; (Summit, NJ), Wareing, James Richard; (Randolph, NJ) Correspondence: Thomas Hoxie; Novartis, Corporate Intellectual Property; One Health Plaza 430/2; East Hanover; NJ; 07936-1080; US Patent Application Number: 20040023974 Date filed: April 2, 2003 Abstract: Compounds of the formula 1provide pharmacological agents which are inhibitors of PTPases, in particular, the compounds of formula I inhibit PTP-1B and TC PTP, and thus may be employed for the treatment of conditions associated with PTPase activity. The compounds of the present invention may also be employed for inhibition of other enzymes with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula I may be employed for prevention or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels. The compounds of the present invention may also be employed in the treatment, prevention or control of a number of conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system. Excerpt(s): This application claims the benefit of Provisional Applications Nos. 60/369,930 and No. 60/369,779, both filed Apr. 3, 2002. or a pharmaceutically acceptable salt thereof; or a prodrug derivative thereof. The compounds of the present invention are inhibitors of protein tyrosine phosphatases (PTPases), in particular, the compounds of formula I inhibit PTPase-1B (PTP-1B) and T-cell PTPase (TC PTP), and thus may be employed for the treatment of conditions mediated by PTPase activity. The compounds of the present invention may also be employed as inhibitors of other enzymes

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characterized with a phosphotyrosine binding region such as the SH2 domain. Accordingly, the compounds of formula I may be employed for prevention or treatment of insulin resistance associated with obesity, glucose intolerance, diabetes mellitus, hypertension and ischemic diseases of the large and small blood vessels. The compounds of the present invention may also be employed in the treatment, prevention or control of a number of conditions that accompany Type 2 diabetes, including hyperlipidemia, hypertriglyceridemia, atherosclerosis, vascular restenosis, irritable bowel syndrome, pancreatitis, adipose cell tumors and carcinomas such as liposarcoma, dyslipidemia, and other disorders where insulin resistance is indicated. In addition, the compounds of the present invention may be employed to treat or prevent cancer, osteoporosis, neurodegenerative and infectious diseases, and diseases involving inflammation and the immune system. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Diagnosis and treatment of human dormancy syndrome Inventor(s): Powell, Michael; (Grass Valley, CA) Correspondence: Thomas A. Ward; Fliesler Dubb Meyer & Lovejoy Llp; Suite 400; Four Embarcadero Center; San Francisco; CA; 94111-4156; US Patent Application Number: 20030228628 Date filed: May 23, 2003 Abstract: New methods for diagnosis of human dormancy syndrome are provided. Human dormancy syndrome is characterized by elevated serum ratio of rT3/fT3 compared to a population of normal subjects from which subjects suffering from fibromyalgia, chronic fatigue, obesity, dementias including Alzheimer's Disease and related dormancy conditions are excluded, and the presence of one or more findings related to reduced activity including torpor, chronic fatigue, insulin resistance, dementias, obesity and the like. Treatment of human dormancy syndrome is directed toward increasing fT3 levels or decreasing rT3 levels, or both, using pharmaceutical and/or behavioral methods. Other conditions that are associated with HDS can also be treated using T3 therapy, with or without specific psychological, behavioral or pharmaceutical therapies. Excerpt(s): This application claims priority under 35 U.S.C.sctn.119 to U.S. Provisional Patent Application Serial No: 60/382,913, filed May 23, 2002, and U.S. Provisional Patent Application Serial No: 60/383,271 filed May 24, 2002, each application herein incorporated fully by reference. This invention relates to methods for diagnosing and treating human dormancy syndrome, a constellation of conditions heretofore unrelated to each other, including fibromyalgia, autoimmune diseases, coronary artery disease, breast cancer, prostate cancer and Alzheimer's disease. Fibromyalgia is known as a diffuse periarticular musculoskeletal pain syndrome, primarily affecting femalse (90%) and is associated with insomnia, cognitive impairment, fatigue and depression. Fibromyalgia is also known to be associated with elevated levels of substance P (SP) in the cerebrospinal fluid (CSF), decreased levels of serotonin (5-HT) and a hyperactive hypothalamic-pituitary-adrenal (HPA) axis. The pathophysiological mechanisms underlying fibromyalgia are unknown, and the condition is considered uncurable. Exercise, cognitive behavioral therapy and antidepressant medication have been shown to diminish the severity of symptoms in some patients, but most patients remain in an unremitting state of illness. Standard laboratory tests are normal for most patients having fibromyalgia, and there is no evidence for autoimmune disease. Interestingly,

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there is an association of fibromyalgia with a significantly higher incidence of childhood and adult physical and emotional abuse and/or trauma. However, these findings have not been reconciled until the discovery of this invention. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Dietary method for modulating glucose metabolism and associated conditions and increasing longevity Inventor(s): Ceddia, Michael Anthony; (Brookville, OH), Rand, Jacqueline Sinclair; (Brisbane, AU), Sunvold, Gregory Dean; (Lewisburg, OH) Correspondence: The Procter & Gamble Company; Intellectual Property Division; Winton Hill Technical Center - Box 161; 6110 Center Hill Avenue; Cincinnati; OH; 45224; US Patent Application Number: 20040001875 Date filed: May 21, 2003 Abstract: The invention provides a method for treating abnormal glucose metabolism and insulin resistance in an animal by feeding a diet comprising high protein and moderate amounts of carbohydrate and fat. The invention also provides a method for treating conditions associated with insulin resistance or decreased longevity by feeding an animal such diets. Excerpt(s): This claims the benefit of U.S. Provisional Application No. 60/384,320, filed May 30, 2002. The present invention relates to methods for treating abnormal conditions associated with glucose metabolism. The invention also relates to methods for increasing longevity, particularly by modulating glucose metabolism and decreasing the development of insulin resistance. Companion animals are known to suffer from many of the same health conditions as humans. Therefore, it is not uncommon for prevention and treatment methods for dogs and cats to closely follow those for humans. For example, diabetes is one of the most frequently diagnosed endocrinopathies of cats and treatment of diabetes in cats is similar to treatment of diabetes in humans. Human therapies such as insulin therapy, oral hypoglycemics, and dietary modulation of glucose metabolism and weight loss are commonly used in both domestic felines and canines. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Food compositions for reducing insulin resistance Inventor(s): Bosley, John Anthony; (Bedford, GB), Brown, Anna Louise; (Bedford, GB), Rogers, Julia Sarah; (Bedford, GB) Correspondence: Morgan Lewis & Bockius Llp; 1111 Pennsylvania Avenue NW; Washington; DC; 20004; US Patent Application Number: 20030171398 Date filed: May 22, 2002 Abstract: The present invention relates to molecules derived from guggulipid extract which are capable of reducing insulin resistance in humans. The invention further relates food compositions and medicaments comprising such molecules which can be used to treat and/or prevent insulin resistance and the symptoms thereof.

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Excerpt(s): The invention relates to the field of natural plant derived ingredients which have beneficial properties to health. More particularly the invention relates to ingredients derived from the Indian plant Commiphora mukul and their novel use in addressing the human condition of insulin resistance and health problems associated therewith. Insulin is a hormone well known to play a key role in maintaining blood glucose levels within healthy parameters. Where the action of insulin is impaired, as is the case in the human condition insulin resistance, a range of health problems can occur. In the short term the health problems associated with insulin resistance comprise chronic fatigue, cognitive impairment and mood swings, whilst long term they include more chronic diseases such as cardiovascular disease, type-II diabetes and polycystic ovary syndrome. Insulin resistance is therefore a complex metabolic condition and the frequency of incidence within the human population makes it highly desirable to develop a means by which it can be controlled or prevented. PPARgamma is a known member of the peroxisome proliferator activated receptor (PPAR) subset of the nuclear hormone receptor superfamily. It is a ligand activated transcription factor and binds DNA in a heterodimeric complex with a second nuclear hormone receptor RXR. PPARgamma has been characterised as an important regulator of lipid metabolism. PPARgamma is suggested as playing a role in insulin sensitivity and other biological activities including effects on inflammation, cancer, cognition and cellular differentiation. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Formulations for the prevention and treatment of insulin resistance and type 2 diabetes mellitus Inventor(s): Pearson, Don C.; (Lakewood, WA), Richardson, Kenneth T.; (Anchorage, AK) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20040034030 Date filed: July 30, 2003 Abstract: The compositions and dosage forms of the invention are clinically useful as methods for increasing the effectiveness, efficiency and safety of biguanides (metformin) and/or sulfonylureas in the prevention and treatment of insulin resistance and diabetes mellitus, alone or in combination, as a nutrient for humans. The carefully chosen active ingredients of the invention are designed in a modular fashion to prevent and rectify adverse events associated with insulin resistance syndrome and diabetes mellitus, and with the clinical use of biguanides (metformin) and/or the sulfonylureas. These modules are: (1) Mitochondrial Metabolic Group, (2) Plasma and Mitochondrial Membrane Integrity Group, (3) Nocturnal Group and, (4) Insulin Alternative Group. When used in concert with a biguanide, a sulfonylurea or with a combination of both, the invention will broaden the clinical usefulness of these drugs. The invention will retard the progression of insulin resistance to type 2 diabetes, and reduce the serious microvascular and macrovascular complications commonly associated with insulin resistance syndrome and diabetes mellitus. Excerpt(s): This application is related to United States provisional patent applications nos. 60/245,471, filed Nov. 3, 2000, 60/245,950, also filed Nov. 3, 2000, and 60/256,033, filed Dec. 13, 2000, all three of which are incorporated herein by reference in their entirety. The present application claims benefits from all three such provisional patent

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applications for all purposes legally capable of being served thereby. This invention is in the field of pharmacology, and relates to single-component or multi-component formulations used to enhance the efficiency and safety in the clinical use of the biguanide metformin, the sulfonylureas or combinations of sulfonylurea-metformin, in the pharmacological treatment of insulin resistance and type 2 diabetes mellitus. Insulin resistance and non-insulin-dependent diabetes are prevalent in up to 35% of the population depending upon the age and nature of the subset. In the United States alone, 16 million people have type 2 diabetes and 13 million have impaired glucose tolerance. In fact type 2 diabetes has reached epidemic proportions worldwide. By 2025, an estimated 300 million people will have diabetes, most of whom will inhabit China, India, and the United States. Because of an aging and increasingly sedentary, obese population with changing, unhealthy diets, insulin resistance is also increasing alarmingly (it is already two to three times more prevalent than type 2 diabetes). This apparent increase in the prevalence of insulin resistance and type 2 diabetes occurs in all ethnic populations, but especially in those that have migrated from their native lands to more urbanized and westernized regions of the world. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Human and mouse e2-protein nucleic acids coding therefor and uses thereof Inventor(s): Brodin, Peter; (Molndal, SE), Thelin, Anders; (Molndal, SE) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20040029141 Date filed: August 12, 2003 Abstract: This invention relates to the regulation of metabolism and in particular to a gene named E2 involved in insulin resistance syndrome. The invention further relates to protein encoded by the gene and to means of regulating their biological activity. In addition the invention relates to the use of the gene and protein to identify therapeutic agents for controlling insulin resistance syndrome and other related disorders such as non-insulin dependent diabetes mellitus (NIDDM), dyslipidemia, obesity and atherosclerosis. Excerpt(s): This invention relates to the regulation of metabolism and in particular to genes involved in insulin resistance syndrome. The invention further relates to proteins encoded by the genes and to means of regulating their biological activity. In addition the invention relates to the use of the genes and proteins to identify therapeutic agents for controlling insulin resistance syndrome and other related disorders such as non-insulin dependent diabetes mellitus (NDDM), dyslipidemia, obesity and atherosclerosis. Insulin resistance syndrome (IRS) is a complex metabolic disorder which initially is associated with elevated levels of insulin. Affected individuals become resistant to the biological action of insulin. In later stages of the syndrome the insulin levels drop and glucose levels rise and the individual will enter a diabetic state (O'Rahilly S., BMJ 1997, 314(7085), 955-959). The drop in insulin levels is probably caused by a collapse of insulin production in the pancreas. The mechanisms behind this disorder are unknown but studies have shown that the development of IRS is multifactorial involving both environmental and genetic components. Obesity is believed to be a major component in the development of IRS and since obesity is increasing in the western world, IRS is also an increasing problem. If untreated IRS will lead to the development of atherosclerosis and premature death. Current treatment is unsatisfactory and new drugs need to be developed. A major problem is that the mechanisms behind the syndrome are unknown

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and that no reliable or relevant experimental models for human drug development are available. At present drug research has to rely on a few rodent models with single gene defects in appetite regulation, or high calorie diet treated rodents. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Inhibition of the beta3 subunit of L-type Ca2+ channels Inventor(s): Berggren, Per-Olof; (Solna, SE), Flockerzi, Veit; (Bierback, DE) Correspondence: Mcdonnell Boehnen Hulbert & Berghoff; 300 South Wacker Drive; Suite 3200; Chicago; IL; 60606; US Patent Application Number: 20030180712 Date filed: March 19, 2003 Abstract: The present invention provides reagents and methods for identifying inhibitors of the L-type Ca.sup.2+ channel.beta.sub.3 protein, which has been demonstrated to be involved in calcium signaling, insulin secretion, and glucose homeostasis. The invention also provides therapeutics and methods for treating a subject with one or more of diabetes, insulin resistance, impaired insulin secretion, and impaired glucose homeostasis, involving the use of inhibitors of an L-type Ca.sup.2+ channel.beta.sub.3 subunit to provide a benefit to the subject. Excerpt(s): This application claims priority to U.S. Provisional Application Serial No. 60/366152 filed Mar. 20, 2002 and to U.S. Provisional Application Serial No. 60/442142 filed Jan. 22, 2003. This invention relates to molecular biology, cell biology, voltage gated calcium channels, calcium signaling, drug discovery, diabetes, insulin resistance, impaired insulin secretion, and impaired glucose homeostasis. Diabetes mellitus (DM) comprises a series of disorders, all characterized by hyperglycemia. Type I ("insulin dependent") DM is characterized by insulin deficiency, whereas Type II ("non-insulin dependent" or "adult-onset") DM is characterized by insulin resistance, impaired insulin secretion, and increased hepatic glucose production. Chronic complications of DM result from hyperglycemia and include retinopathy, neuropathy, nephropathy, and cardiovascular disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Method of screening hypoglycemic substance by using stat inhibitory factor-1 Inventor(s): Kishimoto, Tadamitsu; (Osaka, JP), Naka, Tetsuji; (Osaka, JP) Correspondence: Sughrue Mion, Pllc; 2100 Pennsylvania Avenue, N.W.; Washington; DC; 20037; US Patent Application Number: 20030186215 Date filed: March 10, 2003 Abstract: The present invention discloses a screening method for a substance, which could be a therapeutic agent for diabetes with insulin resistance through regulating a function of a molecule involved in insulin signaling pathway. More specifically, the present invention discloses a screening method for a substance having hypoglycemic activity, which is characterized by contacting a sample to STAT-induced inhibitor of STAT function-1 in the presence of insulin, and by detecting inhibitory activity of STATinduced inhibitor of STAT function-1 by a substance in the sample, as an index.

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Excerpt(s): The present invention relates to a screening method for a substance having hypoglycemic activity which is characterized by contacting a sample to STAT-induced inhibitor of STAT function-1 in the presence of insulin, and by detecting inhibitory activity of STAT-induced inhibitor of STAT function-l by a substance in the sample, as an index. STAT (Signal Transducer and Activator of Transcription) is a molecule that is activated by stimulation with cytokine(s). STAT-induced inhibitor of STAT function-1 is a protein that is induced by STAT and inhibits cytokine signaling through suppressing activation of Janus Kinase (JAK). STAT-induced inhibitor of STAT function-1 (hereinafter, simply referred to as "SSI-1", though the abbreviation "SSI-1", "SOCS-1" or "SIIS-1" have been used) was first isolated from mouse by the inventors of the present invention (PCT Publication No. WO98/30688 and Naka, T. et al, Nature, 387, 924-929 (1997)). So far, eight members of the SSI family molecule, including SSI-2 and SSI-3 (Minamoto, S. et al., Biochem. Biophys. Res. Commun., 237, 79-83 (1997)),have been identified as an inhibitor. The inventors of the present invention have also already isolated human SSI-1 (Minamoto, S. et al., Biochem. Biophys. Res. Commun., 237, 79-83 (1997)). The functional domain of SSI-1 was determined by an experiment using mutant genes of SSI-1 (Narazaki, M. et al., Proc. Natl. Acad. Sci. U.S.A., 95, 13130-13134 (1998)). More specifically, it is known that 24 amino acid residues existing in N-terminus of SH2 domain (pre-SH2) as well as SH2 domain are essential for the suppression of phosphorylation of JAK, and that SSI-1 associates to JAK through its SH2 and pre-SH2 domains. Moreover, part of the biological function of SSI-1 in vivo has been identified by the inventors of the present invention using SSI-1-deficient mice. In SSI-1-deficient mice, apoptosis was detected in several organs such as lymphocytes, heart and liver, in which SSI-1 was expressed as the ages passed, indicating that SSI-1 closely relates to survival of a cell, especially to an inflammation (Naka, T. et al., Proc. Natl. Acad. Sci. U.S.A., 95, 15575-15582 (1998)). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Method of treatment of obesity and paralyzed muscle and ergogenic aids Inventor(s): Winder, William W; (Provo, UT) Correspondence: Madson & Metcalf; Gateway Tower West; Suite 900; 15 West South Temple; Salt Lake City; UT; 84101 Patent Application Number: 20030212034 Date filed: December 2, 2002 Abstract: The invention relates to a method of treating obesity in a mammal. The method includes the step of administering a therapeutically effective amount of an AMP-activated protein kinase activator to the mammal. The mammal may be for example, a human, a rat, a mouse, and the like. The AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal. The activation of the AMP-activated protein kinase activator can produce the benefits of exercise training including the loss of body fat. The invention also relates to a method of treating insulin resistance in a mammal suffering from obesity, type 2 diabetes, or muscle paralysis. To reduce the insulin resistance a therapeutically effective amount of an AMP-activated protein kinase activator is given to the mammal. Excerpt(s): This application is related to and claims the benefit of U.S. Provisional Application Serial No. 60/210,708 of William W. Winder Jun. 9, 2000 and entitled "Use

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of AMP Kinase Activators for Treatment of Obesity and Paralyzed Muscle and as Ergogenic Aids," which is incorporated herein by this reference. The present invention relates to the methods of treatment of obesity and paralyzed muscle. More specifically, the invention relates methods of treatment of obesity and paralyzed muscle through artificial activation of metabolic pathways. Obesity is one of the largest health problems in the United States and is a growing concern for many health care officials. By one account more than 33 percent of adults and 20 percent of children in the United States are considered obese. Obesity is defined as having excessive amounts of body fat. Body fat (adipose tissue) is necessary for certain bodily functions. However, when body fat accumulates to excessive amounts the person is considered obese. Obesity can lead to a number of different illness including: heart disease, high blood pressure, increased cholesterol, diabetes, certain types of cancer, orthopedic problems, musculo-skeletal diseases, decreased flexibility, and difficulty breathing. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods fo treating conditions associated with insulin resistance with aicar, (5amino-4-imidazole carboxamide riboside) and related compounds Inventor(s): Ido, Yasuo; (Brookline, MA), Kraegen, Edward W; (Sydney, AU), Ruderman, Neil; (Newton, MA) Correspondence: Weingarten, Schurgin, Gagnebin & Lebovici Llp; Ten Post Office Square; Boston; MA; 02109; US Patent Application Number: 20030212014 Date filed: March 12, 2003 Abstract: The long-term usage of AICR (5-aminio, 4-imidazole carboxamide riboside) to produce sustained metabolic and biological changes in mammals that overcome insulin resistance, i.e., increase insulin sensitivity, and result in benefits in diseases and conditions such as diabetes, hypertension, atherosclerosis, polycystic ovary syndrome and gallstones is described long-term usage of AICAR, particularly intermittent administration, e.g., three days per week, appears to have some of the positive effects of exercise, having an impact on the amount Of food consumed by a subject and resulting in reduced fat build-up and increase in muscle mass. Therefore, AICAR administration has a positive impact in reducing obesity. AICAR can also Prove useful in preventing or treating vascular diseases associated with hyperglycemia, high plasma levels of free fatty acids (FFA) and triglyceride, and insulin resistance by virtue of the fact that this agent activates fatty acid oxidation. Animal tests have Shown that chronic intermittent treatment with AICAR has not resulted in any noticeable toxic effects. AICAR and related compounds are activators of AMP-activated protein kinase (AMPK) and, furthermore, are effective at decreasing malonyl CoA levels in the animal. Excerpt(s): This application claims the priority of the following applications: U.S. Provisional Application No. 60/222,131, filed Jul. 31, 2000 entitled, USE OF AICAR (5AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS TO TREAT INSULIN RESISTANCE; International Application No. PCT/US00/40607, filed Aug. 9, 2000 entitled, METHOD OF MAINTAINING VASCULAR INTEGRITY USING AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS; and International Application No. PCT/US01/18467 filed Jun. 6, 2001 entitled, USE OF AICAR (5-AMINO-4-IMIDAZOLE CARBOXAMIDE RIBOSIDE) AND RELATED COMPOUNDS FOR THE PREVENTION AND TREATMENT OF OBESITY, the whole of which are hereby incorporated by reference

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herein. AMP-activated protein kinase (AMPK) is a cytoplasmic enzyme that has been shown to exist in both the liver and skeletal muscle. As its name indicates, AMPK is activated by increasing levels of AMP and, secondarily, by an increase in the ratio of AMP to ATP in the cell. AMP levels rise in the cell as ATP is hydrolyzed to ADP and Pi. Two molecules of ADP, through the action of myokinase, also known as adenylate kinase, produce one molecule of ATP and one molecule of AMP. In addition to its activation by AMP, AMPK is activated through phosphorylation by an upstream kinase called AMPK kinase (AMPKK). AMP also allosterically activates AMPKK. Phosphorylation of AMPK by AMPKK makes it a poor substrate for phosphatases. All these factors combined together make AMPK very sensitive to minimal fluctuations in cellular AMP levels. AMPK has several known substrates, specifically enzymes that it can phosphorylate and modulate. In the liver, AMPK has been shown to phosphorylate hydroxymethyl glutaryl CoA (HMGCOA) reductase and acetyl CoA carboxylase (ACC), inhibiting the actions of both enzymes. Reducing HMGCOA reductase activity inhibits cholesterol synthesis, and reducing ACC activity decreases the generation of malonyl CoA, an intermediate in fatty acid synthesis. In skeletal muscle, AMPK also is an inhibitor of carnitine palmitoyl transferase I, which regulates the uptake of fatty acids into mitochondria where they are oxidized. In addition, AMPK has been shown to increase glucose transport into the muscle. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating and/or suppressing insulin resistance Inventor(s): Deshaies, Yves; (Quebec, CA), Labrie, Fernand; (Quebec, CA), Marette, Andre; (Quebec, CA), Martel, Celine; (Quebec, CA), Richard, Denis; (Quebec, CA) Correspondence: Ostrolenk, Faber, Gerb & Soffen, Llp; 1180 Avenue OF The Americas; New York; NY; 10036-8403; US Patent Application Number: 20040034000 Date filed: March 10, 2003 Abstract: Novel methods for the medical treatment and/or prevention of obesity, abdominal fat, and insulin resistance in susceptible warm-blooded animals including humans involves the administration of selective estrogen receptor modulators (SERMs). A combination of a SERM with an amount of estrogen or a sex steroid precursor selected from the group consisting of dehydroepiandrosterone, dehydroepiandrosterone sulfate, androst-5-ene-3b,17b-diol and compounds converted in vivo to one of the foregoing precursors or estrogen is also disclosed. Excerpt(s): This is a continuing application claiming priority of U.S. patent application Ser. No. 09/610,286 filed Jul. 6, 2000, which, in turn, claims priority of U.S. Provisional Application No. 60/142,407, filed Jul. 6, 1999, in the name of Fernand LABRIE et al. and entitled "METHODS OF TREATING AND/OR SUPPRESSING WEIGHT GAIN". The present invention relates to a method for treating and/or preventing obesity (especially abdominal obesity), and to treating or suppressing the acquisition of abnormal insulin resistance, in susceptible warm-blooded animals including humans. The methods involve administering compounds of the general formula I below, or their pharmaceutical compositions. In other embodiments, the methods involve administering a selective estrogen receptor modulator ("SERM") in combination with a sex steroid precursor. Obesity, a condition characterized by excessive bodily fat, is a well known risk factor for many diseases such as cardiovascular diseases, hypertension,

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diabetes and breast cancer. Moreover, personal appearance plays an important part in the overall well-being of most people. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Methods of treating clinical diseases with isoflavones Inventor(s): Banz, William J.; (Creal Springs, IL), Peluso, Michael R.; (Makanda, IL), Shanahan, Michael F.; (Carbondale, IL), Winters, Todd A.; (Murphysboro, IL) Correspondence: Sterne, Kessler, Goldstein & Fox Pllc; 1100 New York Avenue, N.W.; Washington; DC; 20005; US Patent Application Number: 20030180404 Date filed: April 10, 2003 Abstract: The present invention provides a method of treating or preventing certain medical conditions with isoflavones. More specifically, the invention provides a method of treating or preventing one or more of the following medical conditions: hepatic steatosis, steatohepatitis, insulin resistance, impaired glucose tolerance, syndrome X, abnormal platelet function, or abnormal vascular reactivity, with compositions containing isoflavones. Excerpt(s): This application claims the benefit of the filing date of U.S. Provisional Application 60/130,156 filed Apr. 20, 1999. The contents of that application are incorporated herein by reference. The present invention relates, in general, to a method for treating or preventing certain medical clinical conditions with isoflavones. In particular, the present invention relates to a method of treating or preventing one or more of the following medical conditions: hepatic steatosis, steatohepatitis, insulin resistance, impaired glucose tolerance, syndrome X, abnormal platelet function, or abnormal vascular reactivity, with compositions containing isoflavones. Dietary soy protein has been shown to be hypocholesterolemic in human and animal studies (Carroll, K. K. and Kurowska, E. M., J. Nutr. 125:594S-597S (1995)). In humans, the cholesterol-lowering effect has been observed primarily in persons that are hypercholesterolemic prior to dietary intervention (Anderson, J. W., et al., N. Engl. J. Med. 333:276-282 (1995)). Soy protein diets have been particularly beneficial in the treatment of type II hyperlipoproteinernia (Sirtori, C. R., et al., Lancet 1:275-277 (1977); Sirtori, C. R., et al., J. Nutr. 125:598S-605S (1995)), which is characterized by elevated plasma LDL cholesterol (type IIa) or plasma LDL and VLDL cholesterol and triglyceride (type IIb). Hyperlipidemia is associated with the development of atherosclerosis, cardiovascular disease (CVD), and non-insulin dependent diabetes mellitus (NIDDM) (Despres, J.-P., et al., Arteriosclerosis 10:497-51 1 (1990)). Therefore, a hypocholesterolemic effect of soy protein can lower CVD and NIDDM risk. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Methods of treating insulin resistance syndrome and diabetes Inventor(s): Choi-Sledeski, Yong Mi; (Belle Mead, NJ), Ewing, William R.; (Yardley, PA), Herling, Andreas; (Bad Camberg, DE), Jaehne, Gerhard; (Frankfurt, DE), Maguire, Martin P.; (Cambridge, MA), Myers, Michael R.; (Fishers, IN), Pauls, Heinz W.; (Flemington, NJ), Spada, Alfred P.; (Carlsbad, CA) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20030176390 Date filed: May 14, 2002 Abstract: This invention is directed to methods of treating insulin resistance syndrome and diabetes in a patient in need thereof, comprising administering to said patient a pharmaceutically effective amount of a compound derived from adenosine and analogues thereof, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable prodrug thereof, an N-oxide thereof, a hydrate thereof or a solvate thereof, or a pharmaceutical composition comprising such compound. Excerpt(s): This application is entitled to the benefit of earlier filed application EP 01111651.4, filed May 14, 2001. This invention relates to the use of compounds derived from adenosine and analogues thereof according to the general formula (I) as insulin resistance agents. Adenosine has a wide variety of physiological and pharmacological actions including a marked alteration of cardiovascular and renal function. In animals and man, intravenous injection of the adenosine nucleotide causes hypotension. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Modified biological peptides with increased potency Inventor(s): Abribat, Thierry; (Montreal, CA), Gravel, Denis; (St-Lambert, CA), Habi, Abdelkrim; (Anjou, CA) Correspondence: David S Resnick; Nixon Peabody; 101 Federal Street; Boston; MA; 02110; US Patent Application Number: 20030204063 Date filed: March 3, 2003 Abstract: The present invention is concerned with modified biological peptides providing increased potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent, either at the N-terminal of the peptide, the Cterminal of the peptide, on a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. Those peptides exhibit clinical usefulness for example in treating states of insulin resistance associated with pathologies such as type II diabetes. Excerpt(s): The present invention is concerned with modified peptides providing increased biological potency, prolonged activity and/or increased half-life thereof. The modification is made via coupling through an amide bond with at least one conformationally rigid substituent either at the N-terminal of the peptide, the Cterminal of the peptide, or a free amino or carboxyl group along the peptide chain, or at a plurality of these sites. Most peptides are rapidly degraded in a serum medium and as a result, their metabolites may sometimes end up with little or no residual biological activity. To increase the activity of a peptide, various techniques have been proposed.

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One of them is to anchor a hydrophobic chain at the N- or C-terminal of the peptidic sequence or at other residues along the peptidic chain. This technique nevertheless has limitations. For example, if the peptide comprises a long peptidic chain, the fact that a small hydrophobic group is anchored to the N- or C-terminal does not necessarily result in an increased activity of the peptide so-modified. For example, it is known that substituting OH for a more hydrophobic group like --NEt.sub.2 at the C-terminal of a peptide sequence can result in a significantly increased specific activity. However, these results are contradicted by several publications, such as Muranichi et al. in Pharm. Res., 1991, 8, 649-652, which stresses the inefficiency of a lauroyl group as a hydrophobic group at the N-terminal to increase activity. Accordingly, there does not seem to be any general rule or conclusion concerning biological potency, duration of activity and/or half life, that can be derived as a result of the addition of substituents on a peptide chain, whether at the N- or C-terminal, or on certain residues along the peptidic chain. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Modulation of PTEN expression via oligomeric compounds Inventor(s): Baker, Brenda F.; (Carlsbad, CA), Bennett, C. Frank; (Carlsbad, CA), Monia, Brett P.; (Encinitas, CA), Vickers, Timothy; (Oceanside, CA) Correspondence: Cozen O'connor, P.C.; 1900 Market Street; Philadelphia; PA; 191033508; US Patent Application Number: 20040002153 Date filed: January 3, 2003 Abstract: Oligomeric compounds, compositions and methods are provided for modulating the expression of PTEN. The compositions comprise oligomeric compounds, particularly double stranded oligomeric compounds, targeted to nucleic acids encoding PTEN. Methods of using these compounds for modulation of PTEN expression and for treatment of diseases and conditions associated with expression of PTEN are provided. Such conditions include diabetes and hyperproliferative conditions. Methods for decreasing blood glucose levels, inhibiting PEPCK expression, decreasing blood insulin levels, decreasing insulin resistance, increasing insulin sensitivity, decreasing blood triglyceride levels or decreasing blood cholesterol levels in an animal, among others, using the compounds of the invention are also provided. The animal is preferably a human; also preferably the animal is a diabetic animal. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/878,582 filed Jun. 11, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/577,902 filed May 24, 2000, which is a continuation-in-part of PCT application PCT/US99/29594, filed Dec. 14, 1999, which is a continuation of U.S. patent application Ser. No. 09/358,381, filed Jul. 21, 1999, now issued as U.S. Pat. No. 6,020,199, the disclosures of which are hereby incorporated by reference in their entireties. This application also claims priority of U.S. application Ser. No. 60/411,780, filed Sep. 19, 2002, which is herein incorporated by reference in its entirety. The present invention provides compositions and methods for modulating the expression of PTEN. In particular, this invention relates to oligomeric compounds, particularly double stranded oligomeric compounds, hybridizable with nucleic acids encoding human PTEN. Such particularly double stranded oligomeric compounds have been shown to modulate the expression of PTEN. One of the principal mechanisms by which cellular regulation is effected is through the transduction of extracellular signals across the membrane that in turn modulate biochemical pathways within the cell. Protein phosphorylation

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represents one course by which intracellular signals are propagated from molecule to molecule resulting finally in a cellular response. These signal transduction cascades are tightly regulated and often overlap as evidenced by the existence of multiple protein kinase and phosphatase families and isoforms. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Novel heterocyclic analogs of diphenylethylene compounds Inventor(s): Dey, Debendranath; (Fremont, CA), Lee, Arthur; (San Francisco, CA), Medicherla, Satyanarayana; (Cupertino, CA), Nag, Bishwajit; (Union City, CA), Neogi, Partha; (Fremont, CA) Correspondence: Pillsbury Winthrop, Llp; P.O. Box 10500; Mclean; VA; 22102; US Patent Application Number: 20030181494 Date filed: October 8, 2002 Abstract: Novel diphenylethylene compounds and derivatives thereof containing thiazolidinedione or oxazolidinedione moieties are provided which are effective in lowering blood glucose level, serum insulin, triglyceride and free fatty acid levels in animal models of Type II diabetes. The compounds are disclosed as useful for a variety of treatments including the treatment of inflammation, inflammatory and immunological diseases, insulin resistance, hyperlipidemia, coronary artery disease, cancer and multiple sclerosis. Excerpt(s): This is a continuation-in-part of application Ser. No. 09/843,167, filed Apr. 27, 2001, which is a continuation-in-part of application Ser. No. 09/785,554, filed Feb. 20, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/591,105, filed on Jun. 9, 2000, which is a continuation-in-part of Ser. No. 09/287,237, filed on Apr. 6, 1999. The present application is directed to novel compounds formed by chemically coupling diphenylethylene compounds and derivatives thereof with thiazolidine or oxazolidine intermediates. These compounds are effective for providing a variety of useful pharmacological effects. For example, the compounds are useful in lowering blood glucose, serum insulin and triglyceride levels in animal models of type II diabetes. Furthermore, these compounds are useful for treatment of disorders associated with insulin resistance, such as polycystic ovary syndrome, as well as hyperlipidemia, coronary artery disease and peripheral vascular disease, and for the treatment of inflammation and immunological diseases, particularly those mediated by cytokines and cyclooxygenase such as TNF-alpha, IL-1, IL-6 and/or COX-2. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Novel mechanism for identifying drugs for the treatment of type II diabetes Inventor(s): Berggren, Per-Olof; (Solna, SE), Leibiger, Barbara; (Solna, SE), Leibiger, Ingo; (Solna, SE) Correspondence: Timothy A. French; Fish & Richardson P.C.; 225 Franklin Street; Boston; MA; 02110-2804; US Patent Application Number: 20030215804 Date filed: March 28, 2002

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Abstract: Insulin resistance is a central feature of type II diabetes and other diseases, and may affect every tissue of the body, including the pancreatic beta cell. Insulin signaling is mediated by a complex network of diverging and converging pathways, with alternative proteins and isoforms at almost every step in the process. We have previously shown that insulin activates the transcription of its own gene by signaling through Insulin Receptor A type (Ex11-), PI3 kinase and p70 s6 kinase. When studying the mechanisms underlying the glucose-stimulated activation of the glucokinase gene in pancreatic beta cells, we now demonstrate that also here secreted insulin is a key-factor. In contrast to the insulin gene, transcription of the glucokinase gene is promoted by signaling via Insulin Receptor B type (Ex11+) and protein kinase B (c-Akt). These data provide the first evidence for selectivity in insulin action via the two isoforms of the Insulin Receptor, A type (Ex11-) and B type (Ex11+), and reinforce the concept of the beta cell being an important target of insulin action. Excerpt(s): Understanding selectivity in signal transduction is one of the most challenging tasks in current cell biology. Over the years, insulin signaling has served as one of the model examples in hormone-induced signal transduction. Complete loss of either insulin or Insulin Receptors (IRs) is lethal. Malfunction of insulin signaling, referred to as insulin resistance, is one of the major causes of type II diabetes (type 2 diabetes mellitus, non-insulin-dependent diabetes mellitus, NIDDM), the most common metabolic disorder in man. Insulin has been shown to exhibit pielotropic effects, involving mitogenic and/or metabolic events. Moreover, the effect of insulin is tissue-as well as development-dependent. The fact that insulin may transduce its signal through a variety of pathways has been discussed in extensive detail (White and Kahn, 1994). The three major pathways described to date, which employ Insulin Receptors (IRs) as the primary target, include signaling via mitogen activated protein (MAP) kinases, phospholnositol-3 kinase (PI3K) and phospholipase C. The Insulin Receptor, the first step in these cascades, as a result of alternative mRNA spicing of the 11.sup.th exon of the (prepro)Insulin Receptor transcript, exists in two isoforms. The A type, or Ex11(Ullrich et al., 1985), lacks, whereas the B type, or Ex11+ (Ebina et al., 1985), contains the respective sequence coding for 12 amino acids in the C-terminus of the.alpha.-chain of the receptor. To date, no insulin-induced effect has been reported that discriminates signaling via A and B type receptors. In fact, the functional significance of these Insulin Receptor (IR) isoforms remains unclear (for a review see Flier et al 1996). Recent studies have shown that also the insulin-producing pancreatic beta cell is a target for insulin action, with insulin effects on transcription, translation, ion flux and exocytosis of insulin (Leibiger et al., 1998a; Kulkarni et al., 1999; Leibiger et al., 2000). In an animal model with a beta cell-specific knockout for Insulin Receptors, a decrease in glucose stimulated insulin release has been shown and a decrease in the insulin content of the cell (Kulkarni et al., 1999). In addition, disruption of insulin signaling in the beta cell at the level of Insulin Receptor substrate-1 or Insulin Receptor substrate-2 leads to altered growth and function of the beta cell. Consequently, insulin resistance, one of the major causes of type II diabetes may not only affect the function of the `classical` insulin target tissues; muscle, fat and liver, but also apply to the pancreatic beta cell and therefore may affect beta cell function. In the present application, for the first time, selective insulin signaling via the two isoforms of the Insulin Receptor (IR), i.e. IR-A and IR-B type, is shown in a pancreatic beta cell. It is demonstrated that insulin secreted by pancreatic beta cells, upon glucose stimulation, up-regulates insulin gene transcription in an autocrine feedback loop. This autoregulation is mediated by insulin signaling via the A type Insulin Receptor, involving phosphoinositol-3 kinase class Ia, p70s6 kinase and Ca.sup.2+/calmodulin dependent kinases. Stimulation with either glucose or insulin also leads to an up-regulated expression of the beta-cell transcription unit of the

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glucokinase gene (.beta.GK). However, in contrast to insulin-stimulated insulin gene transcription, the effect of insulin on beta cell glucokinase gene transcription occurs via the type B Insulin Receptor and protein kinase B (PKB/c-Akt) involving class II-like phospholnositol-3 kinase. The results described in the present application provide evidence that signaling via either A or B type Insulin Receptors represents a mechanism for selective insulin action. The surprising findings described herein provide the basic for a first IR-isoform-specific readout system. Thus, the pancreatic beta cell can henceforth serve as a screening tool for drugs and insulin mimetics, wherein IR-Aspecific signaling leads to insulin promoter activation and IR-B-specific signaling upregulates the.beta.GK promoter. In a screening system, measurement of either insulinand.beta.GK-mRNA levels or insulin- and.beta.GK-promoter-driven reporter gene expression can be employed as the actual readout tool. The IR-isoform-specific readout system comprised in the invention can further be used as a screening tool that will allow the development of compounds such as drugs and/or insulin mimetics, that selectively activate either IR-A or IR-B-specific signaling cascades, e.g. in the beta cell and in peripheral tissues. The pronounced expression of IR-B in the classical insulin target tissues implies the importance of the IR-B signaling cascade in these tissues. Consequently, the development of compounds that selectively stimulate the IR-B signaling cascade will improve the function of the beta cell (glucose responsiveness and therefore insulin secretion), as well as the function of the peripheral insulin target tissues (glucose uptake and utilization, protein synthesis, lipid synthesis) and thus potentially provide a treatment that covers the two major causes of non-insulindependent diabetes mellitus (NIDDM, type II diabetes), i.e. peripheral insulin resistance and beta cell dysfunction. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oil/fat composition Inventor(s): Hase, Tadashi; (Tochigi, JP), Katsuragi, Yoshihisa; (Tokyo, JP), Koike, Shin; (Tokyo, JP), Murase, Takatoshi; (Tochigi, JP), Takei, Akira; (Tokyo, JP), Yasumasu, Takeshi; (Tokyo, JP) Correspondence: Oblon, Spivak, Mcclelland, Maier & Neustadt, P.C.; 1940 Duke Street; Alexandria; VA; 22314; US Patent Application Number: 20030198727 Date filed: February 10, 2003 Abstract: Provided is an oil/fat composition comprising 10.1 to 94.9 wt. % of a triglyceride, 0.1 to 30 wt. % of a monoglyceride and 5 to 59.9 wt. % of a diglyceride which has, as a fatty acid constituent thereof, 15 to 90 wt. % of an.omega.3-unsaturated fatty acid having less than 20 carbon atoms. The oil/fat composition of the present invention has excellent heat stability, has body-fat-accumulation resisting action, visceral-fat-accumulation resisting action, blood-sugar-level lowering action, insulin resistance improving action and leptin lowering action and is useful for, as well as pharmaceuticals, preventive or remedial food for diabetes or obesity, and feed. Excerpt(s): The present invention relates to an oil/fat composition having a specific glyceride composition and a specific fatty acid composition, having excellent heat stability, having a body-fat-accumulation resisting action and a visceral-fataccumulation resisting action, and being extremely useful for health. Lipids (oils or fats), important nutrients in addition to proteins and carbohydrates, are particularly useful as an energy source. It however has a high calorie (9 kcal/g) and intake of it promotes obesity and can be causative of problems such as life-style related diseases. A meal rich

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in lipids are typically delicious and people of the present day are accustomed to such a meal. In advanced countries under satiation, an increase in lipidic intake has come to be a serious nation-wide problem together with a rise in medical expenses. In recent days, people are highly interested particularly in health promotion and maintenance and preventive treatment of diseases and a number of investigations have been made on the relationship between lipids and obesity or life-style related diseases. Primary investigations to date have been related to fatty acids constituting a triglyceride, a principal component of a lipid. Nutritionally essential fatty acids are, for example, linoleic acid, arachidonic acid and linolenic acid. These fatty acids are known to be utilized in the body as a constituent of a biomembrane or a raw material of eicosanoids (prostaglandin, thromboxanes, leukotrienes, etc.). In addition, it is reported that there is a high possibility of saturated fatty acids in a diet having a blood-serum cholesterol heightening action, leading to atherosclerosis or heart diseases (Lancet, 2, 959(1950)); and a high linoleic acid oil contained much in a diet increases tumor incidence and size of experimental animals (J. National Cancer Institute, 66, 517(1971)). It is described that an oleic-acid-rich and saturated-fatty-acid-poor diet lowers LDL-cholesterol level, while maintaining an HDL-cholesterol level, thereby reducing the risk of heart diseases (J. Lipid Res., 26, 194(1985), New England J. Medicine, 314, 745(1988)). In addition, physiological activities of various.omega.3-unsaturated fatty acids including antithrombus effects of eicosapentaenoic acid contained in a fish oil have drawn attention (Ann. Rev. Nutr., 8, 517(1988)). On the other hand, owing to many double bonds, eicosapentaenoic acid or docosahexaenoic acid involves a problem in stability against oxidation; and eicosapentaenoic acid has an anticoagulant action. Based on the study of intake balance of these fatty acids, a number of research reports have been presented, for example, on a recommendable ratio of saturated fatty acid:monounsaturated fatty acid:polyunsaturated fatty acid or a ratio of 6-unsaturated fatty acid:.omega.3-unsaturated fatty acid. Research is still in progress (Nutrition and Diseases of Oils and Fats", published by Saiwai Shobo, The 6.sup.th edition of Recommended Dietary Allowances for Japanese", Ministry of Health and Welfare). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Oxyiminoalkanoic acid derivatives Inventor(s): Imoto, Hiroshi; (Shiga, JP), Kimura, Hiroyuki; (Osaka, JP), Momose, Yu; (Hyogo, JP), Odaka, Hiroyuki; (Hyogo, JP), Sakamoto, Junichi; (Osaka, JP) Correspondence: Takeda Pharmaceuticals North America, Inc; Intellectual Property Department; 475 Half Day Road; Suite 500; Lincolnshire; IL; 60069; US Patent Application Number: 20030186985 Date filed: December 27, 2002 Abstract: To provide a novel oxyiminoalkanoic acid derivative which has excellent hypoglycemic and hypolipidemic actions and which is used for the prevention or treatment of diabetes mellitus, hyperlipemia, insulin insensitivity, insulin resistance and impaired glucose tolerance.A compound represented by the formula: 1wherein R.sup.1 is an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; X is a bond, --CO--, --CH(OH)-- or a group represented by -NR.sup.6-- wherein R.sup.6 is a hydrogen atom or an optionally substituted alkyl group; n is an integer of 1 to 3; Y is an oxygen atom, a sulfur atom, --SO--, --SO.sub.2-- or a group represented by --NR.sup.7-- wherein R.sup.7 is a hydrogen atom or an optionally alkyl group; ring A is a benzene ring optionally having additional one to three

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substituents; p is an integer of 1 to 8; R.sup.2 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic group; q is an integer of 0 to 6; m is 0 or 1; R.sup.3 is a hydroxy group, OR.sup.8 (R.sup.8 is an optionally substituted hydrocarbon group.) or NR.sup.9R.sup.10 (R.sup.9 and R.sup.10 are the same or different groups which are selected from a hydrogen atom, an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or an optionally substituted acyl group or R.sup.9 and R.sup.10 combine together to form a ring); R.sup.4 and R.sup.5 are the same or different groups which are selected from a hydrogen atom or an optionally substituted hydrocarbon group wherein R.sup.4 may form a ring with R.sup.2; provided that when R.sup.1 is a ethoxymethyl, a C.sub.1-3 alkyl, phenyl or p-methoxyphenyl and q=m=0, R.sup.3 is NR.sup.9R.sup.10; and provided that O-[2-chloro-4-(2-quinolylmethoxy)phenylmethyl]oxime and a methylpyruvate of [2-chloro-4-(2-quinolylmethoxy)phenylmethyl]-2-iminox- ypropionic acid are excluded; or a salt thereof. Excerpt(s): The present invention relates to novel oxyiminoalkanoic acid derivatives having hypoglycemic effect and hypolipidemic effect, a novel pharmaceutical composition and retinoid-related receptor function adjuster comprising an oxyiminoalkanoic acid. Such novel oxyiminoalkanoic acid derivatives, pharmaceutical compositions and retinoid-related receptor function adjusters are useful as an agent for prevention and/or treatment of diabetes mellitus, hyperlipemia, impaired glucose tolerance, an inflammatory disease, an arteriosclerosis and the like. Examples of known oxyiminoalkanoic acid derivatives are the intermediates used in the production of.beta.lactam compounds (Japanese Patent Application KOKAI No.49382/1983, 167576/1984, 77391/1987, 192387/1987, 47186/1991) and a compound having a leukotriene biosynthesis inhibiting effect (e.g., WO96/02507). However, these compounds have not been reported to have hypoglycemic, hypolipidemic effects and retinoid-related receptor function adjuster activity yet. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Pharmaceutical compositions comprising a modulator of adamts-1 Inventor(s): Brodin, Peter; (Molndal, SE), Thelin, Anders; (Molndal, SE) Correspondence: Ropes & Gray Llp; One International Place; Boston; MA; 02110-2624; US Patent Application Number: 20040014636 Date filed: February 21, 2003 Abstract: The present invention is based on the discovery that the metalloproteinase, ADAMTS-1 (A Disintegrin And Metalloproteinase), is associated with obesity, atherosclerosis, insulin resistance syndrome and non-insulin dependent diabetes. The application is directed to methods for screening for specidic modulators of ADAMS-1 activity, and the use of said modulators for treating the above-mentioned diseases. Excerpt(s): The present invention is based on the discovery that the metalloproteinase, ADAMTS-1 (A Disintegrin And Metalloproteinase), is associated with obesity, atherosclerosis, insulin resistance syndrome and non-insulin dependent diabetes. The ADAM (A Disintegrin And Metalloproteinase) family of metalloproteinases, containing 30 members to date, have been identified in organisms ranging from yeast to humans (Wolfsberg et al., 1998; Blobel, 1997; Tang, 2001). They have conserved domain structures. ADAMs have been implicated in diverse biological processes, such as

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shedding of cell surface molecules and adhesion to cells and matrix proteins. For example, ADAM 17 (TACE/TNF.alpha.-convertase) cleaves and releases the membrane bound form of TNF.alpha.; the Drosophila enzyme kuzbanian and its mammalian homologue (ADAM 10) have been shown to cleave the extracellular domain of the transmembrane receptor Notch. ADAMs 1 and 2 (fertilin.alpha. and.beta.) have been shown to be essential for sperm-egg fusion during fertilization. They have also been shown to be potential players in pathological events such as cancer metastasis and inflammation. Within the past 4 years, a new subset of ADAM-related proteins, known as ADAMTS (A Disintegrin-like And Metalloprotease with Thrombospondin type 1 motif), have been identified; there are about 10 known members to date, half of which have no known function. The ADAMTS' differ from the previously known ADAMs by the lack of the transmembrane domain and the presence of variable numbers of thrombospondin type I (ITSP-1) repeats. The fist member, ADAMTS-1, was cloned from a mouse cachexic colon subline and shown to be inducible by IL-1, suggesting a role as an inflammation associated gene (Juno et al., 1997). It was also found up-regulated in the kidney and heart by intravenous administration of lipopolysaccharide (LPS) in mice, again suggesting the gene may be induced during inflammatory responses (Kuno et al., 1997; 1998). The protein is secreted and binds to extracellular matrix and heparin through the thrombospondin and spacer domains (Kuno et al., 1999). Human ADAMTS1 was identified by a separate group searching for proteins containing the antiangiogenic type 1 repeats of thrombopsondin-1, which they called METH-1; the TSP-1 repeats were shown to be required for the potent anti-angiogenic properties observed (Vazquez et al., 1999). METH-1 has also been described in WO 99/37660 and WO 00/71577 (Irulea-Arispe et al). Phylogenetically, ADAMTS-1 has the most homology to ADAMTS-4 and ADAMTS-8. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

PIM-3 kinase as a target for type 2 diabetes mellitus Inventor(s): Korn, Marc; (Offenbach, DE), Mueller, Guenter; (Sulzbach, DE), Schneider, Rudolf; (Niedernhause, DE), Tschank, Georg; (Essenheim, DE) Correspondence: Ross J. Oehler; Aventis Pharmaceuticals INC.; Route 202-206; Mail Code: D303a; Bridgewater; NJ; 08807; US Patent Application Number: 20040038246 Date filed: January 21, 2003 Abstract: The invention relates to isolated nucleic acid molecules and to host cells comprising such nucleic acid molecules. Moreover, the invention relates to a polypeptide having PIM-3 activity and having a definite amino acid sequence, as well as to the use of PIM-3 as a screening agent for identifying anti-type 2 diabetes mellitus drugs and for preparing a medicament for the treatment of insulin resistance or type 2 diabetes mellitus. Excerpt(s): This application claims priority under 35 U.S.C. 119 from European Patent Application No. 02001401.4 filed Jan. 19, 2002 and U.S. Provisional Application No. 60/360,606 filed Mar. 1, 2002, both of which are hereby incorporated by reference in their entirety. The present invention relates to a novel use of PIM-3 kinase, to novel PIM3 kinase subtypes and the use thereof. The rat PIM-3 (originally termed KID-1, KID "kinase induced by depolarisation"), frog PIM-1, and human and murine PIM-1 are all known to have serine/threonine protein kinase activity in in vitro phosphorylation assays. The high polypeptide sequence similarity between human, murine and rat PIM-

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3, frog PIM-1, and human and murine PIM-1, demonstrates that human and murine PIM-3 are a serine/threonine protein kinase. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Prevention and treatment of nonalcoholic fatty liver disease (NAFLD) by antagonism of the receptor to glucose-dependent insulinotropic polypeptide (GIP) Inventor(s): Boylan, Michael O.; (Milton, MA), Wolfe, M. Michael; (Newton, MA) Correspondence: Edwards & Angell, Llp; P.O. Box 9169; Boston; MA; 02209; US Patent Application Number: 20040029805 Date filed: June 13, 2003 Abstract: The present invention concerns the use of various forms of GIP-receptor antagonists to attenuate the insulin response to GIP following meals in animals, such as humans, to prevent, reduce, inhibit and/or treat nonalcoholic fatty liver disease by virtue of its prevention and/or reversal of hyperinsulinemia and insulin resistance. Thus, the use of the GIP-receptor antagonists in any effective form is believed to prevent the development and reverse the process of NAFLD. The present invention is accomplished by administering an effective amount of an antagonistic agent, such as a GIP antagonist or an antisense molecule, to antagonize, block, inhibit or ablate the receptor to Glucose-Dependent Insulinotropic Polypeptide (GIP). Excerpt(s): This application for U.S. Patent relates and claims priority to U.S. provisional application Serial No. 60/389,320, filed Jun. 15, 2002, entitled Prevention and Treatment of Nonalcoholic Fatty Liver Disease (NAFLD) by Antagonism of the Receptor to Glucose-Dependent Insulinotropic polypeptide(GIP), and is incorporated herein by reference in its entirety. Nonalcoholic fatty liver disease (NAFLD) is a disorder with histologic features of alcohol-induced liver disease that occurs in people who do not consume significant amounts of alcohol. Several studies have suggested that this entity is uncommon and that it occurs most often in middle-aged, overweight females. Hyperglycemia with and without evidence of hyperlipidemia is commonly associated with NAFLD and is felt to be a predisposing condition. More recent reports have suggested that NAFLD may be more common than originally suspected and that it may affect individuals who lack the typical risk factors for this disorder. At the present time, the clinical implications of NAFLD have not been clearly defined, although progression to cirrhosis has been noted in many cases. Unfortunately, prior efforts to prevent or treat NAFLD have been limited by a poor understanding of the pathogenesis of this disorder. Recent studies have speculated that NAFLD may represent the end result of several diverse insults. These reports imply that the pathogenesis of NAFLD may be multifactorial and the mechanisms underlying this entity include an amino acid imbalance and endotoxemia associated with overwhelming infection or starvationassociated bacterial translocation. Most recently, studies have suggested that this entity may be due most commonly to hyperinsulinemia and insulin resistance. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Synergistic effect of a sulfonylurea and/or non-sulfonylurea Kchannel blocker, and a phosphodiesterase 3 type inhibitor Inventor(s): Fryburg, David A.; (East Lyme, CT), Parker, Janice C.; (Ledyard, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030216294 Date filed: June 5, 2003 Abstract: The present invention provides methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also provides kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. Excerpt(s): This application is filed claiming priority to U.S. Ser. No. 09/829,874, filed Apr. 10, 2001, now allowed, which claims priority to U.S. Provisional Application Serial No. 60/196,728, filed Apr. 13, 2000. The present invention relates to methods of treating non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance, the methods comprising the step of administering to a patient having or at risk of having non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance a synergistic amount of: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; and 2) a cAMP phosphodiesterase type 3 inhibitor. The present invention also relates to kits and pharmaceutical compositions that comprise: 1) a sulfonylurea, a non-sulfonylurea K.sup.+ ATP channel blocker, or a sulfonylurea and a non-sulfonylurea K.sup.+ ATP channel blocker; 2) a cAMP phosphodiesterase type 3 inhibitor; and 3) an additional compound useful for the treatment of non-insulin dependent diabetes mellitus, insulin resistance, Syndrome X, diabetic neuropathy,

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diabetic nephropathy, diabetic retinopathy, diabetic cardiomyopathy, polycystic ovary syndrome, cataracts, hyperglycemia, or impaired glucose tolerance. In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes can be improved. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of diabetes and diabetic complications with NHE-1 inhibitors Inventor(s): Tracey, W. Ross; (Niantic, CT), Treadway, Judith L.; (Mystic, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030212104 Date filed: May 1, 2003 Abstract: This invention relates to methods of treating or preventing type 2 diabetes, diabetic neuropathy, diabetic cardiomyopathy, cataracts, diabetic retinopathy, foot ulcers, diabetic microangiopathy, diabetic macroangiopathy, diabetic ischemia reperfusion injury, diabetic cardiac ischemia reperfusion injury and/or insulin resistance syndrome (IRS) in mammals, particularly in humans, by administering a sodium-hydrogen exchanger type 1 (NHE-1) inhibitor or a pharmaceutical composition containing such an inhibitor. This invention also relates to combinations comprising NHE-1 inhibitors and a second pharmaceutical agent, said combinations being useful in treating type 2 diabetes, IRS, diabetic neuropathy, diabetic cardiomyopathy, cataracts, diabetic retinopathy, foot ulcers, diabetic ischemia reperfusion injury, diabetic cardiac ischemia reperfusion injury, diabetic microangiopathy and/or diabetic macroangiopathy. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/380,028 filed May 2, 2002. (1) Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which arises when patients lack insulin-producing.beta.-cells in their pancreatic glands, and (2) Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with, inter alia, impaired.beta.-cell function. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Treatment of insulin resistance Inventor(s): Olefsky, Jerrold M.; (Solana Beach, CA), Pillay, Tahir S.; (San Diego, CA) Correspondence: Lisa A. Haile, J.D., PH.D.; Gray Cary Ware & Freidenrich Llp; Suite 1100; 4365 Executive Drive; San Diego; CA; 92121-2133; US Patent Application Number: 20030211540 Date filed: January 28, 2003 Abstract: Methods and compositions are provided for the treatment of insulin-resistance through the inhibition of protein kinase C-mediated phosphorylation of the amino acid residue Ser.sub.1270 of the insulin receptor. Methods for testing candidate compounds suitable for inhibition of serine-phosphorylation by protein kinase C are also provided.

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Excerpt(s): This invention relates to methods and compositions for the treatment of insulin resistance. Insulin resistance is associated with several disease conditions including non-insulin dependent diabestes mellitus (NIDDM), obesity, hypertension, and cardiovascular disease. The most well-studies of these conditions is NIDDM. NIDDM, also termed maturity-onset diabetes or type II diabetes to differentiate it from insulin-dependent diabetes mellitus (IDDM, also termed type I or juvenile diabetes), usually occurs in middle-aged obese people and accounts for 80% to 90% of diagnosed diabetes. In addition to insulin resistance, NIDDM is associated with normal to elevated levels of insulin, hyperglycemia, increased levels of very low density lipoproteins (VLDL), and decreased muscle uptake of glucose. NIDDM is often associated with hypertriglyceridemia. Ketoacidosis, characteristic of IDDM, is not associated with NIDDM except when the patient is subjected to extreme stress (e.g., septic shock or myocardial infarction). NIDDM patients tend to develop many of the same complications associated with IDDM including nerve, eye, kidney, and coronary artery disease. Mounting scientific evidence suggests that NIDDM results from a combination of two components: 1) a hereditary, genetic component (Rotter et al. In:: Rifkin et al., Diabetes Mellitus: Theory and Practice., New York, Elsevier, 1990, pp. 378413); and 2) an acquired component (Seely et al. In: Moller, Ed. Insulin Resistance and Its Clinical Disorders. England, John Wile & Sons, Ltd., 1993, pp. 187-252; Olefsky In: Efendic, et al. Eds. New Concepts in the Pathogenesis of NIDDM. New York, Plenum Publishing Corp., 1993; Olefsky, In: DeGroot, et al., Eds. DeGroot Textbook of Endocrinology., 3rd Ed., Philadelphia, W. B. Saunders and Co., 1994). The genetic component of NIDDM is responsible for the first stage of the disease, termed the "prediabetic" state. The prediabetic state is characterized by hyperinsulinemia and "primary" insulin resistance. Insulin responsiveness in the prediabetic state is sufficient to maintain normal glucose tolerance (NGT) or at least impaired glucose tolerance (IGT). Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of insulin resistance syndrome and type 2 diabetes with PDE9 inhibitors Inventor(s): Fryburg, David A.; (East Lyme, CT), Gibbs, Earl Michael; (Oakdale, CT) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20040023989 Date filed: October 29, 2002 Abstract: This invention is directed to a method of treating insulin resistance syndrome (IRS), hypertension and/or type 2 diabetes in a mammal comprising administering to said mammal a cGMP PDE9 inhibitor or a pharmaceutical composition thereof. This invention is also directed to such methods wherein said cGMP PDE9 inhibitor is used in combination with other agents to treat IRS, hypertension and/or type 2 diabetes. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/336,981 filed Oct. 2, 2001. This invention relates to the use of cGMP PDE9 inhibitors for the treatment of type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, type 1 diabetes and/or insulin resistance syndrome (IRS). This invention also relates to combinations comprising cGMP PDE9 inhibitors and other agents, said combinations being useful in treating type 2 diabetes, hyperglycemia, dyslipidemia, impaired glucose tolerance, type 1 diabetes and/or insulin resistance syndrome. IRS, as defined herein, means the concomitant existence in a subject of two or more of: hyperinsulinemia, dyslipidemia, hypertension, type 2 diabetes or impaired glucose tolerance, hyperuricemia or gout, a pro-coagulant state, atherosclerosis and/or truncal

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obesity. At the center of IRS, also known as "Syndrome X" and "Metabolic Syndrome" in the biomedical literature, is the common feature of tissue resistance to the action of insulin. This impaired biological response to insulin is manifested in the metabolic and vascular effects of insulin. Although there are monogenic syndromes of insulin resistance (IR), in which a definite gene has been identified as the cause of insulin resistance (such as leprechaunism), these are relatively rare. By contrast, the more common presentation of the IRS is associated with obesity (particularly abdominal) and appears to be polygenic. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Treatment of the insulin resistance syndrome Inventor(s): Fryburg, David Albert; (Groton, CT), Gibbs, Earl Michael; (Groton, CT), Koppiker, Nandan Parmanand; (Sandwich, GB) Correspondence: Pfizer INC.; Patent Department, Ms8260-1611; Eastern Point Road; Groton; CT; 06340; US Patent Application Number: 20030166662 Date filed: February 19, 2003 Abstract: Use of a selective cGMP PDE5 inhibitor or a pharmaceutical composition thereof in the preparation of a medicament for the curative, palliative or prophylactic treatment of the insulin resistance syndrome wherein the insulin resistance syndrome means the concomitant existence in a subject of two or more of dyslipidemia; hypertension; type 2 diabetes mellitus, impaired glucose tolerance (IGT) or a family history of diabetes; hyperuricaemia and/or gout; a pro-coagulant state; atherosclerosis; or truncal obesity wherein said use can occur alone or in combination with other agents to treat the insulin resistance syndrome or individual aspects of the insulin resistance syndrome. Excerpt(s): This invention relates to the use of selective cGMP PDE5 inhibitors and in particular to selective cGMP PDE5 inhibitor compounds such as the compound sildenafil for the treatment of the Insulin Resistance Syndrome. The Insulin Resistance Syndrome as defined herein means the concomitant existence in a subject of two or more of: dyslipidemia, hypertension, type 2 diabetes mellitus or impaired glucose tolerance (IGT) or a family history of type 2 diabetes mellitus, hyperuricaemia and/or gout, a pro-coagulant state, atherosclerosis, truncal obesity. A family history of type 2 diabetes mellitus as defined herein means having a first degree relation, sibling, parent or grandparent with type 2 diabetes mellitus. At the centre of the Insulin Resistance Syndrome, also known as "Syndrome X" and "Metabolic Syndrome" in the biomedical literature is the common feature of tissue resistance to the action of insulin. This impaired biological response to insulin can be manifested in both the metabolic and vascular effects of insulin. Although there are monogenic syndromes of insulin resistance (IR), in which a definite gene has been identified as the cause of insulin resistance (such as leprechaunism), these are relatively rare. By contrast, the more common presentation of the IRS is associated with obesity (particularly abdominal) and appears to be polygenic. 6. Atherosclerosis. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use Inventor(s): Wikstrom, Per; (Upplands Vasby, SE), Gronberg, Alvar; (Knivsta, SE) Correspondence: Fish & Richardson PC; 225 Franklin ST; Boston; MA; 02110; US Patent Application Number: 20030225117 Date filed: April 17, 2003 Abstract: The present invention relates to the use of NAD(P)H oxidase inhibitors to increase cellular uptake of glucose and in the treatment and/or prevention of diseases caused by insulin resistance or diseases related thereto, such as type II diabetes. Specifically, the invention relates to a method for identifying an agent useful for the treatment or prophylaxis of a medical condition associated with elevated levels of blood glucose, the method comprising (i) contacting a candidate agent with a mammalian NAD(P)H oxidase or NAD(P)H oxidase complex; and (ii) determining whether said candidate agent inhibits the biological activities of the NAD(P)H oxidase or NAD(P)H oxidase complex. Excerpt(s): This application claims priority from Swedish Patent Application No. 0201152-6, filed Apr. 17, 2002, and U.S. Provisional Patent Application Serial No. 60/410,626, filed Sep. 13, 2002. These applications are incorporated herein by reference in their entirety. The present invention relates to the use of NAD(P)H oxidase inhibitors to increase cellular uptake of glucose and in the treatment and/or prevention of diseases caused by insulin resistance or diseases related thereto, such as type II diabetes. A large number of people suffer, or are predisposed to suffer from disturbances in their metabolism. One such disturbance includes insulin resistance, which is characteristic of the metabolic syndrome (syndrome X), polycystic ovary syndrome, obesity and type II diabetes, diseases that are rapidly growing in number in the western world. These diseases are multi-factorial and their mechanism or physiology are, in the majority of cases, not well characterized or understood. Type II diabetes includes the most prevalent form of diabetes, which results from insulin resistance with an insulin secretory defect. Pharmacological treatments such as metformin and rosiglitazone have an ameliorating effect on insulin resistance and are believed to increase the effectiveness of endogenous insulin and thereby contribute to the lowering of elevated blood glucose levels in type II diabetes patients. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use for endothelin converting enzyme 2 (ECE-2) in the diagnosis and treatment of metabolic disorders Inventor(s): White, David; (Braintree, MA) Correspondence: Kerri Pollard Schray; Millennium Pharmaceuticals, INC.; 75 Sidney Street; Cambridge; MA; 02139; US Patent Application Number: 20030232044 Date filed: June 3, 2003 Abstract: The invention relates to methods and compositions for the diagnosis and treatment of metabolic disorders including, but not limited to, obesity, diabetes, overweight, insulin resistance, anorexia, and cachexia; and disorders of appetite regulation, including hyperphagia. The invention further provides methods for identifying a compound capable of treating a metabolic disorder or a disorder of

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appetite regulation. The invention also provides methods for identifying a compound capable of modulating a metabolic activity or regulation of appetite. Yet further, the invention provides methods for modulating a metabolic activity and methods for modulating appetite regulation. In addition, the invention provides methods for treating a subject having a metabolic disorder or a disorder of appetite regulation characterized by aberrant ECE-2 polypeptide activity or aberrant ECE-2 nucleic acid expression. Excerpt(s): This application claims the benefit of U.S. Provisional Application No. 60/386,333, filed Jun. 5, 2002, the contents of which are incorporated herein by this reference. Obesity represents the most prevalent of body weight disorders, affecting an estimated 30 to 50% of the middle-aged population in the western world. Other body weight disorders, such as anorexia nervosa and bulimia nervosa, which together affect approximately 0.2% of the female population of the western world, also pose serious health threats. Further, such disorders as anorexia and cachexia (wasting) are also prominent features of other diseases such as cancer, cystic fibrosis, and AIDS. Obesity, defined as a body mass index (BMI) of 30 kg/M.sup.2 or more, contributes to diseases such as coronary artery disease, hypertension, stroke, diabetes, hyperlipidemia and some cancers. (See, e.g., Nishina, P. M. et al. (1994), Metab. 43:554-558; Grundy, S. M. & Barnett, J. P. (1990), Dis. Mon. 36:641-731). Obesity is a complex multifactorial chronic disease that develops from an interaction of genotype and the environment and involves social, behavioral, cultural, physiological, metabolic and genetic factors. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives for treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia Inventor(s): Luo, Jian; (Brisbane, CA), Luskey, Kenneth L.; (Saratoga, CA) Correspondence: Townsend And Townsend And Crew, Llp; Two Embarcadero Center; Eighth Floor; San Francisco; CA; 94111-3834; US Patent Application Number: 20030220399 Date filed: March 4, 2003 Abstract: The present invention provides the use of (-) (3-trihalomethylphenoxy) (4halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. Excerpt(s): This application is a continuation-in-part of U.S. patent application Ser. No. 09/703,487 filed Oct. 31, 2000 which is a continuation of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999; this application is a continuation-in-part of U.S. patent application Ser. No. 09/585,907 filed on Jun. 2, 2000 which is a continuation-in-part of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999; this application is a continuation-in-part of U.S. patent application Ser. No. 09/724,788 filed Nov. 28, 2000 which is a continuation in part of U.S. patent application Ser. No. 09/585,907 filed on Jun. 2, 2000 which is a continuation-in-part of U.S. patent application Ser. No. 09/325,997 filed on Jun. 4, 1999. The contents of these priority applications are each herein individually incorporated by reference for all purposes. The present invention relates to the use of (-) (3-trihalomethylphenoxy) (4-halophenyl) acetic acid derivatives and compositions in the treatment of insulin resistance, Type 2 diabetes, hyperlipidemia and hyperuricemia. Diabetes mellitus, commonly called diabetes, refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose, referred to as hyperglycemia. See, e.g., LeRoith, D. et

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al., (eds.), DIABETES MELLITUS (Lippincott-Raven Publishers, Philadelphia, Pa. U.S.A. 1996), and all references cited therein. According to the American Diabetes Association, diabetes mellitus is estimated to affect approximately 6% of the world population. Uncontrolled hyperglycemia is associated with increased and premature mortality due to an increased risk for microvascular and macrovascular diseases, including nephropathy, neuropathy, retinopathy, hypertension, cerebrovascular disease and coronary heart disease. Therefore, control of glucose homeostasis is a critically important approach for the treatment of diabetes. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of amp kinase activators for treatment type 2 diabetes and insulin resistance Inventor(s): Winder, William W; (Provo, UT) Correspondence: Madson & Metcalf; Gateway Tower West; Suite 900; 15 West South Temple; Salt Lake City; UT; 84101 Patent Application Number: 20030212013 Date filed: December 3, 2002 Abstract: A method of treating type 2 diabetes in a mammal is provided. The method includes the step of administering a therapeutically effective amount of an AMPactivated protein kinase activator to the mammal. The mammal may be for example, a human, a rat, a mouse, and the like. The AMP-activated protein kinase activator can be subcutaneously injected into the mammal or administered in any other manner that provides for uptake of the AMP-activated protein kinase activator into the cells of the mammal. The activation of the AMP-activated protein kinase activator can produce the benefits of exercise training including the translocation of GLUT4 in the muscle cells of the mammal. A method of treating insulin resistance in a mammal is also provided. To treat the insulin resistance a therapeutically effective amount of an AMP-activated protein kinase activator is given to the mammal. Excerpt(s): This application is related to and claims the benefit of U.S. Provisional Application Serial No. 60/212,476 of William W. Winder filed Jun. 16, 2000 and entitled "Use of AMP Kinase Activators for Treatment of Type 2 Diabetes," which is incorporated herein by this reference. The present invention relates to the methods of treatment of type 2 diabetes and insulin resistance. More specifically, the invention relates to methods of treatment of type 2 diabetes and insulin resistance through artificial activation of AMP kinase. Type 2 diabetes is characterized by relative insensitivity to the actions of insulin on glucose uptake. American Diabetes Association: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes 1998; 21:S5-S19, 1998; Ferrannini, E Endocr Rev 19:477-490 (1997); Gerich, J E Endocr Rev 19:491-503 (1997). In the early stages of this disease, increased insulin secretion can compensate for the insensitivity, but in later stages, insulin deficiency can occur resulting in marked hyperglycemia. Patients with Type 2 diabetes also have dyslipidemia and increased hepatic glucose production. In order to understand the insulin-insensitivity, it is important to understand the basic mechanisms for glucose uptake into the muscle cell, since skeletal muscle represents a large proportion of the insulin-sensitive tissue in the body. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of cholinesterase antagonists to treat insulin resistance Inventor(s): Lautt, Wilfred Wayne; (Manitoba, CA) Correspondence: Merchant & Gould PC; P.O. Box 2903; Minneapolis; MN; 55402-0903; US Patent Application Number: 20030235609 Date filed: January 24, 2003 Abstract: There is provided a method of reducing insulin resistance in a mammalian subject comprising administering a suitable acetylcholine esterase antagonist Excerpt(s): This application claims priority of invention from U.S. patent application No. 60/350,958, filed Jan. 25, 2002. The invention relates to the field of treatments for insulin resistance. Insulin resistance is a significant health challenge for a wide range of patients, including those with type II diabetes, metabolic obesity, and various liver conditions. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

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Use of integrin-linked kinase inhibitors for treating insulin resistance, hyperglycemia and diabetes Inventor(s): Bhanot, Sanjay; (Carlsbad, CA) Correspondence: Jane Massey Licata; Licata & Tyrrell P.C.; 66 E. Main Street; Marlton; NJ; 08053; US Patent Application Number: 20040006005 Date filed: July 2, 2002 Abstract: The present invention features methods for treating conditions of insulin resistance, hyperglycemia and/or diabetes. In a broad embodiment, the methods comprise the step of administering to a mammal in need of treatment a therapeutically effective amount of an ILK inhibitor. ILK inhibitors in accordance with the present invention includes small molecules, antibodies, peptides, and antisense compounds. In one embodiment, antisense compounds in accordance with the present invention comprise antisense oligomers. Excerpt(s): Insulin resistance is a metabolic abnormality that may lead to impaired glucose tolerance and diabetes mellitus. Cellular manifestations of insulin resistance include impaired insulin-stimulated glucose uptake by peripheral tissues and impaired glucose disposal. In the liver, there is increased conversion of substrates to glucose in the presence of insulin. This hepatic insulin resistance is associated with decreased activity of glucokinase, and increased activity of gluconeogenic enzymes. Many patients have insulin resistance and impaired glucose tolerance for several years before progressing to diabetes mellitus. Diabetes mellitus is a syndrome characterized by abnormal insulin secretion associated with hyperglycemia and decreased glucose tolerance. A National Diabetes Data Group (NDDG) of the National Institutes of Health distinguishes several subclasses of diabetes. These include insulin-dependent diabetes mellitus (Type I), a ketosis-prone type of diabetes associated with histocompatibility antigens on chromosome 6 and with islet cell antibodies, and non-insulin-dependent diabetes mellitus (Type II), a non-ketosis-prone type of diabetes not secondary to other diseases or conditions. Type II diabetes is characterized by tissue insensitivity or resistance to insulin and impaired pancreatic B cell response to glucose. (Karam, J. H., in Basic

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Clinical Pharmacology, 5th Ed., B. G. Katzung, ed, Appleton & Lange, Norwalk, Conn., 1992, pp. 586-601). Current therapy for treatment of insulin resistance is injection of high doses of insulin to provide greater availability to insulin receptors in the tissues. Very high doses of insulin may ultimately be required, and the resulting high circulating levels of insulin cause some of the side effects such as diabetic nephropathy. This "therapy" may in fact worsen the disease. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html •

Use of leptin antagonists for the treatment of diabetes Inventor(s): Cawthorne, Michael; (Horsham, GB), Emilsson, Valur; (Kopavogur, IS), Liu, Yong-Ling; (Great Bookham, GB) Correspondence: Glaxosmithkline; Corporate Intellectual Property - Uw2220; P.O. Box 1539; King OF Prussia; PA; 19406-0939; US Patent Application Number: 20040048773 Date filed: October 17, 2002 Abstract: The use of an antagonist of leptin for the manufacture of a medicament for the treamtne tof disorders resulting from deficiencies in insulin secretion, hyperglycaemia and insulin resistance. Excerpt(s): The invention relates to a novel use, in particular a use for the treatment of diabetes and complications thereof. Non-insulin-dependent diabetes (NIDDM) is known to be caused by insulin resistance (particularly in skeletal muscle, adipose tissue and liver) and an inadequate insulin secretion from the beta-cells of the Islets of Langerhans in the pancreas. Thus, despite hyperinsulinaemia there is insufficient insulin to compensate for the insulin resistance and to maintain blood glucose in the desirable range. Pelleymounter et al (Science, 1995, 269, 540-543) have reported that the ob polypeptide or "leptin" lowers both plasma insulin and glucose levels in the genetically obese ob/ob mouse. Web site: http://appft1.uspto.gov/netahtml/PTO/search-bool.html

Keeping Current In order to stay informed about patents and patent applications dealing with insulin resistance, you can access the U.S. Patent Office archive via the Internet at the following Web address: http://www.uspto.gov/patft/index.html. You will see two broad options: (1) Issued Patent, and (2) Published Applications. To see a list of issued patents, perform the following steps: Under “Issued Patents,” click “Quick Search.” Then, type “insulin resistance” (or synonyms) into the “Term 1” box. After clicking on the search button, scroll down to see the various patents which have been granted to date on insulin resistance. You can also use this procedure to view pending patent applications concerning insulin resistance. Simply go back to http://www.uspto.gov/patft/index.html. Select “Quick Search” under “Published Applications.” Then proceed with the steps listed above.

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CHAPTER 6. BOOKS ON INSULIN RESISTANCE Overview This chapter provides bibliographic book references relating to insulin resistance. In addition to online booksellers such as www.amazon.com and www.bn.com, excellent sources for book titles on insulin resistance include the Combined Health Information Database and the National Library of Medicine. Your local medical library also may have these titles available for loan.

Book Summaries: Federal Agencies The Combined Health Information Database collects various book abstracts from a variety of healthcare institutions and federal agencies. To access these summaries, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. You will need to use the “Detailed Search” option. To find book summaries, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer. For the format option, select “Monograph/Book.” Now type “insulin resistance” (or synonyms) into the “For these words:” box. You should check back periodically with this database which is updated every three months. The following is a typical result when searching for books on insulin resistance: •

Insulin Resistance Source: Malden, MA: Blackwell Science, Inc. 2002. 190 p. Contact: Available from Blackwell Science, Inc. 350 Main Street, Commerce Place, Malden, MA 02148. (800) 215-1000 or (617) 388-8250. Fax (617) 388-8270. E-mail: [email protected]. Website: www.blackwell-science.com. PRICE: $49.95. ISBN: 0632056622. Summary: Insulin resistance, defined as a reduced biological action of insulin, has emerged as a major factor in the development and progression of a number of common noncommunicable diseases in humans. The role of insulin resistance in the etiology of type 2 diabetes is particularly well established. However, insulin resistance has also come to be regarded as a key component of a broader syndrome of common metabolic defects that conspire to increase the risk of atherosclerotic coronary heart disease. This

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book summarizes the current state of knowledge about insulin resistance, a condition that embraces many different medical specialties. Three sections cover the pathophysiology of insulin resistance, insulin resistance in clinical medicine, and the management of insulin resistance and associated conditions. Key points are highlighted in the margins of the text and chapters include tables and illustrations; reference lists are provided at the end of each major section. A subject index concludes the handbook. •

Insulin Resistance: The Metabolic Syndrome X Source: Totowa, NJ: Humana Press, Inc. 1999. 384 p. Contact: Available from Humana Press, Inc. Customer Service, 999 Riverview Drive, Suite 208, Totowa, NJ 07512. (973) 256-1699. Fax (973) 256-8341. E-mail: [email protected]. PRICE: $145.00 plus shipping and handling. ISBN: 0896035883. Summary: This book summarizes the current understanding of how insulin resistance and its compensating hyperinsulinemia play a role in the pathogenesis and clinical course of high blood pressure, cardiovascular disease, and polycystic ovary disease. Part one focuses on genetic and lifestyle factors that contribute to the differences in insulin action that exist in the population at large. Topics include the genetic determinants of insulin resistance, ethnic variation in insulin resistance and risk of type 2 diabetes, fetal effects on insulin resistance and glucose tolerance, obesity and insulin resistance, the role of body fat distribution in insulin resistance, physical activity and insulin resistance in humans, and insulin resistance in smokers and other long-term users of nicotine. Part two focuses on the pathophysiologic consequences of insulin resistance and the efforts made to compensate for this defect to prevent decompensation of glucose homeostasis. Topics include insulin resistance and inhibitors of insulin receptor tyrosine kinase, nuclear magnetic resonance studies on the mechanism of insulin resistance, skeletal muscle insulin resistance in humans, the role of the liver in insulin action and resistance, the pathophysiological consequences of adipose tissue insulin resistance, and insulin action and endothelial function. Part three considers the clinical syndromes excluding type 2 diabetes, that are related to insulin resistance. Topics include the implications of insulin resistance and dyslipidemia for coronary heart disease risk; insulin resistance and blood pressure; microalbuminuria and insulin resistance; plasminogen activation inhibitor, obesity, and insulin resistance; insulin resistance and cardiovascular disease; and insulin resistance effects on sex hormones and ovulation in the polycystic ovary syndrome. Numerous figures. 31 tables. Numerous references.

Book Summaries: Online Booksellers Commercial Internet-based booksellers, such as Amazon.com and Barnes&Noble.com, offer summaries which have been supplied by each title’s publisher. Some summaries also include customer reviews. Your local bookseller may have access to in-house and commercial databases that index all published books (e.g. Books in Print). IMPORTANT NOTE: Online booksellers typically produce search results for medical and non-medical books. When searching for “insulin resistance” at online booksellers’ Web sites, you may discover non-medical books that use the generic term “insulin resistance” (or a synonym) in their titles. The following is indicative of the results you might find when searching for “insulin resistance” (sorted alphabetically by title; follow the hyperlink to view more details at Amazon.com):

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Blood Sugar Blues : Overcoming the Hidden Dangers of Insulin Resistance by Miryam Ehrlich Williamson, R. Paul St. Amand M.D. (2001); ISBN: 0802776108; http://www.amazon.com/exec/obidos/ASIN/0802776108/icongroupinterna

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Clinician's Manual on Insulin Resistance: The Dysmetabolic Syndrome by H. E. Lebovitz (2002); ISBN: 1858739373; http://www.amazon.com/exec/obidos/ASIN/1858739373/icongroupinterna

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Insulin Resistance : Insulin Action and its Disturbances in Disease by Sudhesh Kumar (Editor), Steven O'Rahilly (Editor); ISBN: 0470850086; http://www.amazon.com/exec/obidos/ASIN/0470850086/icongroupinterna

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Insulin Resistance and Cardiovascular Disease by S. O'Rahilly (1999); ISBN: 1901978095; http://www.amazon.com/exec/obidos/ASIN/1901978095/icongroupinterna

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Insulin Resistance and Insulin Resistance Syndrome by Eleazar Shafrir (Editor), et al; ISBN: 0415291976; http://www.amazon.com/exec/obidos/ASIN/0415291976/icongroupinterna

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Insulin Resistance in Human Disease: Proceedings of the 7th Korea-Japan Symposium on Diabetes Mellitus, Seoul, Korea, 13-14 April 1993 (Internationa) by Kap Bum Huh, et al; ISBN: 0444816046; http://www.amazon.com/exec/obidos/ASIN/0444816046/icongroupinterna

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Insulin Resistance, Metabolic Diseases and Diabetic Complications by Gaetano Crepaldi (Editor), et al; ISBN: 0444500227; http://www.amazon.com/exec/obidos/ASIN/0444500227/icongroupinterna

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Insulin Resistance: the Metabolic Syndrome X by Gerald M. Reaven (Editor), Ami Laws (Editor); ISBN: 0896035883; http://www.amazon.com/exec/obidos/ASIN/0896035883/icongroupinterna

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Insulin Resistance by Andrew J. Krentz; ISBN: 0632056622; http://www.amazon.com/exec/obidos/ASIN/0632056622/icongroupinterna

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Insulin Resistance by David E. Moller (Editor); ISBN: 0471939773; http://www.amazon.com/exec/obidos/ASIN/0471939773/icongroupinterna

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Lipids and Insulin Resistance: The Role of Fatty Acid Metabolism and Fuel Partitioning (Annals of the New York Academy of Sciences, Vol 967) by International Smolenice Insulin Symposium on "Lipids and Insulin Resis, et al (2002); ISBN: 1573313688; http://www.amazon.com/exec/obidos/ASIN/1573313688/icongroupinterna

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Lipids and Syndromes of Insulin Resistance: From Molecular Biology to Clinical Medicine (Annals of the New York Academy Ofsciences, Vol. 827) by I. Klimes (Editor), et al (1997); ISBN: 1573310700; http://www.amazon.com/exec/obidos/ASIN/1573310700/icongroupinterna

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Magnesium and the Insulin Resistance Syndrome (Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, 1088) by Arvo Hanni (2001); ISBN: 915545142X; http://www.amazon.com/exec/obidos/ASIN/915545142X/icongroupinterna

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Muscle Morphology & the Insulin Resistance Syndrome: A Population-Based Study of 70 Year-Old Men in Uppsala by Anu Hedman (2001); ISBN: 9155450830; http://www.amazon.com/exec/obidos/ASIN/9155450830/icongroupinterna

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Plasminogen Activator Inhibitor-1 & the Insulin Resistance Syndrome (Comprehensive Summaries of Uppsala Dissertations from the Faculty of mediciNe, 1150) by Liisa Byberg (2002); ISBN: 9155453074; http://www.amazon.com/exec/obidos/ASIN/9155453074/icongroupinterna

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Syndrome X : Managing Insulin Resistance by Deborah S. Romaine (Author), et al (2000); ISBN: 0380814447; http://www.amazon.com/exec/obidos/ASIN/0380814447/icongroupinterna

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Syndrome X: The Complete Nutritional Program to Prevent and Reverse Insulin Resistance by Jack Challem (Author), et al (2000); ISBN: 0471358355; http://www.amazon.com/exec/obidos/ASIN/0471358355/icongroupinterna

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The Metabolic Syndrome X: Convergence of Insulin Resistance, Glucose Intolerance, Hypertension, Obesity, and Dyslipidemias-Searching for the Underlying Defeats (Annals of the New York Academy of Sciences (Cloth), Vol 892) by Barbara Caleen Hansen (Editor), et al; ISBN: 157331207X; http://www.amazon.com/exec/obidos/ASIN/157331207X/icongroupinterna

Chapters on Insulin Resistance In order to find chapters that specifically relate to insulin resistance, an excellent source of abstracts is the Combined Health Information Database. You will need to limit your search to book chapters and insulin resistance using the “Detailed Search” option. Go to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find book chapters, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Book Chapter.” Type “insulin resistance” (or synonyms) into the “For these words:” box. The following is a typical result when searching for book chapters on insulin resistance: •

Insulin Resistance and Hypertension Source: in Schrier, R.W. and Wilcox, C.S., eds. Atlas of Diseases of the Kidney. Volume 3: Hypertension and the Kidney. Philadelphia, PA: Current Medicine, Inc. 1999. p. 5.1-5.10. Contact: Available from Blackwell Science, Inc. 350 Main Street, Malden, MA 02148. (800) 215-1000 or (781) 388-8250. Fax (781) 388-8270. E-mail: [email protected]. PRICE: $75.00 plus shipping and handling. ISBN: 063204389X. Summary: This chapter uses a series of figures to discuss insulin resistance and hypertension. Insulin resistance is associated with increased risk of cardiovascular disease, and it may be the link between hypertension and dyslipidemia. Data show that approximately 25 percent to 40 percent of nonobese, nondiabetic patients who have hypertension are insulin resistant. Researchers have also observed insulin resistance in genetic and acquired animal models of hypertension. A syndrome, termed syndrome X, includes a constellation of insulin resistance, decreased high density lipoprotein cholesterol, and hypertension. Although various causes have been proposed, it is unclear whether insulin resistance or reactive hyperinsulinemia, or both, actually cause hypertension. Recent findings that insulin sensitizing agents attenuate the development of hypertension provide support for this hypothesis. However, these agents may lower blood pressure by different mechanisms. Type 2 diabetes represents an extreme of insulin resistance. The prevalence of hypertension increases twofold to threefold among people who have diabetes. Hypertension is associated with a fourfold increase in mortality among patients who have type 2 diabetes, and antihypertensive drug therapy

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has a beneficial effect on both macrovascular and microvascular disease. Although there is some concern that diuretics may augment insulin resistance, people who have diabetes benefit from antihypertensive therapy with diuretics. Different antihypertensive drugs have different renal protective effects. Angiotensin converting enzyme inhibitors decrease proteinuria and retard the progression of renal insufficiency in people who have diabetes but normal blood pressure and hypertension. Findings from studies evaluating the effects of calcium antagonists on the progression of diabetic nephropathy are varied. Additional studies are needed to evaluate the antihypertensive potential of insulin sensitizing agents in people who have type 2 diabetes. 31 figures. 19 references. •

Regional Body Fat Distribution, the Insulin Resistance-Dyslipidemic Syndrome, and the Risk of Type 2 Diabetes and Coronary Heart Disease Source: in Devlin, J.T. and Schneider, S.H., eds. Handbook of Exercise in Diabetes. Alexandria, VA: American Diabetes Association. 2002. p. 197-234. Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $69.95 plus shipping and handling. ISBN: 1580400191. Summary: Visceral adipose tissue accumulation is an important factor to consider in the evaluation of health risks associated with obesity. This chapter is from a book that provides a practical, comprehensive guide to diabetes and exercise for health care professionals involved in patient care. In this chapter, the authors consider regional body fat distribution, the insulin resistance-dyslipidemic syndrome, and the risk of type 2 diabetes and coronary heart disease. The simultaneous presence of hyperinsulinemia, hyperapolipoprotein B, and small, dense LDL particles is associated with a 20 fold increase in the risk of ischemic heart disease. A simple and inexpensive screening test to identify a high risk form of abdominal obesity is to determine if the patient has the following: a waist circumference greater than 90 centimeters and triglyceride levels greater than 2.0 mmol per liter. Improvements in the metabolic risk profile resulting from endurance exercise training are more related to the volume of exercise than to its intensity. The authors conclude that from a public health standpoint, the greatest benefit would be to transform the largely sedentary population into moderately active individuals. Physicians and health professionals should keep in mind that the changes in lifestyle associated with the best compliance are those that are likely to have the greatest long term impact on cardiovascular health. 8 figures. 3 tables. 148 references.

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CHAPTER 7. MULTIMEDIA ON INSULIN RESISTANCE Overview In this chapter, we show you how to keep current on multimedia sources of information on insulin resistance. We start with sources that have been summarized by federal agencies, and then show you how to find bibliographic information catalogued by the National Library of Medicine.

Video Recordings An excellent source of multimedia information on insulin resistance is the Combined Health Information Database. You will need to limit your search to “Videorecording” and “insulin resistance” using the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find video productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Videorecording (videotape, videocassette, etc.).” Type “insulin resistance” (or synonyms) into the “For these words:” box. The following is a typical result when searching for video recordings on insulin resistance: •

Managing Diabetes in the Primary Care Setting: A Team Approach Source: Secaucus, NJ: Network for Continuing Medical Education. 1997. (videocassette). Contact: Available from Network for Continuing Medical Education. 1425 Broad Street, Clifton, NJ 07013. (800) 223-0272 or (973) 473-9500. Fax (973) 591-1224. PRICE: Call for pricing information. Order number 726. Summary: In this telecourse video, Dr. Bruce A. Ellsweig addresses current issues in diagnosis, tight glucose control, lifestyle modification, and pharmacologic therapy to illustrate the primary care physician's role in the team approach to managing diabetes. Dr. Ellsweig refers to diabetes as a group of disorders characterized by an impaired ability to manage glucose in the body. Specific topics include the fasting plasma glucose test, the revised diabetes nomenclature, American Diabetes Association testing recommendations, oral agents and insulin, HbA1c, the Diabetes Control and Complications Trial (DCCT), patient compliance, patient referral, and diabetic emergencies. The video emphasizes the role of a team approach to diabetes

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management. Three case presentations address the importance of patient compliance. After completing this telecourse, participating physicians should be able to identify patients at risk for developing type 2 diabetes, explain insulin resistance and its consequences, describe the utility of 'tight control' in managing diabetes, describe the roles of various team members in diabetes management, and list the therapeutic options for diabetes management. A post-telecourse quiz concludes the video. (AA-M). •

Diabetes Management: A Clinical Update Source: Secaucus, NJ: Network for Continuing Medical Education. 1994. (videocassette). Contact: Available from Network for Continuing Medical Education. 1425 Broad Street, Clifton, NJ 07013. (800) 223-0272 or (973) 473-9500. Fax (973) 591-1224. PRICE: Call for pricing information. Order number 667. Summary: In this video, Dr. F. Xavier Pi-Sunyer provides suggestions for implementing updated American Diabetes Association (ADA) nutritional recommendations and the results of the Diabetes Control and Complications Trial (DCCT) into daily practice. Six sections address management issues, ADA nutrition recommendations, DCCT results, patient compliance, and complications management. Because it is now known that diabetes predisposes a person to coronary heart disease, health care professionals must be concerned with blood lipids and hypertension, as well as blood glucose control. According to the ADA, the goals of medical nutrition therapy include maintaining nearnormal blood glucose, achieving optimum lipids, maintaining reasonable body weight, preventing and treating complications, and improving overall health. Dr. Pi-Sunyer notes that therapy should be individualized according to the patient's insulin resistance, activity levels, body weight, and body fat distribution. Primary care physicians should have some knowledge of diet therapy and the benefits of exercise; they should not simply resort to oral agents and insulin. The video notes that referring patients to a registered dietitian is sometimes advantageous. After completing this telecourse, physicians should be able to apply the updated ADA dietary recommendations, list management goals for people with type 1 and type 2 diabetes, describe the DCCT results, and list the benefits of self monitoring blood glucose. Viewers should consult their Network for Continuing Medical Education program guides for credit information, learning objectives, and instructions for completing the telecourse. (AA-M).

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In the Practice of Medicine, Which Lipids Should Be Measured and When? Source: Atlanta, GA: Emory University Office of Medical Television. 1996. (videocassette). Contact: Available from Robert W. Woodruff Health Sciences Center, Emory University. Office of Medical Television, 1364 Clifton Road, Box M-16, Atlanta, GA 30322. (404) 7279797. Fax (404) 727-9798. PRICE: $75.00. Also available for rental; contact producer for current fee. Item number 96-4. Summary: In this videotape program, Dr. Virgil Brown reviews the most recent recommendations for the diagnosis and management of dyslipidemias. These include placing more emphasis on low levels of LDL and its impact on drug choice, and the importance of weight loss and physical activity as components of dietary therapy. After discussing risk factors for coronary artery disease (CAD), he stratifies therapeutic targets for LDL cholesterol lowering according to the presence of established CAD (secondary prophylaxis) and risk factors. Dr. Brown then discusses the steps to be taken in the evaluation of dyslipidemic patients, including the exclusion of secondary causes. The

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insulin resistance syndrome and familial dyslipidemic hypertension are also discussed. He concludes by commenting on when family members of a dyslipidemic patient should be evaluated. (AA-M). •

Strategies for the Prevention and Treatment of Macrovascular Complications of Type 2 Diabetes Source: Kansas City, MO: American Academy of Family Physicians. 1998. (videocassette). Contact: Available from American Academy of Family Physicians. 8880 Ward Parkway, Kansas City, MO 64114-2797. (800) 274-2237. PRICE: $17.95 for members; $25.00 for nonmembers, plus shipping and handling. Summary: The macrovascular (large blood vessel) complications of diabetes account for the majority of the morbidity (related illness) and mortality (death) associated with the disease. In particular, people with type 2 diabetes are at increased risk for cardiovascular disease, since they exhibit many independent risk factors for heart disease, including obesity, hypertension (high blood pressure), and dyslipidemia (disordered levels of fats in the blood). This continuing education program features a videocassette and study guide that discuss why people with diabetes are at increased risk for macrovascular complications and how to reduce the patient's risk of cardiovascular disease. Topics include hyperglycemia (high blood glucose levels) and cardiovascular disease, insulin resistance and cardiovascular disease, the benefits of improved glycemic control, recommended target glycemic goals, nonpharmacologic therapies for diabetes (diet, exercise, patient education), pharmacologic (drug) therapies for diabetes (insulin secretagogues, insulin sensitizers, alpha-glucosidase inhibitors, and insulin), determining the optimal drug treatment regimen for individual patients, and treating cardiovascular risk factors. The program recommends that patients should be seen quarterly or more often, depending upon the severity of their disease, and target goals for HbA1c (glycosylated hemoglobin, a measurement of blood glucose levels over time) and fasting blood glucose should be established at the initial visit and discussed directly with the patient. Patients should be reminded at every office visit that weight loss and regular exercise are the most important aspects of controlling their diabetes and reducing the risk of macrovascular disease. A sample patient education hand out is included in the study guide. Through this program, users can qualify for one credit hour of Continuing Medical Education (CME) in category 1; the appropriate posttest is provided. 5 figures. 14 tables. 15 references.

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Diabetes and Weight Control: Change for a Lifetime Source: Timonium, MD: Milner-Fenwick, Inc. 200x. (videocassette). Contact: Available from Milner-Fenwick, Inc. 2125 Greenspring Drive, Timonium, MD 21093-3100. (800) 432-8433. Fax (410) 252-6316. Website: www.milner-fenwick.com. PRICE: First 15 days free of charge to healthcare professionals; plus shipping and handling. Order number: DB-35. Summary: This video examines the relationship between excess weight, lack of activity, and the development of the insulin resistance characteristic of type 2 diabetes. Weight loss can reduce the risk of diabetic complications and heart disease, and reduce or eliminate the need for medication. Topics related to the issue of long-term weight control include limiting fat and total calories, controlling portion size, eating a variety of foods, spreading food intake throughout the day, and exercising. Patient interviews are

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used to explore the psychosocial issues associated with weight control. The video also includes weight loss tips and learning tools such as a food diary.

Audio Recordings The Combined Health Information Database contains abstracts on audio productions. To search CHID, go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. To find audio productions, use the drop boxes at the bottom of the search page where “You may refine your search by.” Select the dates and language you prefer, and the format option “Sound Recordings.” Type “insulin resistance” (or synonyms) into the “For these words:” box. The following is a typical result when searching for sound recordings on insulin resistance: •

Effective Drug Therapy for Diabetes Mellitus Source: Alexandria, VA: American Diabetes Association. 1998. (audiocassette). Contact: Available from American Diabetes Association (ADA). Order Fulfillment Department, P.O. Box 930850, Atlanta, GA 31193-0850. (800) 232-6733. Fax (770) 4429742. Website: www.diabetes.org. PRICE: $17.95 for members; $22.95 for nonmembers; plus shipping and handling. ISBN: 1580400213. Summary: These audiocassettes provide information on effective drug therapy for diabetes mellitus. They feature articles first published in 'Clinical Diabetes.' An article on the use of metformin to treat diabetes provides an overview of this agent. Another article describes the use of acarbose to inhibit alpha-glucosidase. This agent decreases postprandial hyperglycemia by delaying carbohydrate digestion and absorption. A third article focuses on the use of lispro insulin, a rapid acting synthetic analog, to treat diabetes. Topics include the molecular structure of lispro insulin, immunologic concerns, and clinical applications and concerns. Another article deals with the use of troglitazone, a thiazolidinedione that improves insulin resistance without stimulating insulin secretion, to treat diabetes and the insulin resistance syndrome. Topics include the pathophysiology of impaired glucose tolerance and type 2 diabetes, the pathophysiological basis of pharmacological therapy, clinical studies, the effects of troglitazone on body weight and lipids, and the safety and adverse effects of the agent. An article on the use of combination oral agent and insulin therapy in patients who have type 2 diabetes includes discussions of the rationale for the use of combination therapy and the mechanism of action, efficacy, and side effects of various oral agents combined with insulin. The final article focuses on converting patients who have type 2 diabetes from insulin-requiring to noninsulin-requiring. Topics include the disadvantages of insulin utilization in people who have type 2 diabetes, once daily insulin and combination oral therapy, improved glycemic control on oral therapy, weight loss on combination oral therapy, oral monotherapy, and other potential drug combinations.

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CHAPTER 8. PERIODICALS AND NEWS ON INSULIN RESISTANCE Overview In this chapter, we suggest a number of news sources and present various periodicals that cover insulin resistance.

News Services and Press Releases One of the simplest ways of tracking press releases on insulin resistance is to search the news wires. In the following sample of sources, we will briefly describe how to access each service. These services only post recent news intended for public viewing. PR Newswire To access the PR Newswire archive, simply go to http://www.prnewswire.com/. Select your country. Type “insulin resistance” (or synonyms) into the search box. You will automatically receive information on relevant news releases posted within the last 30 days. The search results are shown by order of relevance. Reuters Health The Reuters’ Medical News and Health eLine databases can be very useful in exploring news archives relating to insulin resistance. While some of the listed articles are free to view, others are available for purchase for a nominal fee. To access this archive, go to http://www.reutershealth.com/en/index.html and search by “insulin resistance” (or synonyms). The following was recently listed in this archive for insulin resistance: •

Myocyte PPAR-gamma plays key role in insulin resistance Source: Reuters Industry Breifing Date: November 18, 2003

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Weight loss tied to decrease in inflammatory proteins, improved insulin resistance Source: Reuters Medical News Date: June 24, 2003

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Hepatitis C virus directly involved in insulin resistance Source: Reuters Medical News Date: March 09, 2004

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Racial differences evident in development of insulin resistance Source: Reuters Medical News Date: March 03, 2004

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Hepatitis C virus-induced insulin resistance contributes to hepatic fibrogenesis Source: Reuters Medical News Date: December 17, 2003

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Impaired mitochondrial function may lead to age-related insulin resistance Source: Reuters Medical News Date: May 15, 2003

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Aggressive treatment reverses SLE-related type B insulin resistance syndrome Source: Reuters Industry Breifing Date: May 05, 2003

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Insulin resistance, not hyperglycemia, predicts CAD in type 1 diabetes Source: Reuters Medical News Date: April 25, 2003

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Vascular inflammation, insulin resistance improve after weight loss Source: Reuters Medical News Date: April 09, 2003

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Early neonatal weight gain associated with insulin resistance in adolescence Source: Reuters Medical News Date: March 27, 2003

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Eating breakfast may decrease risk of obesity and insulin resistance Source: Reuters Medical News Date: March 10, 2003

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Adiponectin deficiency linked to insulin resistance in HIV-related lipodystrophy Source: Reuters Medical News Date: January 08, 2003

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Response to insulin resistance varies by ethnicity Source: Reuters Health eLine Date: December 25, 2002

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Insulin resistance in children a function of current weight rather than birth weight Source: Reuters Medical News Date: December 20, 2002

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Gemfibrozil may reduce risk of cardiac events in men with diabetes or insulin resistance Source: Reuters Medical News Date: December 18, 2002

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Adiposity and insulin resistance in Indians may originate in utero Source: Reuters Medical News Date: December 18, 2002

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Liver fat content increased in HAART-associated lipodystrophy, insulin resistance Source: Reuters Industry Breifing Date: December 03, 2002

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JNK activity mediates obesity-induced insulin resistance Source: Reuters Medical News Date: November 20, 2002

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Reduced glucose uptake in muscle underlies HAART-related insulin resistance Source: Reuters Medical News Date: November 13, 2002

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Adolescent hypertension associated with insulin resistance Source: Reuters Industry Breifing Date: October 30, 2002

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"Hypertriglyceridemic waist" predicts presence of insulin resistance syndrome Source: Reuters Medical News Date: October 30, 2002

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Visceral fat removal stops insulin resistance in rats Source: Reuters Medical News Date: October 23, 2002

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Temocapril improves insulin resistance in diabetic mouse model Source: Reuters Industry Breifing Date: September 19, 2002

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Recurrent miscarriage linked to insulin resistance Source: Reuters Medical News Date: September 17, 2002

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Insulin resistance linked to repeat miscarriages Source: Reuters Health eLine Date: September 16, 2002

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High glycemic load and insulin resistance combine to increase pancreatic cancer risk Source: Reuters Medical News Date: September 10, 2002

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Both obesity and insulin resistance independently predict cardiovascular risk Source: Reuters Medical News Date: September 05, 2002

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Amprenavir-based therapy not linked to insulin resistance Source: Reuters Industry Breifing Date: August 26, 2002

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Insulin resistance, impaired glucose tolerance linked to CVD risk Source: Reuters Medical News Date: August 20, 2002

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Preconception obesity plus gestational DM increases risk of insulin resistance syndrome Source: Reuters Medical News Date: August 16, 2002

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Insulin resistance linked to low testosterone levels in men Source: Reuters Medical News Date: June 21, 2002

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Insulin resistance not linked to cardiac hypertrophy in hypertensive patients Source: Reuters Medical News Date: June 05, 2002

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Melanocortin agonist may reduce obesity and insulin resistance Source: Reuters Industry Breifing Date: June 04, 2002

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Selective hypothalamic insulin resistance contributes to obesity, diabetes Source: Reuters Medical News Date: May 20, 2002 The NIH

Within MEDLINEplus, the NIH has made an agreement with the New York Times Syndicate, the AP News Service, and Reuters to deliver news that can be browsed by the public. Search news releases at http://www.nlm.nih.gov/medlineplus/alphanews_a.html. MEDLINEplus allows you to browse across an alphabetical index. Or you can search by date at the following Web page: http://www.nlm.nih.gov/medlineplus/newsbydate.html. Often, news items are indexed by MEDLINEplus within its search engine. Business Wire Business Wire is similar to PR Newswire. To access this archive, simply go to http://www.businesswire.com/. You can scan the news by industry category or company name. Market Wire Market Wire is more focused on technology than the other wires. To browse the latest press releases by topic, such as alternative medicine, biotechnology, fitness, healthcare, legal, nutrition, and pharmaceuticals, access Market Wire’s Medical/Health channel at http://www.marketwire.com/mw/release_index?channel=MedicalHealth. Or simply go to Market Wire’s home page at http://www.marketwire.com/mw/home, type “insulin resistance” (or synonyms) into the search box, and click on “Search News.” As this service is technology oriented, you may wish to use it when searching for press releases covering diagnostic procedures or tests. Search Engines Medical news is also available in the news sections of commercial Internet search engines. See the health news page at Yahoo (http://dir.yahoo.com/Health/News_and_Media/), or you can use this Web site’s general news search page at http://news.yahoo.com/. Type in “insulin resistance” (or synonyms). If you know the name of a company that is relevant to insulin resistance, you can go to any stock trading Web site (such as http://www.etrade.com/) and search for the company name there. News items across various news sources are reported on indicated hyperlinks. Google offers a similar service at http://news.google.com/.

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BBC Covering news from a more European perspective, the British Broadcasting Corporation (BBC) allows the public free access to their news archive located at http://www.bbc.co.uk/. Search by “insulin resistance” (or synonyms).

Newsletter Articles Use the Combined Health Information Database, and limit your search criteria to “newsletter articles.” Again, you will need to use the “Detailed Search” option. Go directly to the following hyperlink: http://chid.nih.gov/detail/detail.html. Go to the bottom of the search page where “You may refine your search by.” Select the dates and language that you prefer. For the format option, select “Newsletter Article.” Type “insulin resistance” (or synonyms) into the “For these words:” box. You should check back periodically with this database as it is updated every three months. The following is a typical result when searching for newsletter articles on insulin resistance: •

Researchers Investigate New Obesity-related Disease Source: WIN Notes. p. 4, 10. Summer 2002. Contact: Weight-control Information Network, 1 WIN Way, Bethesda, MD 20992-3665. (202) 828-1025. Summary: Nonalcoholic steatohepatitis (NASH) is a liver disease that occurs most often in adults over the age of 40 who are overweight or have diabetes, insulin resistance, or hyperlipidemia. NASH resembles alcoholic liver disease, however, people with NASH drink little or no alcohol. Although most people with NASH are middle-aged, obese, and diabetic, the disease may also strike children and normal-weight adults without diabetes. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) is funding a 5-year study of NASH in hopes of finding prevention and treatment approaches. Scientists are uncertain about what causes NASH, but believe it is a combination of insulin resistance and oxidative stress. NIDDK plans to establish a NASH Clinical Research Network to study this poorly understood disease. Researchers will investigate NASH's origin, contributing factors, natural history, and complications. They hope to identify safe and effective methods to prevent and treat this increasingly common disease.

•

Your Exercise Rx Source: Nutrition Action Health Letter. 29(10):1, 3-7. December 2002. Contact: Center for Science in the Public Interest. 1875 Connecticut Ave., NW, Suite 300, Washington, DC 20009-5728. www.cspinet.org. Summary: This article discusses exercise to lose weight, reduce the risk of chronic disease, and gain strength and flexibility. Exercise as it relates to heart disease, insulin resistance, osteoporosis, and arthritis are discussed. Differences in exercises for older and younger adults, as well as men and women are also discussed. Diagrams and descriptions of strength moves and stretches are provided.

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Smoking Cessation: More than Complication Prevention Source: Diabetes Care in Nova Scotia. 10(3): 1-2. July 2000. Contact: Available from Diabetes Care Program of Nova Scotia. P.O. Box 9000, 1278 Tower Road, Bethune Building, Suite 577, Halifax, Nova Scotia B3H 2Y9. (902) 473-3219. Fax (902) 473-3911. E-mail: [email protected]. Summary: This article discusses the role of smoking in the development of type 2 diabetes. Although various studies have identified smoking as an independent risk factor for the development of type 2 diabetes, the mechanism by which cigarette smoking increases this risk is not clear. Substances in cigarette smoke may increase the levels of counterregulatory hormones to insulin, which may contribute to insulin resistance. In addition, nicotine impairs insulin action in the liver, adipose tissue, and muscle. Habitual smokers, especially those at risk for type 2 diabetes, should be advised to quit smoking or at least reduce the number of cigarettes smoked per day. However, health professionals cite various barriers to delivering cessation advice, including lack of time and payment for smoking cessation services, actual or perceived lack of knowledge and skill in cessation counseling, and low expectations regarding the efficacy of cessation counseling. The Agency for Health Care Policy and Research has identified the characteristics of successful smoking cessation interventions, including being delivered by a health care provider, offering either individual or group counseling, having greater person to person contact, providing aversive smoking techniques, being of long duration, and using pharmacotherapy. 5 references.

•

Malnutrition in the Hemodialysis Patient Source: Renal Nutrition Forum. 14(4): 1-4. Fall 1995. Contact: Available from Renal Nutrition Forum. 2246 Poinciana Road, Winter Park, FL 32792. (407) 774-0631. Summary: This article presents a brief overview of research addressing nutritional status in the hemodialysis (HD) patient and the relationship between malnutrition, morbidity, and mortality. The article is also intended to help the dietitian in preventing malnutrition in the HD patient by offering suggestions for therapy. Dialysis factors which may contribute to malnutrition include an increase in muscle protein degradation caused by blood contact with the dialyzer membrane; inadequate dialysis resulting in a uremic state which leads to nausea, vomiting, and loss of appetite; and loss of amino acids and peptides in dialysate. Hormonal disturbances include insulin resistance, increased circulating levels of catabolic hormones such as insulin and parathyroid hormone, and decreased levels of anabolic hormones such as growth factor and erythropoietin caused by deterioration of kidney function. Gastrointestinal factors include gastroparesis, malabsorption, gastritis, esophagitis, and constipation. The author reports on studies documenting that malnutrition greatly increases morbidity and mortality in the HD patient. HD patients should ingest 1.2 grams of protein per kilogram of actual body weight, where 50 percent is high biological value protein. An adequate energy intake is vital for the efficient utilization of dietary protein. The most important factor in improving malnutrition in this population is to assure adequate dialysis. The author concludes with a section on interventions for patients who continue to have poor appetites, even if dialysis delivery is optimal. 1 table. 15 references.

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How to Avoid Adult Onset Diabetes Source: Nutrition Action Healthletter. 23(7): 3-5. September 1996.

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Contact: Available from Nutrition Action Healthletter. CSPI, P.O. Box 96611, Washington, DC 20090-6611. (800) 237-4874. Summary: This article, from a consumer health newsletter, offers guidelines for avoiding noninsulin-dependent diabetes (NIDDM). Topics include the prevalence of NIDDM; how NIDDM impacts the body; insulin resistance; the symptoms of diabetes; and the role of weight loss and exercise in preventing NIDDM onset. The authors briefly report on research into the possible use of chromium and antioxidant supplements in preventing diabetes; and research that investigates whether certain foods can play a preventive role. One chart helps readers to figure out whether their Body Mass Index (BMI) is in the recommended range; another chart lists the calories burned by various common activities and exercise options. 2 tables. 8 references.

Academic Periodicals covering Insulin Resistance Numerous periodicals are currently indexed within the National Library of Medicine’s PubMed database that are known to publish articles relating to insulin resistance. In addition to these sources, you can search for articles covering insulin resistance that have been published by any of the periodicals listed in previous chapters. To find the latest studies published, go to http://www.ncbi.nlm.nih.gov/pubmed, type the name of the periodical into the search box, and click “Go.” If you want complete details about the historical contents of a journal, you can also visit the following Web site: http://www.ncbi.nlm.nih.gov/entrez/jrbrowser.cgi. Here, type in the name of the journal or its abbreviation, and you will receive an index of published articles. At http://locatorplus.gov/, you can retrieve more indexing information on medical periodicals (e.g. the name of the publisher). Select the button “Search LOCATORplus.” Then type in the name of the journal and select the advanced search option “Journal Title Search.”

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APPENDICES

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APPENDIX A. PHYSICIAN RESOURCES Overview In this chapter, we focus on databases and Internet-based guidelines and information resources created or written for a professional audience.

NIH Guidelines Commonly referred to as “clinical” or “professional” guidelines, the National Institutes of Health publish physician guidelines for the most common diseases. Publications are available at the following by relevant Institute11: •

Office of the Director (OD); guidelines consolidated across agencies available at http://www.nih.gov/health/consumer/conkey.htm

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National Institute of General Medical Sciences (NIGMS); fact sheets available at http://www.nigms.nih.gov/news/facts/

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National Library of Medicine (NLM); extensive encyclopedia (A.D.A.M., Inc.) with guidelines: http://www.nlm.nih.gov/medlineplus/healthtopics.html

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National Cancer Institute (NCI); guidelines available at http://www.cancer.gov/cancerinfo/list.aspx?viewid=5f35036e-5497-4d86-8c2c714a9f7c8d25

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National Eye Institute (NEI); guidelines available at http://www.nei.nih.gov/order/index.htm

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National Heart, Lung, and Blood Institute (NHLBI); guidelines available at http://www.nhlbi.nih.gov/guidelines/index.htm

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National Human Genome Research Institute (NHGRI); research available at http://www.genome.gov/page.cfm?pageID=10000375

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National Institute on Aging (NIA); guidelines available at http://www.nia.nih.gov/health/

11

These publications are typically written by one or more of the various NIH Institutes.

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National Institute on Alcohol Abuse and Alcoholism (NIAAA); guidelines available at http://www.niaaa.nih.gov/publications/publications.htm

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National Institute of Allergy and Infectious Diseases (NIAID); guidelines available at http://www.niaid.nih.gov/publications/

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National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS); fact sheets and guidelines available at http://www.niams.nih.gov/hi/index.htm

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National Institute of Child Health and Human Development (NICHD); guidelines available at http://www.nichd.nih.gov/publications/pubskey.cfm

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National Institute on Deafness and Other Communication Disorders (NIDCD); fact sheets and guidelines at http://www.nidcd.nih.gov/health/

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National Institute of Dental and Craniofacial Research (NIDCR); guidelines available at http://www.nidr.nih.gov/health/

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National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK); guidelines available at http://www.niddk.nih.gov/health/health.htm

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National Institute on Drug Abuse (NIDA); guidelines available at http://www.nida.nih.gov/DrugAbuse.html

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National Institute of Environmental Health Sciences (NIEHS); environmental health information available at http://www.niehs.nih.gov/external/facts.htm

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National Institute of Mental Health (NIMH); guidelines available at http://www.nimh.nih.gov/practitioners/index.cfm

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National Institute of Neurological Disorders and Stroke (NINDS); neurological disorder information pages available at http://www.ninds.nih.gov/health_and_medical/disorder_index.htm

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National Institute of Nursing Research (NINR); publications on selected illnesses at http://www.nih.gov/ninr/news-info/publications.html

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National Institute of Biomedical Imaging and Bioengineering; general information at http://grants.nih.gov/grants/becon/becon_info.htm

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Center for Information Technology (CIT); referrals to other agencies based on keyword searches available at http://kb.nih.gov/www_query_main.asp

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National Center for Complementary and Alternative Medicine (NCCAM); health information available at http://nccam.nih.gov/health/

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National Center for Research Resources (NCRR); various information directories available at http://www.ncrr.nih.gov/publications.asp

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Office of Rare Diseases; various fact sheets available at http://rarediseases.info.nih.gov/html/resources/rep_pubs.html

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Centers for Disease Control and Prevention; various fact sheets on infectious diseases available at http://www.cdc.gov/publications.htm

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NIH Databases In addition to the various Institutes of Health that publish professional guidelines, the NIH has designed a number of databases for professionals.12 Physician-oriented resources provide a wide variety of information related to the biomedical and health sciences, both past and present. The format of these resources varies. Searchable databases, bibliographic citations, full-text articles (when available), archival collections, and images are all available. The following are referenced by the National Library of Medicine:13 •

Bioethics: Access to published literature on the ethical, legal, and public policy issues surrounding healthcare and biomedical research. This information is provided in conjunction with the Kennedy Institute of Ethics located at Georgetown University, Washington, D.C.: http://www.nlm.nih.gov/databases/databases_bioethics.html

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HIV/AIDS Resources: Describes various links and databases dedicated to HIV/AIDS research: http://www.nlm.nih.gov/pubs/factsheets/aidsinfs.html

•

NLM Online Exhibitions: Describes “Exhibitions in the History of Medicine”: http://www.nlm.nih.gov/exhibition/exhibition.html. Additional resources for historical scholarship in medicine: http://www.nlm.nih.gov/hmd/hmd.html

•

Biotechnology Information: Access to public databases. The National Center for Biotechnology Information conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information for the better understanding of molecular processes affecting human health and disease: http://www.ncbi.nlm.nih.gov/

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Population Information: The National Library of Medicine provides access to worldwide coverage of population, family planning, and related health issues, including family planning technology and programs, fertility, and population law and policy: http://www.nlm.nih.gov/databases/databases_population.html

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Cancer Information: Access to cancer-oriented databases: http://www.nlm.nih.gov/databases/databases_cancer.html

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Profiles in Science: Offering the archival collections of prominent twentieth-century biomedical scientists to the public through modern digital technology: http://www.profiles.nlm.nih.gov/

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Chemical Information: Provides links to various chemical databases and references: http://sis.nlm.nih.gov/Chem/ChemMain.html

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Clinical Alerts: Reports the release of findings from the NIH-funded clinical trials where such release could significantly affect morbidity and mortality: http://www.nlm.nih.gov/databases/alerts/clinical_alerts.html

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Space Life Sciences: Provides links and information to space-based research (including NASA): http://www.nlm.nih.gov/databases/databases_space.html

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MEDLINE: Bibliographic database covering the fields of medicine, nursing, dentistry, veterinary medicine, the healthcare system, and the pre-clinical sciences: http://www.nlm.nih.gov/databases/databases_medline.html

12

Remember, for the general public, the National Library of Medicine recommends the databases referenced in MEDLINEplus (http://medlineplus.gov/ or http://www.nlm.nih.gov/medlineplus/databases.html). 13 See http://www.nlm.nih.gov/databases/databases.html.

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Toxicology and Environmental Health Information (TOXNET): Databases covering toxicology and environmental health: http://sis.nlm.nih.gov/Tox/ToxMain.html

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Visible Human Interface: Anatomically detailed, three-dimensional representations of normal male and female human bodies: http://www.nlm.nih.gov/research/visible/visible_human.html

The NLM Gateway14 The NLM (National Library of Medicine) Gateway is a Web-based system that lets users search simultaneously in multiple retrieval systems at the U.S. National Library of Medicine (NLM). It allows users of NLM services to initiate searches from one Web interface, providing one-stop searching for many of NLM’s information resources or databases.15 To use the NLM Gateway, simply go to the search site at http://gateway.nlm.nih.gov/gw/Cmd. Type “insulin resistance” (or synonyms) into the search box and click “Search.” The results will be presented in a tabular form, indicating the number of references in each database category. Results Summary Category Journal Articles Books / Periodicals / Audio Visual Consumer Health Meeting Abstracts Other Collections Total

Items Found 19453 62 671 136 173 20495

HSTAT16 HSTAT is a free, Web-based resource that provides access to full-text documents used in healthcare decision-making.17 These documents include clinical practice guidelines, quickreference guides for clinicians, consumer health brochures, evidence reports and technology assessments from the Agency for Healthcare Research and Quality (AHRQ), as well as AHRQ’s Put Prevention Into Practice.18 Simply search by “insulin resistance” (or synonyms) at the following Web site: http://text.nlm.nih.gov.

14

Adapted from NLM: http://gateway.nlm.nih.gov/gw/Cmd?Overview.x.

15

The NLM Gateway is currently being developed by the Lister Hill National Center for Biomedical Communications (LHNCBC) at the National Library of Medicine (NLM) of the National Institutes of Health (NIH). 16 Adapted from HSTAT: http://www.nlm.nih.gov/pubs/factsheets/hstat.html. 17 18

The HSTAT URL is http://hstat.nlm.nih.gov/.

Other important documents in HSTAT include: the National Institutes of Health (NIH) Consensus Conference Reports and Technology Assessment Reports; the HIV/AIDS Treatment Information Service (ATIS) resource documents; the Substance Abuse and Mental Health Services Administration's Center for Substance Abuse Treatment (SAMHSA/CSAT) Treatment Improvement Protocols (TIP) and Center for Substance Abuse Prevention (SAMHSA/CSAP) Prevention Enhancement Protocols System (PEPS); the Public Health Service (PHS) Preventive Services Task Force's Guide to Clinical Preventive Services; the independent, nonfederal Task Force on Community Services’ Guide to Community Preventive Services; and the Health Technology Advisory Committee (HTAC) of the Minnesota Health Care Commission (MHCC) health technology evaluations.

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Coffee Break: Tutorials for Biologists19 Coffee Break is a general healthcare site that takes a scientific view of the news and covers recent breakthroughs in biology that may one day assist physicians in developing treatments. Here you will find a collection of short reports on recent biological discoveries. Each report incorporates interactive tutorials that demonstrate how bioinformatics tools are used as a part of the research process. Currently, all Coffee Breaks are written by NCBI staff.20 Each report is about 400 words and is usually based on a discovery reported in one or more articles from recently published, peer-reviewed literature.21 This site has new articles every few weeks, so it can be considered an online magazine of sorts. It is intended for general background information. You can access the Coffee Break Web site at the following hyperlink: http://www.ncbi.nlm.nih.gov/Coffeebreak/.

Other Commercial Databases In addition to resources maintained by official agencies, other databases exist that are commercial ventures addressing medical professionals. Here are some examples that may interest you: •

CliniWeb International: Index and table of contents to selected clinical information on the Internet; see http://www.ohsu.edu/cliniweb/.

•

Medical World Search: Searches full text from thousands of selected medical sites on the Internet; see http://www.mwsearch.com/.

The Genome Project and Insulin Resistance In the following section, we will discuss databases and references which relate to the Genome Project and insulin resistance. Online Mendelian Inheritance in Man (OMIM) The Online Mendelian Inheritance in Man (OMIM) database is a catalog of human genes and genetic disorders authored and edited by Dr. Victor A. McKusick and his colleagues at Johns Hopkins and elsewhere. OMIM was developed for the World Wide Web by the National Center for Biotechnology Information (NCBI).22 The database contains textual information, pictures, and reference information. It also contains copious links to NCBI’s Entrez database of MEDLINE articles and sequence information. 19 Adapted 20

from http://www.ncbi.nlm.nih.gov/Coffeebreak/Archive/FAQ.html.

The figure that accompanies each article is frequently supplied by an expert external to NCBI, in which case the source of the figure is cited. The result is an interactive tutorial that tells a biological story. 21 After a brief introduction that sets the work described into a broader context, the report focuses on how a molecular understanding can provide explanations of observed biology and lead to therapies for diseases. Each vignette is accompanied by a figure and hypertext links that lead to a series of pages that interactively show how NCBI tools and resources are used in the research process. 22 Adapted from http://www.ncbi.nlm.nih.gov/. Established in 1988 as a national resource for molecular biology information, NCBI creates public databases, conducts research in computational biology, develops software tools for analyzing genome data, and disseminates biomedical information--all for the better understanding of molecular processes affecting human health and disease.

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To search the database, go to http://www.ncbi.nlm.nih.gov/Omim/searchomim.html. Type “insulin resistance” (or synonyms) into the search box, and click “Submit Search.” If too many results appear, you can narrow the search by adding the word “clinical.” Each report will have additional links to related research and databases. In particular, the option “Database Links” will search across technical databases that offer an abundance of information. The following is an example of the results you can obtain from the OMIM for insulin resistance: •

Pseudoacromegaly with Severe Insulin Resistance Web site: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=602511 Genes and Disease (NCBI - Map)

The Genes and Disease database is produced by the National Center for Biotechnology Information of the National Library of Medicine at the National Institutes of Health. This Web site categorizes each disorder by system of the body. Go to http://www.ncbi.nlm.nih.gov/disease/, and browse the system pages to have a full view of important conditions linked to human genes. Since this site is regularly updated, you may wish to revisit it from time to time. The following systems and associated disorders are addressed: •

Cancer: Uncontrolled cell division. Examples: Breast and ovarian cancer, Burkitt lymphoma, chronic myeloid leukemia, colon cancer, lung cancer, malignant melanoma, multiple endocrine neoplasia, neurofibromatosis, p53 tumor suppressor, pancreatic cancer, prostate cancer, Ras oncogene, RB: retinoblastoma, von Hippel-Lindau syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Cancer.html

•

Immune System: Fights invaders. Examples: Asthma, autoimmune polyglandular syndrome, Crohn’s disease, DiGeorge syndrome, familial Mediterranean fever, immunodeficiency with Hyper-IgM, severe combined immunodeficiency. Web site: http://www.ncbi.nlm.nih.gov/disease/Immune.html

•

Metabolism: Food and energy. Examples: Adreno-leukodystrophy, atherosclerosis, Best disease, Gaucher disease, glucose galactose malabsorption, gyrate atrophy, juvenile-onset diabetes, obesity, paroxysmal nocturnal hemoglobinuria, phenylketonuria, Refsum disease, Tangier disease, Tay-Sachs disease. Web site: http://www.ncbi.nlm.nih.gov/disease/Metabolism.html

•

Muscle and Bone: Movement and growth. Examples: Duchenne muscular dystrophy, Ellis-van Creveld syndrome, Marfan syndrome, myotonic dystrophy, spinal muscular atrophy. Web site: http://www.ncbi.nlm.nih.gov/disease/Muscle.html

•

Nervous System: Mind and body. Examples: Alzheimer disease, amyotrophic lateral sclerosis, Angelman syndrome, Charcot-Marie-Tooth disease, epilepsy, essential tremor, fragile X syndrome, Friedreich’s ataxia, Huntington disease, Niemann-Pick disease, Parkinson disease, Prader-Willi syndrome, Rett syndrome, spinocerebellar atrophy, Williams syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Brain.html

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•

Signals: Cellular messages. Examples: Ataxia telangiectasia, Cockayne syndrome, glaucoma, male-patterned baldness, SRY: sex determination, tuberous sclerosis, Waardenburg syndrome, Werner syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Signals.html

•

Transporters: Pumps and channels. Examples: Cystic fibrosis, deafness, diastrophic dysplasia, Hemophilia A, long-QT syndrome, Menkes syndrome, Pendred syndrome, polycystic kidney disease, sickle cell anemia, Wilson’s disease, Zellweger syndrome. Web site: http://www.ncbi.nlm.nih.gov/disease/Transporters.html Entrez

Entrez is a search and retrieval system that integrates several linked databases at the National Center for Biotechnology Information (NCBI). These databases include nucleotide sequences, protein sequences, macromolecular structures, whole genomes, and MEDLINE through PubMed. Entrez provides access to the following databases: •

3D Domains: Domains from Entrez Structure, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Books: Online books, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=books

•

Genome: Complete genome assemblies, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Genome

•

NCBI’s Protein Sequence Information Survey Results: Web site: http://www.ncbi.nlm.nih.gov/About/proteinsurvey/

•

Nucleotide Sequence Database (Genbank): Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Nucleotide

•

OMIM: Online Mendelian Inheritance in Man, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=OMIM

•

PopSet: Population study data sets, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Popset

•

ProbeSet: Gene Expression Omnibus (GEO), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=geo

•

Protein Sequence Database: Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Protein

•

PubMed: Biomedical literature (PubMed), Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed

•

Structure: Three-dimensional macromolecular structures, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Structure

•

Taxonomy: Organisms in GenBank, Web site: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=Taxonomy

To access the Entrez system at the National Center for Biotechnology Information, go to http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=genome, and then

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select the database that you would like to search. The databases available are listed in the drop box next to “Search.” Enter “insulin resistance” (or synonyms) into the search box and click “Go.” Jablonski’s Multiple Congenital Anomaly/Mental Retardation (MCA/MR) Syndromes Database23 This online resource has been developed to facilitate the identification and differentiation of syndromic entities. Special attention is given to the type of information that is usually limited or completely omitted in existing reference sources due to space limitations of the printed form. At http://www.nlm.nih.gov/mesh/jablonski/syndrome_toc/toc_a.html, you can search across syndromes using an alphabetical index. Search by keywords at http://www.nlm.nih.gov/mesh/jablonski/syndrome_db.html. The Genome Database24 Established at Johns Hopkins University in Baltimore, Maryland in 1990, the Genome Database (GDB) is the official central repository for genomic mapping data resulting from the Human Genome Initiative. In the spring of 1999, the Bioinformatics Supercomputing Centre (BiSC) at the Hospital for Sick Children in Toronto, Ontario assumed the management of GDB. The Human Genome Initiative is a worldwide research effort focusing on structural analysis of human DNA to determine the location and sequence of the estimated 100,000 human genes. In support of this project, GDB stores and curates data generated by researchers worldwide who are engaged in the mapping effort of the Human Genome Project (HGP). GDB’s mission is to provide scientists with an encyclopedia of the human genome which is continually revised and updated to reflect the current state of scientific knowledge. Although GDB has historically focused on gene mapping, its focus will broaden as the Genome Project moves from mapping to sequence, and finally, to functional analysis. To access the GDB, simply go to the following hyperlink: http://www.gdb.org/. Search “All Biological Data” by “Keyword.” Type “insulin resistance” (or synonyms) into the search box, and review the results. If more than one word is used in the search box, then separate each one with the word “and” or “or” (using “or” might be useful when using synonyms).

23

Adapted from the National Library of Medicine: http://www.nlm.nih.gov/mesh/jablonski/about_syndrome.html. 24 Adapted from the Genome Database: http://gdbwww.gdb.org/gdb/aboutGDB.html - mission.

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APPENDIX B. PATIENT RESOURCES Overview Official agencies, as well as federally funded institutions supported by national grants, frequently publish a variety of guidelines written with the patient in mind. These are typically called “Fact Sheets” or “Guidelines.” They can take the form of a brochure, information kit, pamphlet, or flyer. Often they are only a few pages in length. Since new guidelines on insulin resistance can appear at any moment and be published by a number of sources, the best approach to finding guidelines is to systematically scan the Internet-based services that post them.

Patient Guideline Sources The remainder of this chapter directs you to sources which either publish or can help you find additional guidelines on topics related to insulin resistance. Due to space limitations, these sources are listed in a concise manner. Do not hesitate to consult the following sources by either using the Internet hyperlink provided, or, in cases where the contact information is provided, contacting the publisher or author directly. The National Institutes of Health The NIH gateway to patients is located at http://health.nih.gov/. From this site, you can search across various sources and institutes, a number of which are summarized below. Topic Pages: MEDLINEplus The National Library of Medicine has created a vast and patient-oriented healthcare information portal called MEDLINEplus. Within this Internet-based system are “health topic pages” which list links to available materials relevant to insulin resistance. To access this system, log on to http://www.nlm.nih.gov/medlineplus/healthtopics.html. From there you can either search using the alphabetical index or browse by broad topic areas. Recently, MEDLINEplus listed the following when searched for “insulin resistance”:

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Other guides Diabetes http://www.nlm.nih.gov/medlineplus/diabetes.html Fragile X Syndrome http://www.nlm.nih.gov/medlineplus/fragilexsyndrome.html Genetic Brain Disorders http://www.nlm.nih.gov/medlineplus/geneticbraindisorders.html Heart Diseases http://www.nlm.nih.gov/medlineplus/heartdiseases.html Hormones http://www.nlm.nih.gov/medlineplus/hormones.html Metabolic Syndrome X http://www.nlm.nih.gov/medlineplus/metabolicsyndromex.html Ovarian Cysts http://www.nlm.nih.gov/medlineplus/ovariancysts.html

Within the health topic page dedicated to insulin resistance, the following was listed: •

General/Overviews Metabolic Syndrome Source: Cleveland Clinic Foundation http://www.clevelandclinic.org/health/healthinfo/docs/3000/3057.asp?index=10783 Metabolic Syndrome Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=DS00522 Syndrome X or Metabolic Syndrome Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=534

•

Diagnosis/Symptoms Lab Values Important in Defining Obesity Syndrome Source: American Association for Clinical Chemistry http://www.labtestsonline.org/news/obesity020131.html

•

Specific Conditions/Aspects Insulin Resistance and Pre-Diabetes Source: National Diabetes Information Clearinghouse http://diabetes.niddk.nih.gov/dm/pubs/insulinresistance/index.htm Metabolic Syndrome Source: American Diabetes Association http://www.diabetes.org/weightloss-andexercise/weightloss/metabolicsyndrome.jsp

Patient Resources 231 Syndrome X Source: Mayo Foundation for Medical Education and Research http://www.mayoclinic.com/invoke.cfm?id=AN00404 •

Organizations American Diabetes Association http://www.diabetes.org/ American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=1200000 National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov/

•

Prevention/Screening Incremental Lifestyle Changes Can Ward Off Syndrome X Source: Cleveland Clinic Foundation http://www.clevelandclinic.org/health/healthinfo/docs/3000/3053.asp?index=10807

•

Research Association of the Metabolic Syndrome and Chronic Kidney Disease in U.S. Adults Source: American College of Physicians http://www.annals.org/cgi/content/full/140/3/I-39 CRP (C-Reactive Protein) Improves Cardiovascular Risk Prediction in Metabolic Syndrome Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3007985 Men with 3 of 5 Metabolic Abnormalities Risk Diabetes, Heart Disease Source: American Heart Association http://www.americanheart.org/presenter.jhtml?identifier=3013637

•

Statistics Prevalence among U.S. Adults of a Metabolic Syndrome Associated with Obesity Source: Centers for Disease Control and Prevention http://www.cdc.gov/nccdphp/dnpa/obesity/trend/metabolic.htm

You may also choose to use the search utility provided by MEDLINEplus at the following Web address: http://www.nlm.nih.gov/medlineplus/. Simply type a keyword into the search box and click “Search.” This utility is similar to the NIH search utility, with the exception that it only includes materials that are linked within the MEDLINEplus system (mostly patient-oriented information). It also has the disadvantage of generating unstructured results. We recommend, therefore, that you use this method only if you have a very targeted search.

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The Combined Health Information Database (CHID) CHID Online is a reference tool that maintains a database directory of thousands of journal articles and patient education guidelines on insulin resistance. CHID offers summaries that describe the guidelines available, including contact information and pricing. CHID’s general Web site is http://chid.nih.gov/. To search this database, go to http://chid.nih.gov/detail/detail.html. In particular, you can use the advanced search options to look up pamphlets, reports, brochures, and information kits. The following was recently posted in this archive: •

Insulin Resistance and Pre-Diabetes Source: Bethesda, MD: National Diabetes Information Clearinghouse (NDIC). 2003. 8 p. Contact: Available from National Diabetes Information Clearinghouse (NDIC). 1 Information Way, Bethesda, MD 20892-3560. (800) 860-8747 or (301) 654-3327. Fax (301) 634-0716. E-mail: [email protected]. Also available at http://www.niddk.nih.gov/. PRICE: Full-text available online at no charge; $5.00 for package of 25. Order number: 03-4893. Summary: Insulin resistance is a silent condition that increases the changes of developing diabetes and heart disease. This fact sheet describes insulin resistance and pre-diabetes and how readers can make lifestyle changes to help prevent diabetes and other health problems. Topics include the role of insulin; the interplay between insulin resistance, prediabetes and type 2 diabetes; the causes of insulin resistance; symptoms; metabolic syndrome; diagnostic tests used to confirm the presence of diabetes and prediabetes, including fasting blood glucose tests, glucose tolerance test, and insulin measure; strategies to reverse insulin resistance, including physical activity, appropriate weight loss, control of blood pressure, control of cholesterol levels, and stopping smoking; and the drugs that are used to improve response to insulin. One additional section briefly reports on future research projects in this area. The fact sheet concludes with a brief description of the goals and activities of the National Diabetes Information Clearinghouse (NDIC).

•

Insulin Resistance Syndrome Source: American Family Physician. 63(6): 1165-1166. March 15, 2001. Contact: Available from American Academy of Family Physicians. 11400 Tomahawk Creek Parkway, Leawood, KS 66211-2672. (800) 274-2237. Website: www.aafp.org. Summary: This fact sheet uses a question and answer format to provide people who have insulin resistance syndrome with information on the diagnosis and treatment of the syndrome. Insulin resistance occurs when the tissues stop responding to insulin, allowing insulin to accumulate in the blood. There is no test for insulin resistance syndrome, but a doctor may suspect the syndrome in a patient who has a history of diabetes in first degree relatives; patients with a personal history of gestational diabetes, polycystic ovary syndrome, or impaired glucose tolerance; and obese patients, particularly those with abdominal obesity. Insulin resistance syndrome may be prevented by maintaining a healthy weight, exercising, and eating a lot of dietary fiber. 1 figure. 1 table.

Patient Resources 233 Healthfinder™ Healthfinder™ is sponsored by the U.S. Department of Health and Human Services and offers links to hundreds of other sites that contain healthcare information. This Web site is located at http://www.healthfinder.gov. Again, keyword searches can be used to find guidelines. The following was recently found in this database: •

The Pima Indians: Pathfinders for Health Summary: By studying Pima Indian volunteers, researchers have determined that diabetes runs in families, as does insulin resistance, and obesity. Source: National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health http://www.healthfinder.gov/scripts/recordpass.asp?RecordType=0&RecordID=2624 The NIH Search Utility

The NIH search utility allows you to search for documents on over 100 selected Web sites that comprise the NIH-WEB-SPACE. Each of these servers is “crawled” and indexed on an ongoing basis. Your search will produce a list of various documents, all of which will relate in some way to insulin resistance. The drawbacks of this approach are that the information is not organized by theme and that the references are often a mix of information for professionals and patients. Nevertheless, a large number of the listed Web sites provide useful background information. We can only recommend this route, therefore, for relatively rare or specific disorders, or when using highly targeted searches. To use the NIH search utility, visit the following Web page: http://search.nih.gov/index.html. Additional Web Sources A number of Web sites are available to the public that often link to government sites. These can also point you in the direction of essential information. The following is a representative sample: •

AOL: http://search.aol.com/cat.adp?id=168&layer=&from=subcats

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Family Village: http://www.familyvillage.wisc.edu/specific.htm

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Google: http://directory.google.com/Top/Health/Conditions_and_Diseases/

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Med Help International: http://www.medhelp.org/HealthTopics/A.html

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Open Directory Project: http://dmoz.org/Health/Conditions_and_Diseases/

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Yahoo.com: http://dir.yahoo.com/Health/Diseases_and_Conditions/

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WebMDHealth: http://my.webmd.com/health_topics

Finding Associations There are several Internet directories that provide lists of medical associations with information on or resources relating to insulin resistance. By consulting all of associations

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listed in this chapter, you will have nearly exhausted all sources for patient associations concerned with insulin resistance. The National Health Information Center (NHIC) The National Health Information Center (NHIC) offers a free referral service to help people find organizations that provide information about insulin resistance. For more information, see the NHIC’s Web site at http://www.health.gov/NHIC/ or contact an information specialist by calling 1-800-336-4797. Directory of Health Organizations The Directory of Health Organizations, provided by the National Library of Medicine Specialized Information Services, is a comprehensive source of information on associations. The Directory of Health Organizations database can be accessed via the Internet at http://www.sis.nlm.nih.gov/Dir/DirMain.html. It is composed of two parts: DIRLINE and Health Hotlines. The DIRLINE database comprises some 10,000 records of organizations, research centers, and government institutes and associations that primarily focus on health and biomedicine. To access DIRLINE directly, go to the following Web site: http://dirline.nlm.nih.gov/. Simply type in “insulin resistance” (or a synonym), and you will receive information on all relevant organizations listed in the database. Health Hotlines directs you to toll-free numbers to over 300 organizations. You can access this database directly at http://www.sis.nlm.nih.gov/hotlines/. On this page, you are given the option to search by keyword or by browsing the subject list. When you have received your search results, click on the name of the organization for its description and contact information. The Combined Health Information Database Another comprehensive source of information on healthcare associations is the Combined Health Information Database. Using the “Detailed Search” option, you will need to limit your search to “Organizations” and “insulin resistance”. Type the following hyperlink into your Web browser: http://chid.nih.gov/detail/detail.html. To find associations, use the drop boxes at the bottom of the search page where “You may refine your search by.” For publication date, select “All Years.” Then, select your preferred language and the format option “Organization Resource Sheet.” Type “insulin resistance” (or synonyms) into the “For these words:” box. You should check back periodically with this database since it is updated every three months. The National Organization for Rare Disorders, Inc. The National Organization for Rare Disorders, Inc. has prepared a Web site that provides, at no charge, lists of associations organized by health topic. You can access this database at the following Web site: http://www.rarediseases.org/search/orgsearch.html. Type “insulin resistance” (or a synonym) into the search box, and click “Submit Query.”

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APPENDIX C. FINDING MEDICAL LIBRARIES Overview In this Appendix, we show you how to quickly find a medical library in your area.

Preparation Your local public library and medical libraries have interlibrary loan programs with the National Library of Medicine (NLM), one of the largest medical collections in the world. According to the NLM, most of the literature in the general and historical collections of the National Library of Medicine is available on interlibrary loan to any library. If you would like to access NLM medical literature, then visit a library in your area that can request the publications for you.25

Finding a Local Medical Library The quickest method to locate medical libraries is to use the Internet-based directory published by the National Network of Libraries of Medicine (NN/LM). This network includes 4626 members and affiliates that provide many services to librarians, health professionals, and the public. To find a library in your area, simply visit http://nnlm.gov/members/adv.html or call 1-800-338-7657.

Medical Libraries in the U.S. and Canada In addition to the NN/LM, the National Library of Medicine (NLM) lists a number of libraries with reference facilities that are open to the public. The following is the NLM’s list and includes hyperlinks to each library’s Web site. These Web pages can provide information on hours of operation and other restrictions. The list below is a small sample of

25

Adapted from the NLM: http://www.nlm.nih.gov/psd/cas/interlibrary.html.

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libraries recommended by the National Library of Medicine (sorted alphabetically by name of the U.S. state or Canadian province where the library is located)26: •

Alabama: Health InfoNet of Jefferson County (Jefferson County Library Cooperative, Lister Hill Library of the Health Sciences), http://www.uab.edu/infonet/

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Alabama: Richard M. Scrushy Library (American Sports Medicine Institute)

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Arizona: Samaritan Regional Medical Center: The Learning Center (Samaritan Health System, Phoenix, Arizona), http://www.samaritan.edu/library/bannerlibs.htm

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California: Kris Kelly Health Information Center (St. Joseph Health System, Humboldt), http://www.humboldt1.com/~kkhic/index.html

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California: Community Health Library of Los Gatos, http://www.healthlib.org/orgresources.html

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California: Consumer Health Program and Services (CHIPS) (County of Los Angeles Public Library, Los Angeles County Harbor-UCLA Medical Center Library) - Carson, CA, http://www.colapublib.org/services/chips.html

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California: Gateway Health Library (Sutter Gould Medical Foundation)

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California: Health Library (Stanford University Medical Center), http://wwwmed.stanford.edu/healthlibrary/

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California: Patient Education Resource Center - Health Information and Resources (University of California, San Francisco), http://sfghdean.ucsf.edu/barnett/PERC/default.asp

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California: Redwood Health Library (Petaluma Health Care District), http://www.phcd.org/rdwdlib.html

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California: Los Gatos PlaneTree Health Library, http://planetreesanjose.org/

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California: Sutter Resource Library (Sutter Hospitals Foundation, Sacramento), http://suttermedicalcenter.org/library/

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California: Health Sciences Libraries (University of California, Davis), http://www.lib.ucdavis.edu/healthsci/

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California: ValleyCare Health Library & Ryan Comer Cancer Resource Center (ValleyCare Health System, Pleasanton), http://gaelnet.stmarysca.edu/other.libs/gbal/east/vchl.html

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California: Washington Community Health Resource Library (Fremont), http://www.healthlibrary.org/

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Colorado: William V. Gervasini Memorial Library (Exempla Healthcare), http://www.saintjosephdenver.org/yourhealth/libraries/

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Connecticut: Hartford Hospital Health Science Libraries (Hartford Hospital), http://www.harthosp.org/library/

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Connecticut: Healthnet: Connecticut Consumer Health Information Center (University of Connecticut Health Center, Lyman Maynard Stowe Library), http://library.uchc.edu/departm/hnet/

26

Abstracted from http://www.nlm.nih.gov/medlineplus/libraries.html.

Finding Medical Libraries 239

•

Connecticut: Waterbury Hospital Health Center Library (Waterbury Hospital, Waterbury), http://www.waterburyhospital.com/library/consumer.shtml

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Delaware: Consumer Health Library (Christiana Care Health System, Eugene du Pont Preventive Medicine & Rehabilitation Institute, Wilmington), http://www.christianacare.org/health_guide/health_guide_pmri_health_info.cfm

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Delaware: Lewis B. Flinn Library (Delaware Academy of Medicine, Wilmington), http://www.delamed.org/chls.html

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Georgia: Family Resource Library (Medical College of Georgia, Augusta), http://cmc.mcg.edu/kids_families/fam_resources/fam_res_lib/frl.htm

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Georgia: Health Resource Center (Medical Center of Central Georgia, Macon), http://www.mccg.org/hrc/hrchome.asp

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Hawaii: Hawaii Medical Library: Consumer Health Information Service (Hawaii Medical Library, Honolulu), http://hml.org/CHIS/

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Idaho: DeArmond Consumer Health Library (Kootenai Medical Center, Coeur d’Alene), http://www.nicon.org/DeArmond/index.htm

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Illinois: Health Learning Center of Northwestern Memorial Hospital (Chicago), http://www.nmh.org/health_info/hlc.html

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Illinois: Medical Library (OSF Saint Francis Medical Center, Peoria), http://www.osfsaintfrancis.org/general/library/

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Kentucky: Medical Library - Services for Patients, Families, Students & the Public (Central Baptist Hospital, Lexington), http://www.centralbap.com/education/community/library.cfm

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Kentucky: University of Kentucky - Health Information Library (Chandler Medical Center, Lexington), http://www.mc.uky.edu/PatientEd/

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Louisiana: Alton Ochsner Medical Foundation Library (Alton Ochsner Medical Foundation, New Orleans), http://www.ochsner.org/library/

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Louisiana: Louisiana State University Health Sciences Center Medical LibraryShreveport, http://lib-sh.lsuhsc.edu/

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Maine: Franklin Memorial Hospital Medical Library (Franklin Memorial Hospital, Farmington), http://www.fchn.org/fmh/lib.htm

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Maine: Gerrish-True Health Sciences Library (Central Maine Medical Center, Lewiston), http://www.cmmc.org/library/library.html

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Maine: Hadley Parrot Health Science Library (Eastern Maine Healthcare, Bangor), http://www.emh.org/hll/hpl/guide.htm

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Maine: Maine Medical Center Library (Maine Medical Center, Portland), http://www.mmc.org/library/

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Maine: Parkview Hospital (Brunswick), http://www.parkviewhospital.org/

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Maine: Southern Maine Medical Center Health Sciences Library (Southern Maine Medical Center, Biddeford), http://www.smmc.org/services/service.php3?choice=10

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Maine: Stephens Memorial Hospital’s Health Information Library (Western Maine Health, Norway), http://www.wmhcc.org/Library/

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•

Manitoba, Canada: Consumer & Patient Health Information Service (University of Manitoba Libraries), http://www.umanitoba.ca/libraries/units/health/reference/chis.html

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Manitoba, Canada: J.W. Crane Memorial Library (Deer Lodge Centre, Winnipeg), http://www.deerlodge.mb.ca/crane_library/about.asp

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Maryland: Health Information Center at the Wheaton Regional Library (Montgomery County, Dept. of Public Libraries, Wheaton Regional Library), http://www.mont.lib.md.us/healthinfo/hic.asp

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Massachusetts: Baystate Medical Center Library (Baystate Health System), http://www.baystatehealth.com/1024/

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Massachusetts: Boston University Medical Center Alumni Medical Library (Boston University Medical Center), http://med-libwww.bu.edu/library/lib.html

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Massachusetts: Lowell General Hospital Health Sciences Library (Lowell General Hospital, Lowell), http://www.lowellgeneral.org/library/HomePageLinks/WWW.htm

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Massachusetts: Paul E. Woodard Health Sciences Library (New England Baptist Hospital, Boston), http://www.nebh.org/health_lib.asp

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Massachusetts: St. Luke’s Hospital Health Sciences Library (St. Luke’s Hospital, Southcoast Health System, New Bedford), http://www.southcoast.org/library/

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Massachusetts: Treadwell Library Consumer Health Reference Center (Massachusetts General Hospital), http://www.mgh.harvard.edu/library/chrcindex.html

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Massachusetts: UMass HealthNet (University of Massachusetts Medical School, Worchester), http://healthnet.umassmed.edu/

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Michigan: Botsford General Hospital Library - Consumer Health (Botsford General Hospital, Library & Internet Services), http://www.botsfordlibrary.org/consumer.htm

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Michigan: Helen DeRoy Medical Library (Providence Hospital and Medical Centers), http://www.providence-hospital.org/library/

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Michigan: Marquette General Hospital - Consumer Health Library (Marquette General Hospital, Health Information Center), http://www.mgh.org/center.html

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Michigan: Patient Education Resouce Center - University of Michigan Cancer Center (University of Michigan Comprehensive Cancer Center, Ann Arbor), http://www.cancer.med.umich.edu/learn/leares.htm

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Michigan: Sladen Library & Center for Health Information Resources - Consumer Health Information (Detroit), http://www.henryford.com/body.cfm?id=39330

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Montana: Center for Health Information (St. Patrick Hospital and Health Sciences Center, Missoula)

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National: Consumer Health Library Directory (Medical Library Association, Consumer and Patient Health Information Section), http://caphis.mlanet.org/directory/index.html

•

National: National Network of Libraries of Medicine (National Library of Medicine) provides library services for health professionals in the United States who do not have access to a medical library, http://nnlm.gov/

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National: NN/LM List of Libraries Serving the Public (National Network of Libraries of Medicine), http://nnlm.gov/members/

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Nevada: Health Science Library, West Charleston Library (Las Vegas-Clark County Library District, Las Vegas), http://www.lvccld.org/special_collections/medical/index.htm

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New Hampshire: Dartmouth Biomedical Libraries (Dartmouth College Library, Hanover), http://www.dartmouth.edu/~biomed/resources.htmld/conshealth.htmld/

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New Jersey: Consumer Health Library (Rahway Hospital, Rahway), http://www.rahwayhospital.com/library.htm

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New Jersey: Dr. Walter Phillips Health Sciences Library (Englewood Hospital and Medical Center, Englewood), http://www.englewoodhospital.com/links/index.htm

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New Jersey: Meland Foundation (Englewood Hospital and Medical Center, Englewood), http://www.geocities.com/ResearchTriangle/9360/

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New York: Choices in Health Information (New York Public Library) - NLM Consumer Pilot Project participant, http://www.nypl.org/branch/health/links.html

•

New York: Health Information Center (Upstate Medical University, State University of New York, Syracuse), http://www.upstate.edu/library/hic/

•

New York: Health Sciences Library (Long Island Jewish Medical Center, New Hyde Park), http://www.lij.edu/library/library.html

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New York: ViaHealth Medical Library (Rochester General Hospital), http://www.nyam.org/library/

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Ohio: Consumer Health Library (Akron General Medical Center, Medical & Consumer Health Library), http://www.akrongeneral.org/hwlibrary.htm

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Oklahoma: The Health Information Center at Saint Francis Hospital (Saint Francis Health System, Tulsa), http://www.sfh-tulsa.com/services/healthinfo.asp

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Oregon: Planetree Health Resource Center (Mid-Columbia Medical Center, The Dalles), http://www.mcmc.net/phrc/

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Pennsylvania: Community Health Information Library (Milton S. Hershey Medical Center, Hershey), http://www.hmc.psu.edu/commhealth/

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Pennsylvania: Community Health Resource Library (Geisinger Medical Center, Danville), http://www.geisinger.edu/education/commlib.shtml

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Pennsylvania: HealthInfo Library (Moses Taylor Hospital, Scranton), http://www.mth.org/healthwellness.html

•

Pennsylvania: Hopwood Library (University of Pittsburgh, Health Sciences Library System, Pittsburgh), http://www.hsls.pitt.edu/guides/chi/hopwood/index_html

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Pennsylvania: Koop Community Health Information Center (College of Physicians of Philadelphia), http://www.collphyphil.org/kooppg1.shtml

•

Pennsylvania: Learning Resources Center - Medical Library (Susquehanna Health System, Williamsport), http://www.shscares.org/services/lrc/index.asp

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Pennsylvania: Medical Library (UPMC Health System, Pittsburgh), http://www.upmc.edu/passavant/library.htm

•

Quebec, Canada: Medical Library (Montreal General Hospital), http://www.mghlib.mcgill.ca/

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•

South Dakota: Rapid City Regional Hospital Medical Library (Rapid City Regional Hospital), http://www.rcrh.org/Services/Library/Default.asp

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Texas: Houston HealthWays (Houston Academy of Medicine-Texas Medical Center Library), http://hhw.library.tmc.edu/

•

Washington: Community Health Library (Kittitas Valley Community Hospital), http://www.kvch.com/

•

Washington: Southwest Washington Medical Center Library (Southwest Washington Medical Center, Vancouver), http://www.swmedicalcenter.com/body.cfm?id=72

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ONLINE GLOSSARIES The Internet provides access to a number of free-to-use medical dictionaries. The National Library of Medicine has compiled the following list of online dictionaries: •

ADAM Medical Encyclopedia (A.D.A.M., Inc.), comprehensive medical reference: http://www.nlm.nih.gov/medlineplus/encyclopedia.html

•

MedicineNet.com Medical Dictionary (MedicineNet, Inc.): http://www.medterms.com/Script/Main/hp.asp

•

Merriam-Webster Medical Dictionary (Inteli-Health, Inc.): http://www.intelihealth.com/IH/

•

Multilingual Glossary of Technical and Popular Medical Terms in Eight European Languages (European Commission) - Danish, Dutch, English, French, German, Italian, Portuguese, and Spanish: http://allserv.rug.ac.be/~rvdstich/eugloss/welcome.html

•

On-line Medical Dictionary (CancerWEB): http://cancerweb.ncl.ac.uk/omd/

•

Rare Diseases Terms (Office of Rare Diseases): http://ord.aspensys.com/asp/diseases/diseases.asp

•

Technology Glossary (National Library of Medicine) - Health Care Technology: http://www.nlm.nih.gov/nichsr/ta101/ta10108.htm

Beyond these, MEDLINEplus contains a very patient-friendly encyclopedia covering every aspect of medicine (licensed from A.D.A.M., Inc.). The ADAM Medical Encyclopedia can be accessed at http://www.nlm.nih.gov/medlineplus/encyclopedia.html. ADAM is also available on commercial Web sites such as drkoop.com (http://www.drkoop.com/) and Web MD (http://my.webmd.com/adam/asset/adam_disease_articles/a_to_z/a).

Online Dictionary Directories The following are additional online directories compiled by the National Library of Medicine, including a number of specialized medical dictionaries: •

Medical Dictionaries: Medical & Biological (World Health Organization): http://www.who.int/hlt/virtuallibrary/English/diction.htm#Medical

•

MEL-Michigan Electronic Library List of Online Health and Medical Dictionaries (Michigan Electronic Library): http://mel.lib.mi.us/health/health-dictionaries.html

•

Patient Education: Glossaries (DMOZ Open Directory Project): http://dmoz.org/Health/Education/Patient_Education/Glossaries/

•

Web of Online Dictionaries (Bucknell University): http://www.yourdictionary.com/diction5.html#medicine

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INSULIN RESISTANCE DICTIONARY The definitions below are derived from official public sources, including the National Institutes of Health [NIH] and the European Union [EU]. 3-dimensional: 3-D. A graphic display of depth, width, and height. Three-dimensional radiation therapy uses computers to create a 3-dimensional picture of the tumor. This allows doctors to give the highest possible dose of radiation to the tumor, while sparing the normal tissue as much as possible. [NIH] Abdomen: That portion of the body that lies between the thorax and the pelvis. [NIH] Abdominal: Having to do with the abdomen, which is the part of the body between the chest and the hips that contains the pancreas, stomach, intestines, liver, gallbladder, and other organs. [NIH] Abdominal fat: Fat (adipose tissue) that is centrally distributed between the thorax and pelvis and that induces greater health risk. [NIH] Abdominal Pain: Sensation of discomfort, distress, or agony in the abdominal region. [NIH] Aberrant: Wandering or deviating from the usual or normal course. [EU] Ablate: In surgery, is to remove. [NIH] Ablation: The removal of an organ by surgery. [NIH] Acanthosis Nigricans: A circumscribed melanosis consisting of a brown-pigmented, velvety verrucosity or fine papillomatosis appearing in the axillae and other body folds. It occurs in association with endocrine disorders, underlying malignancy, administration of certain drugs, or as in inherited disorder. [NIH] Acceptor: A substance which, while normally not oxidized by oxygen or reduced by hydrogen, can be oxidized or reduced in presence of a substance which is itself undergoing oxidation or reduction. [NIH] Acetylcholine: A neurotransmitter. Acetylcholine in vertebrates is the major transmitter at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. It is generally not used as an administered drug because it is broken down very rapidly by cholinesterases, but it is useful in some ophthalmological applications. [NIH] Acne: A disorder of the skin marked by inflammation of oil glands and hair glands. [NIH] Actin: Essential component of the cell skeleton. [NIH] Acyl: Chemical signal used by bacteria to communicate. [NIH] Adaptation: 1. The adjustment of an organism to its environment, or the process by which it enhances such fitness. 2. The normal ability of the eye to adjust itself to variations in the intensity of light; the adjustment to such variations. 3. The decline in the frequency of firing of a neuron, particularly of a receptor, under conditions of constant stimulation. 4. In dentistry, (a) the proper fitting of a denture, (b) the degree of proximity and interlocking of restorative material to a tooth preparation, (c) the exact adjustment of bands to teeth. 5. In microbiology, the adjustment of bacterial physiology to a new environment. [EU] Adenine: A purine base and a fundamental unit of adenine nucleotides. [NIH] Adenosine: A nucleoside that is composed of adenine and d-ribose. Adenosine or adenosine derivatives play many important biological roles in addition to being components of DNA

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and RNA. Adenosine itself is a neurotransmitter. [NIH] Adenylate Kinase: An enzyme that catalyzes the phosphorylation of AMP to ADP in the presence of ATP or inorganic triphosphate. EC 2.7.4.3. [NIH] Adipocytes: Fat-storing cells found mostly in the abdominal cavity and subcutaneous tissue. Fat is usually stored in the form of tryglycerides. [NIH] Adipose Tissue: Connective tissue composed of fat cells lodged in the meshes of areolar tissue. [NIH] Adjustment: The dynamic process wherein the thoughts, feelings, behavior, and biophysiological mechanisms of the individual continually change to adjust to the environment. [NIH] Adolescence: The period of life beginning with the appearance of secondary sex characteristics and terminating with the cessation of somatic growth. The years usually referred to as adolescence lie between 13 and 18 years of age. [NIH] Adrenal Cortex: The outer layer of the adrenal gland. It secretes mineralocorticoids, androgens, and glucocorticoids. [NIH] Adrenal Glands: Paired glands situated in the retroperitoneal tissues at the superior pole of each kidney. [NIH] Adrenal insufficiency: The reduced secretion of adrenal glands. [NIH] Adrenergic: Activated by, characteristic of, or secreting epinephrine or substances with similar activity; the term is applied to those nerve fibres that liberate norepinephrine at a synapse when a nerve impulse passes, i.e., the sympathetic fibres. [EU] Adverse Effect: An unwanted side effect of treatment. [NIH] Aerobic: In biochemistry, reactions that need oxygen to happen or happen when oxygen is present. [NIH] Aerobic Exercise: A type of physical activity that includes walking, jogging, running, and dancing. Aerobic training improves the efficiency of the aerobic energy-producing systems that can improve cardiorespiratory endurance. [NIH] Aerobic Metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, oxidative metabolism, or cell respiration. [NIH] Aerobic Respiration: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as oxidative metabolism, cell respiration, or aerobic metabolism. [NIH] Afferent: Concerned with the transmission of neural impulse toward the central part of the nervous system. [NIH] Affinity: 1. Inherent likeness or relationship. 2. A special attraction for a specific element, organ, or structure. 3. Chemical affinity; the force that binds atoms in molecules; the tendency of substances to combine by chemical reaction. 4. The strength of noncovalent chemical binding between two substances as measured by the dissociation constant of the complex. 5. In immunology, a thermodynamic expression of the strength of interaction between a single antigen-binding site and a single antigenic determinant (and thus of the stereochemical compatibility between them), most accurately applied to interactions among simple, uniform antigenic determinants such as haptens. Expressed as the association constant (K litres mole -1), which, owing to the heterogeneity of affinities in a population of antibody molecules of a given specificity, actually represents an average value (mean intrinsic association constant). 6. The reciprocal of the dissociation constant. [EU]

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Age Factors: Age as a constituent element or influence contributing to the production of a result. It may be applicable to the cause or the effect of a circumstance. It is used with human or animal concepts but should be differentiated from aging, a physiological process, and time factors which refers only to the passage of time. [NIH] Age of Onset: The age or period of life at which a disease or the initial symptoms or manifestations of a disease appear in an individual. [NIH] Agonist: In anatomy, a prime mover. In pharmacology, a drug that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally occurring substances. [EU] Airway: A device for securing unobstructed passage of air into and out of the lungs during general anesthesia. [NIH] Albumin: 1. Any protein that is soluble in water and moderately concentrated salt solutions and is coagulable by heat. 2. Serum albumin; the major plasma protein (approximately 60 per cent of the total), which is responsible for much of the plasma colloidal osmotic pressure and serves as a transport protein carrying large organic anions, such as fatty acids, bilirubin, and many drugs, and also carrying certain hormones, such as cortisol and thyroxine, when their specific binding globulins are saturated. Albumin is synthesized in the liver. Low serum levels occur in protein malnutrition, active inflammation and serious hepatic and renal disease. [EU] Aldosterone: (11 beta)-11,21-Dihydroxy-3,20-dioxopregn-4-en-18-al. A hormone secreted by the adrenal cortex that functions in the regulation of electrolyte and water balance by increasing the renal retention of sodium and the excretion of potassium. [NIH] Algorithms: A procedure consisting of a sequence of algebraic formulas and/or logical steps to calculate or determine a given task. [NIH] Alimentary: Pertaining to food or nutritive material, or to the organs of digestion. [EU] Alkaline: Having the reactions of an alkali. [EU] Alkaloid: A member of a large group of chemicals that are made by plants and have nitrogen in them. Some alkaloids have been shown to work against cancer. [NIH] Alleles: Mutually exclusive forms of the same gene, occupying the same locus on homologous chromosomes, and governing the same biochemical and developmental process. [NIH] Allergen: An antigenic substance capable of producing immediate-type hypersensitivity (allergy). [EU] Allograft: An organ or tissue transplant between two humans. [NIH] Alopecia: Absence of hair from areas where it is normally present. [NIH] Alpha-1: A protein with the property of inactivating proteolytic enzymes such as leucocyte collagenase and elastase. [NIH] Alternative medicine: Practices not generally recognized by the medical community as standard or conventional medical approaches and used instead of standard treatments. Alternative medicine includes the taking of dietary supplements, megadose vitamins, and herbal preparations; the drinking of special teas; and practices such as massage therapy, magnet therapy, spiritual healing, and meditation. [NIH] Ameliorating: A changeable condition which prevents the consequence of a failure or accident from becoming as bad as it otherwise would. [NIH] Amenorrhea: Absence of menstruation. [NIH] Amino Acid Sequence: The order of amino acids as they occur in a polypeptide chain. This

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is referred to as the primary structure of proteins. It is of fundamental importance in determining protein conformation. [NIH] Amino Acid Substitution: The naturally occurring or experimentally induced replacement of one or more amino acids in a protein with another. If a functionally equivalent amino acid is substituted, the protein may retain wild-type activity. Substitution may also diminish or eliminate protein function. Experimentally induced substitution is often used to study enzyme activities and binding site properties. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins. [NIH] Amlodipine: 2-((2-Aminoethoxy)methyl)-4-(2-chlorophenyl)-1,4-dihydro-6-methyl-3,5pyridinedicarboxylic acid 3-ethyl 5-methyl ester. A long-acting dihydropyridine calcium channel blocker. It is effective in the treatment of angina pectoris and hypertension. [NIH] Ammonia: A colorless alkaline gas. It is formed in the body during decomposition of organic materials during a large number of metabolically important reactions. [NIH] Amnion: The extraembryonic membrane which contains the embryo and amniotic fluid. [NIH]

Amniotic Fluid: Amniotic cavity fluid which is produced by the amnion and fetal lungs and kidneys. [NIH] Amphetamine: A powerful central nervous system stimulant and sympathomimetic. Amphetamine has multiple mechanisms of action including blocking uptake of adrenergics and dopamine, stimulation of release of monamines, and inhibiting monoamine oxidase. Amphetamine is also a drug of abuse and a psychotomimetic. The l- and the d,l-forms are included here. The l-form has less central nervous system activity but stronger cardiovascular effects. The d-form is dextroamphetamine. [NIH] Anabolic: Relating to, characterized by, or promoting anabolism. [EU] Anaesthesia: Loss of feeling or sensation. Although the term is used for loss of tactile sensibility, or of any of the other senses, it is applied especially to loss of the sensation of pain, as it is induced to permit performance of surgery or other painful procedures. [EU] Anal: Having to do with the anus, which is the posterior opening of the large bowel. [NIH] Analgesic: An agent that alleviates pain without causing loss of consciousness. [EU] Analog: In chemistry, a substance that is similar, but not identical, to another. [NIH] Analogous: Resembling or similar in some respects, as in function or appearance, but not in origin or development;. [EU] Analysis of Variance: A statistical technique that isolates and assesses the contributions of categorical independent variables to variation in the mean of a continuous dependent variable. [NIH] Anatomical: Pertaining to anatomy, or to the structure of the organism. [EU] Androgen suppression: Treatment to suppress or block the production of male hormones. Androgen suppression is achieved by surgical removal of the testicles, by taking female sex hormones, or by taking other drugs. Also called androgen ablation. [NIH] Androgen-Binding Protein: Carrier proteins produced in the Sertoli cells of the testis, secreted into the seminiferous tubules, and transported via the efferent ducts to the

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epididymis. They participate in the transport of androgens. Androgen-binding protein has the same amino acid sequence as sex hormone binding-globulin. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Androgens: A class of sex hormones associated with the development and maintenance of the secondary male sex characteristics, sperm induction, and sexual differentiation. In addition to increasing virility and libido, they also increase nitrogen and water retention and stimulate skeletal growth. [NIH] Anemia: A reduction in the number of circulating erythrocytes or in the quantity of hemoglobin. [NIH] Aneurysm: A sac formed by the dilatation of the wall of an artery, a vein, or the heart. [NIH] Angina: Chest pain that originates in the heart. [NIH] Angina Pectoris: The symptom of paroxysmal pain consequent to myocardial ischemia usually of distinctive character, location and radiation, and provoked by a transient stressful situation during which the oxygen requirements of the myocardium exceed the capacity of the coronary circulation to supply it. [NIH] Angiopathy: Disease of the blood vessels (arteries, veins, and capillaries) that occurs when someone has diabetes for a long time. There are two types of angiopathy: macroangiopathy and microangiopathy. In macroangiopathy, fat and blood clots build up in the large blood vessels, stick to the vessel walls, and block the flow of blood. In microangiopathy, the walls of the smaller blood vessels become so thick and weak that they bleed, leak protein, and slow the flow of blood through the body. Then the cells, for example, the ones in the center of the eye, do not get enough blood and may be damaged. [NIH] Angiotensin converting enzyme inhibitor: A drug used to decrease pressure inside blood vessels. [NIH] Angiotensinogen: An alpha-globulin of which a fragment of 14 amino acids is converted by renin to angiotensin I, the inactive precursor of angiotensin II. It is a member of the serpin superfamily. [NIH] Animal model: An animal with a disease either the same as or like a disease in humans. Animal models are used to study the development and progression of diseases and to test new treatments before they are given to humans. Animals with transplanted human cancers or other tissues are called xenograft models. [NIH] Anions: Negatively charged atoms, radicals or groups of atoms which travel to the anode or positive pole during electrolysis. [NIH] Anorexia: Lack or loss of appetite for food. Appetite is psychologic, dependent on memory and associations. Anorexia can be brought about by unattractive food, surroundings, or company. [NIH] Anorexia Nervosa: The chief symptoms are inability to eat, weight loss, and amenorrhea. [NIH]

Anovulation: Suspension or cessation of ovulation in animals and humans. [NIH] Antagonism: Interference with, or inhibition of, the growth of a living organism by another living organism, due either to creation of unfavorable conditions (e. g. exhaustion of food supplies) or to production of a specific antibiotic substance (e. g. penicillin). [NIH] Anterior Cerebral Artery: Artery formed by the bifurcation of the internal carotid artery. Branches of the anterior cerebral artery supply the caudate nucleus, internal capsule, putamen, septal nuclei, gyrus cinguli, and surfaces of the frontal lobe and parietal lobe. [NIH] Anthropometric measurements: Measurements of human body height, weight, and size of component parts, including skinfold measurement. Used to study and compare the relative

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proportions under normal and abnormal conditions. [NIH] Anthropometry: The technique that deals with the measurement of the size, weight, and proportions of the human or other primate body. [NIH] Antiallergic: Counteracting allergy or allergic conditions. [EU] Antibacterial: A substance that destroys bacteria or suppresses their growth or reproduction. [EU] Antibiotic: A drug used to treat infections caused by bacteria and other microorganisms. [NIH]

Antibodies: Immunoglobulin molecules having a specific amino acid sequence by virtue of which they interact only with the antigen that induced their synthesis in cells of the lymphoid series (especially plasma cells), or with an antigen closely related to it. [NIH] Antibody: A type of protein made by certain white blood cells in response to a foreign substance (antigen). Each antibody can bind to only a specific antigen. The purpose of this binding is to help destroy the antigen. Antibodies can work in several ways, depending on the nature of the antigen. Some antibodies destroy antigens directly. Others make it easier for white blood cells to destroy the antigen. [NIH] Anticoagulant: A drug that helps prevent blood clots from forming. Also called a blood thinner. [NIH] Anticonvulsant: An agent that prevents or relieves convulsions. [EU] Antidepressant: A drug used to treat depression. [NIH] Antidiabetic: An agent that prevents or alleviates diabetes. [EU] Antidiabetic Agent: A substance that helps a person with diabetes control the level of glucose (sugar) in the blood so that the body works as it should. [NIH] Antigen: Any substance which is capable, under appropriate conditions, of inducing a specific immune response and of reacting with the products of that response, that is, with specific antibody or specifically sensitized T-lymphocytes, or both. Antigens may be soluble substances, such as toxins and foreign proteins, or particulate, such as bacteria and tissue cells; however, only the portion of the protein or polysaccharide molecule known as the antigenic determinant (q.v.) combines with antibody or a specific receptor on a lymphocyte. Abbreviated Ag. [EU] Antihypertensive: An agent that reduces high blood pressure. [EU] Anti-inflammatory: Having to do with reducing inflammation. [NIH] Anti-Inflammatory Agents: Substances that reduce or suppress inflammation. [NIH] Antimetabolite: A chemical that is very similar to one required in a normal biochemical reaction in cells. Antimetabolites can stop or slow down the reaction. [NIH] Antineoplastic: Inhibiting or preventing the development of neoplasms, checking the maturation and proliferation of malignant cells. [EU] Antioxidant: A substance that prevents damage caused by free radicals. Free radicals are highly reactive chemicals that often contain oxygen. They are produced when molecules are split to give products that have unpaired electrons. This process is called oxidation. [NIH] Antipyretic: An agent that relieves or reduces fever. Called also antifebrile, antithermic and febrifuge. [EU] Antiviral: Destroying viruses or suppressing their replication. [EU] Apnea: A transient absence of spontaneous respiration. [NIH] Apnoea: Cessation of breathing. [EU]

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Apolipoproteins: The protein components of lipoproteins which remain after the lipids to which the proteins are bound have been removed. They play an important role in lipid transport and metabolism. [NIH] Apoptosis: One of the two mechanisms by which cell death occurs (the other being the pathological process of necrosis). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA (DNA fragmentation) at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth. [NIH] Appetite Regulation: Physiologic mechanisms which regulate or control the appetite and food intake. [NIH] Aqueous: Having to do with water. [NIH] Arachidonic Acid: An unsaturated, essential fatty acid. It is found in animal and human fat as well as in the liver, brain, and glandular organs, and is a constituent of animal phosphatides. It is formed by the synthesis from dietary linoleic acid and is a precursor in the biosynthesis of prostaglandins, thromboxanes, and leukotrienes. [NIH] Arginine: An essential amino acid that is physiologically active in the L-form. [NIH] Aromatase: An enzyme which converts androgens to estrogens by desaturating ring A of the steroid. This enzyme complex is located in the endoplasmic reticulum of estrogenproducing cells including ovaries, placenta, testicular Sertoli and Leydig cells, adipose, and brain tissues. The enzyme complex has two components, one of which is the CYP19 gene product, the aromatase cytochrome P-450. The other component is NADPH-cytochrome P450 reductase which transfers reducing equivalents to P-450(arom). EC 1.14.13.-. [NIH] Aromatic: Having a spicy odour. [EU] Arterial: Pertaining to an artery or to the arteries. [EU] Arteries: The vessels carrying blood away from the heart. [NIH] Arterioles: The smallest divisions of the arteries located between the muscular arteries and the capillaries. [NIH] Arteriolosclerosis: Sclerosis and thickening of the walls of the smaller arteries (arterioles). Hyaline arteriolosclerosis, in which there is homogeneous pink hyaline thickening of the arteriolar walls, is associated with benign nephrosclerosis. Hyperplastic arteriolosclerosis, in which there is a concentric thickening with progressive narrowing of the lumina may be associated with malignant hypertension, nephrosclerosis, and scleroderma. [EU] Arteriosclerosis: Thickening and loss of elasticity of arterial walls. Atherosclerosis is the most common form of arteriosclerosis and involves lipid deposition and thickening of the intimal cell layers within arteries. Additional forms of arteriosclerosis involve calcification of the media of muscular arteries (Monkeberg medial calcific sclerosis) and thickening of the walls of small arteries or arterioles due to cell proliferation or hyaline deposition (arteriolosclerosis). [NIH] Aspirin: A drug that reduces pain, fever, inflammation, and blood clotting. Aspirin belongs to the family of drugs called nonsteroidal anti-inflammatory agents. It is also being studied in cancer prevention. [NIH] Asymptomatic: Having no signs or symptoms of disease. [NIH] Ataxia: Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharnyx, larnyx, and other structures.

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Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. [NIH] Atherogenic: Causing the formation of plaque in the lining of the arteries. [NIH] Atrial: Pertaining to an atrium. [EU] Atrioventricular: Pertaining to an atrium of the heart and to a ventricle. [EU] Atrium: A chamber; used in anatomical nomenclature to designate a chamber affording entrance to another structure or organ. Usually used alone to designate an atrium of the heart. [EU] Atrophy: Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. [NIH] Attenuated: Strain with weakened or reduced virulence. [NIH] Atypical: Irregular; not conformable to the type; in microbiology, applied specifically to strains of unusual type. [EU] Autoantibodies: Antibodies that react with self-antigens (autoantigens) of the organism that produced them. [NIH] Autoantigens: Endogenous tissue constituents that have the ability to interact with autoantibodies and cause an immune response. [NIH] Autodigestion: Autolysis; a condition found in disease of the stomach: the stomach wall is digested by the gastric juice. [NIH] Autoimmune disease: A condition in which the body recognizes its own tissues as foreign and directs an immune response against them. [NIH] Autoimmunity: Process whereby the immune system reacts against the body's own tissues. Autoimmunity may produce or be caused by autoimmune diseases. [NIH] Autonomic: Self-controlling; functionally independent. [EU] Autonomic Nervous System: The enteric, parasympathetic, and sympathetic nervous systems taken together. Generally speaking, the autonomic nervous system regulates the internal environment during both peaceful activity and physical or emotional stress. Autonomic activity is controlled and integrated by the central nervous system, especially the hypothalamus and the solitary nucleus, which receive information relayed from visceral afferents; these and related central and sensory structures are sometimes (but not here) considered to be part of the autonomic nervous system itself. [NIH] Autosuggestion: Suggestion coming from the subject himself. [NIH] Axillary: Pertaining to the armpit area, including the lymph nodes that are located there. [NIH]

Axillary Artery: The continuation of the subclavian artery; it distributes over the upper limb, axilla, chest and shoulder. [NIH] Bacteria: Unicellular prokaryotic microorganisms which generally possess rigid cell walls, multiply by cell division, and exhibit three principal forms: round or coccal, rodlike or bacillary, and spiral or spirochetal. [NIH] Bacterial Translocation: The passage of viable bacteria from the gastrointestinal tract to extra-intestinal sites, such as the mesenteric lymph node complex, liver, spleen, kidney, and blood. Factors that promote bacterial translocation include overgrowth with gram-negative enteric bacilli, impaired host immune defenses, and injury to the intestinal mucosa resulting

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in increased intestinal permeability. These mechanisms can act in concert to promote synergistically the systemic spread of indigenous translocating bacteria to cause lethal sepsis. [NIH] Bactericidal: Substance lethal to bacteria; substance capable of killing bacteria. [NIH] Bacteriophage: A virus whose host is a bacterial cell; A virus that exclusively infects bacteria. It generally has a protein coat surrounding the genome (DNA or RNA). One of the coliphages most extensively studied is the lambda phage, which is also one of the most important. [NIH] Bacterium: Microscopic organism which may have a spherical, rod-like, or spiral unicellular or non-cellular body. Bacteria usually reproduce through asexual processes. [NIH] Basal Ganglia: Large subcortical nuclear masses derived from the telencephalon and located in the basal regions of the cerebral hemispheres. [NIH] Basal Ganglia Diseases: Diseases of the basal ganglia including the putamen; globus pallidus; claustrum; amygdala; and caudate nucleus. Dyskinesias (most notably involuntary movements and alterations of the rate of movement) represent the primary clinical manifestations of these disorders. Common etiologies include cerebrovascular disease; neurodegenerative diseases; and craniocerebral trauma. [NIH] Base: In chemistry, the nonacid part of a salt; a substance that combines with acids to form salts; a substance that dissociates to give hydroxide ions in aqueous solutions; a substance whose molecule or ion can combine with a proton (hydrogen ion); a substance capable of donating a pair of electrons (to an acid) for the formation of a coordinate covalent bond. [EU] Basement Membrane: Ubiquitous supportive tissue adjacent to epithelium and around smooth and striated muscle cells. This tissue contains intrinsic macromolecular components such as collagen, laminin, and sulfated proteoglycans. As seen by light microscopy one of its subdivisions is the basal (basement) lamina. [NIH] Basophils: Granular leukocytes characterized by a relatively pale-staining, lobate nucleus and cytoplasm containing coarse dark-staining granules of variable size and stainable by basic dyes. [NIH] Benzene: Toxic, volatile, flammable liquid hydrocarbon biproduct of coal distillation. It is used as an industrial solvent in paints, varnishes, lacquer thinners, gasoline, etc. Benzene causes central nervous system damage acutely and bone marrow damage chronically and is carcinogenic. It was formerly used as parasiticide. [NIH] Bilateral: Affecting both the right and left side of body. [NIH] Bile: An emulsifying agent produced in the liver and secreted into the duodenum. Its composition includes bile acids and salts, cholesterol, and electrolytes. It aids digestion of fats in the duodenum. [NIH] Bile Ducts: Tubes that carry bile from the liver to the gallbladder for storage and to the small intestine for use in digestion. [NIH] Biliary: Having to do with the liver, bile ducts, and/or gallbladder. [NIH] Biliary Tract: The gallbladder and its ducts. [NIH] Bilirubin: A bile pigment that is a degradation product of heme. [NIH] Bioavailability: The degree to which a drug or other substance becomes available to the target tissue after administration. [EU] Biochemical: Relating to biochemistry; characterized by, produced by, or involving chemical reactions in living organisms. [EU] Biogenesis: The origin of life. It includes studies of the potential basis for life in organic

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compounds but excludes studies of the development of altered forms of life through mutation and natural selection, which is evolution. [NIH] Biogenic Amines: A group of naturally occurring amines derived by enzymatic decarboxylation of the natural amino acids. Many have powerful physiological effects (e.g., histamine, serotonin, epinephrine, tyramine). Those derived from aromatic amino acids, and also their synthetic analogs (e.g., amphetamine), are of use in pharmacology. [NIH] Biological therapy: Treatment to stimulate or restore the ability of the immune system to fight infection and disease. Also used to lessen side effects that may be caused by some cancer treatments. Also known as immunotherapy, biotherapy, or biological response modifier (BRM) therapy. [NIH] Biomarkers: Substances sometimes found in an increased amount in the blood, other body fluids, or tissues and that may suggest the presence of some types of cancer. Biomarkers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and GI tract cancers), and PSA (prostate cancer). Also called tumor markers. [NIH] Biopsy: Removal and pathologic examination of specimens in the form of small pieces of tissue from the living body. [NIH] Biosynthesis: The building up of a chemical compound in the physiologic processes of a living organism. [EU] Biotechnology: Body of knowledge related to the use of organisms, cells or cell-derived constituents for the purpose of developing products which are technically, scientifically and clinically useful. Alteration of biologic function at the molecular level (i.e., genetic engineering) is a central focus; laboratory methods used include transfection and cloning technologies, sequence and structure analysis algorithms, computer databases, and gene and protein structure function analysis and prediction. [NIH] Biotin: Hexahydro-2-oxo-1H-thieno(3,4-d)imidazole-4-pentanoic acid. Growth factor present in minute amounts in every living cell. It occurs mainly bound to proteins or polypeptides and is abundant in liver, kidney, pancreas, yeast, and milk.The biotin content of cancerous tissue is higher than that of normal tissue. [NIH] Bladder: The organ that stores urine. [NIH] Bloating: Fullness or swelling in the abdomen that often occurs after meals. [NIH] Blood Cell Count: A count of the number of leukocytes and erythrocytes per unit volume in a sample of venous blood. A complete blood count (CBC) also includes measurement of the hemoglobin, hematocrit, and erythrocyte indices. [NIH] Blood Coagulation: The process of the interaction of blood coagulation factors that results in an insoluble fibrin clot. [NIH] Blood Glucose: Glucose in blood. [NIH] Blood Platelets: Non-nucleated disk-shaped cells formed in the megakaryocyte and found in the blood of all mammals. They are mainly involved in blood coagulation. [NIH] Blood pressure: The pressure of blood against the walls of a blood vessel or heart chamber. Unless there is reference to another location, such as the pulmonary artery or one of the heart chambers, it refers to the pressure in the systemic arteries, as measured, for example, in the forearm. [NIH] Blood vessel: A tube in the body through which blood circulates. Blood vessels include a network of arteries, arterioles, capillaries, venules, and veins. [NIH] Body Composition: The relative amounts of various components in the body, such as percent body fat. [NIH]

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Body Fluids: Liquid components of living organisms. [NIH] Body Image: Individuals' personal concept of their bodies as objects in and bound by space, independently and apart from all other objects. [NIH] Body Mass Index: One of the anthropometric measures of body mass; it has the highest correlation with skinfold thickness or body density. [NIH] Bolus: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus infusion. [NIH] Bolus infusion: A single dose of drug usually injected into a blood vessel over a short period of time. Also called bolus. [NIH] Bolus injection: The injection of a drug (or drugs) in a high quantity (called a bolus) at once, the opposite of gradual administration (as in intravenous infusion). [EU] Bone Marrow: The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. [NIH] Bone Marrow Transplantation: The transference of bone marrow from one human or animal to another. [NIH] Bone scan: A technique to create images of bones on a computer screen or on film. A small amount of radioactive material is injected into a blood vessel and travels through the bloodstream; it collects in the bones and is detected by a scanner. [NIH] Bowel: The long tube-shaped organ in the abdomen that completes the process of digestion. There is both a small and a large bowel. Also called the intestine. [NIH] Bowel Movement: Body wastes passed through the rectum and anus. [NIH] Brachial: All the nerves from the arm are ripped from the spinal cord. [NIH] Brachial Artery: The continuation of the axillary artery; it branches into the radial and ulnar arteries. [NIH] Bradykinin: A nonapeptide messenger that is enzymatically produced from kallidin in the blood where it is a potent but short-lived agent of arteriolar dilation and increased capillary permeability. Bradykinin is also released from mast cells during asthma attacks, from gut walls as a gastrointestinal vasodilator, from damaged tissues as a pain signal, and may be a neurotransmitter. [NIH] Branch: Most commonly used for branches of nerves, but applied also to other structures. [NIH]

Breakdown: A physical, metal, or nervous collapse. [NIH] Broad-spectrum: Effective against a wide range of microorganisms; said of an antibiotic. [EU] Buccal: Pertaining to or directed toward the cheek. In dental anatomy, used to refer to the buccal surface of a tooth. [EU] Bulimia: Episodic binge eating. The episodes may be associated with the fear of not being able to stop eating, depressed mood, or self-deprecating thoughts (binge-eating disorder) and may frequently be terminated by self-induced vomiting (bulimia nervosa). [NIH] Burns: Injuries to tissues caused by contact with heat, steam, chemicals (burns, chemical), electricity (burns, electric), or the like. [NIH] Burns, Electric: Burns produced by contact with electric current or from a sudden discharge

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of electricity. [NIH] Cachexia: General ill health, malnutrition, and weight loss, usually associated with chronic disease. [NIH] Calcification: Deposits of calcium in the tissues of the breast. Calcification in the breast can be seen on a mammogram, but cannot be detected by touch. There are two types of breast calcification, macrocalcification and microcalcification. Macrocalcifications are large deposits and are usually not related to cancer. Microcalcifications are specks of calcium that may be found in an area of rapidly dividing cells. Many microcalcifications clustered together may be a sign of cancer. [NIH] Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. [NIH] Calcium channel blocker: A drug used to relax the blood vessel and heart muscle, causing pressure inside blood vessels to drop. It also can regulate heart rhythm. [NIH] Calcium Channels: Voltage-dependent cell membrane glycoproteins selectively permeable to calcium ions. They are categorized as L-, T-, N-, P-, Q-, and R-types based on the activation and inactivation kinetics, ion specificity, and sensitivity to drugs and toxins. The L- and T-types are present throughout the cardiovascular and central nervous systems and the N-, P-, Q-, & R-types are located in neuronal tissue. [NIH] Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins. [NIH]

Calculi: An abnormal concretion occurring mostly in the urinary and biliary tracts, usually composed of mineral salts. Also called stones. [NIH] Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels. [NIH] Caloric intake: Refers to the number of calories (energy content) consumed. [NIH] Calpain: Cysteine proteinase found in many tissues. Hydrolyzes a variety of endogenous proteins including neuropeptides, cytoskeletal proteins, proteins from smooth muscle, cardiac muscle, liver, platelets and erythrocytes. Two subclasses having high and low calcium sensitivity are known. Removes Z-discs and M-lines from myofibrils. Activates phosphorylase kinase and cyclic nucleotide-independent protein kinase. [NIH] Capillary: Any one of the minute vessels that connect the arterioles and venules, forming a network in nearly all parts of the body. Their walls act as semipermeable membranes for the interchange of various substances, including fluids, between the blood and tissue fluid; called also vas capillare. [EU] Capsules: Hard or soft soluble containers used for the oral administration of medicine. [NIH] Carbamazepine: An anticonvulsant used to control grand mal and psychomotor or focal seizures. Its mode of action is not fully understood, but some of its actions resemble those of phenytoin; although there is little chemical resemblance between the two compounds, their three-dimensional structure is similar. [NIH]

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Carbohydrate: An aldehyde or ketone derivative of a polyhydric alcohol, particularly of the pentahydric and hexahydric alcohols. They are so named because the hydrogen and oxygen are usually in the proportion to form water, (CH2O)n. The most important carbohydrates are the starches, sugars, celluloses, and gums. They are classified into mono-, di-, tri-, polyand heterosaccharides. [EU] Carbon Dioxide: A colorless, odorless gas that can be formed by the body and is necessary for the respiration cycle of plants and animals. [NIH] Carcinogenesis: The process by which normal cells are transformed into cancer cells. [NIH] Carcinogenic: Producing carcinoma. [EU] Carcinogens: Substances that increase the risk of neoplasms in humans or animals. Both genotoxic chemicals, which affect DNA directly, and nongenotoxic chemicals, which induce neoplasms by other mechanism, are included. [NIH] Carcinoma: Cancer that begins in the skin or in tissues that line or cover internal organs. [NIH]

Cardiac: Having to do with the heart. [NIH] Cardiac Output: The volume of blood passing through the heart per unit of time. It is usually expressed as liters (volume) per minute so as not to be confused with stroke volume (volume per beat). [NIH] Cardiomyopathy: A general diagnostic term designating primary myocardial disease, often of obscure or unknown etiology. [EU] Cardiorespiratory: Relating to the heart and lungs and their function. [EU] Cardiovascular: Having to do with the heart and blood vessels. [NIH] Cardiovascular disease: Any abnormal condition characterized by dysfunction of the heart and blood vessels. CVD includes atherosclerosis (especially coronary heart disease, which can lead to heart attacks), cerebrovascular disease (e.g., stroke), and hypertension (high blood pressure). [NIH] Carnitine: Constituent of striated muscle and liver. It is used therapeutically to stimulate gastric and pancreatic secretions and in the treatment of hyperlipoproteinemias. [NIH] Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes. [NIH] Catabolism: Any destructive metabolic process by which organisms convert substances into excreted compounds. [EU] Cataracts: In medicine, an opacity of the crystalline lens of the eye obstructing partially or totally its transmission of light. [NIH] Catecholamine: A group of chemical substances manufactured by the adrenal medulla and secreted during physiological stress. [NIH] Catheters: A small, flexible tube that may be inserted into various parts of the body to inject or remove liquids. [NIH] Caudal: Denoting a position more toward the cauda, or tail, than some specified point of reference; same as inferior, in human anatomy. [EU] Causal: Pertaining to a cause; directed against a cause. [EU] Cause of Death: Factors which produce cessation of all vital bodily functions. They can be analyzed from an epidemiologic viewpoint. [NIH] Caveolae: Endocytic/exocytic cell membrane structures rich in glycosphingolipids, cholesterol, and lipid-anchored membrane proteins that function in endocytosis

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(potocytosis), transcytosis, and signal transduction. Caveolae assume various shapes from open pits to closed vesicles. Caveolar coats are composed of caveolins. [NIH] Caveolins: The main structural proteins of caveolae. Several distinct genes for caveolins have been identified. [NIH] Cecum: The beginning of the large intestine. The cecum is connected to the lower part of the small intestine, called the ileum. [NIH] Cell: The individual unit that makes up all of the tissues of the body. All living things are made up of one or more cells. [NIH] Cell Death: The termination of the cell's ability to carry out vital functions such as metabolism, growth, reproduction, responsiveness, and adaptability. [NIH] Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function which takes place during the development of the embryo and leads to the formation of specialized cells, tissues, and organs. [NIH] Cell Division: The fission of a cell. [NIH] Cell membrane: Cell membrane = plasma membrane. The structure enveloping a cell, enclosing the cytoplasm, and forming a selective permeability barrier; it consists of lipids, proteins, and some carbohydrates, the lipids thought to form a bilayer in which integral proteins are embedded to varying degrees. [EU] Cell Membrane Structures: Structures which are part of the cell membrane or have cell membrane as a major part of their structure. [NIH] Cell proliferation: An increase in the number of cells as a result of cell growth and cell division. [NIH] Cell Respiration: The metabolic process of all living cells (animal and plant) in which oxygen is used to provide a source of energy for the cell. [NIH] Cell Size: The physical dimensions of a cell. It refers mainly to changes in dimensions correlated with physiological or pathological changes in cells. [NIH] Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability. [NIH] Central fat distribution: The waist circumference is an index of body fat distribution. Increasing waist circumference is accompanied by increasing frequencies of overt type 2 diabetes, dyslipidemia, hypertension, coronary heart disease, stroke, and early mortality. In the body fat patterns called android type (apple shaped) fat is deposited around the waist and upper abdominal area and appears most often in men. Abdominal body fat is thought to be associated with a rapid mobilization of fatty acids rather than resulting from other fat depots, although it remains a point of contention. If abdominal fat is indeed more active than other fat depots, it would then provide a mechanism by which we could explain (in part) the increase in blood lipid and glucose levels. The latter have been clearly associated with an increased risk for cardiovascular disease, hypertension, and type 2 diabetes. The gynoid type (pear-shaped) of body fat is usually seen in women. The fat is deposited around the hips, thighs, and buttocks, and presumably is used as energy reserve during pregnancy and lactation. [NIH] Central Nervous System: The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. [NIH] Cerebellar: Pertaining to the cerebellum. [EU] Cerebral: Of or pertaining of the cerebrum or the brain. [EU]

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Cerebral Infarction: The formation of an area of necrosis in the cerebrum caused by an insufficiency of arterial or venous blood flow. Infarcts of the cerebrum are generally classified by hemisphere (i.e., left vs. right), lobe (e.g., frontal lobe infarction), arterial distribution (e.g., infarction, anterior cerebral artery), and etiology (e.g., embolic infarction). [NIH]

Cerebrospinal: Pertaining to the brain and spinal cord. [EU] Cerebrospinal fluid: CSF. The fluid flowing around the brain and spinal cord. Cerebrospinal fluid is produced in the ventricles in the brain. [NIH] Cerebrovascular: Pertaining to the blood vessels of the cerebrum, or brain. [EU] Cerebrum: The largest part of the brain. It is divided into two hemispheres, or halves, called the cerebral hemispheres. The cerebrum controls muscle functions of the body and also controls speech, emotions, reading, writing, and learning. [NIH] Chemopreventive: Natural or synthetic compound used to intervene in the early precancerous stages of carcinogenesis. [NIH] Cholesterol: The principal sterol of all higher animals, distributed in body tissues, especially the brain and spinal cord, and in animal fats and oils. [NIH] Cholesterol Esters: Fatty acid esters of cholesterol which constitute about two-thirds of the cholesterol in the plasma. The accumulation of cholesterol esters in the arterial intima is a characteristic feature of atherosclerosis. [NIH] Cholinergic: Resembling acetylcholine in pharmacological action; stimulated by or releasing acetylcholine or a related compound. [EU] Chromatin: The material of chromosomes. It is a complex of DNA, histones, and nonhistone proteins (chromosomal proteins, non-histone) found within the nucleus of a cell. [NIH] Chromium: A trace element that plays a role in glucose metabolism. It has the atomic symbol Cr, atomic number 24, and atomic weight 52. According to the Fourth Annual Report on Carcinogens (NTP85-002,1985), chromium and some of its compounds have been listed as known carcinogens. [NIH] Chromosomal: Pertaining to chromosomes. [EU] Chromosome: Part of a cell that contains genetic information. Except for sperm and eggs, all human cells contain 46 chromosomes. [NIH] Chronic: A disease or condition that persists or progresses over a long period of time. [NIH] Chronic Disease: Disease or ailment of long duration. [NIH] Chronic renal: Slow and progressive loss of kidney function over several years, often resulting in end-stage renal disease. People with end-stage renal disease need dialysis or transplantation to replace the work of the kidneys. [NIH] Chylomicrons: A class of lipoproteins that carry dietary cholesterol and triglycerides from the small intestines to the tissues. [NIH] Clamp: A u-shaped steel rod used with a pin or wire for skeletal traction in the treatment of certain fractures. [NIH] Cleave: A double-stranded cut in DNA with a restriction endonuclease. [NIH] Clinical Medicine: The study and practice of medicine by direct examination of the patient. [NIH]

Clinical study: A research study in which patients receive treatment in a clinic or other medical facility. Reports of clinical studies can contain results for single patients (case reports) or many patients (case series or clinical trials). [NIH]

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Clinical trial: A research study that tests how well new medical treatments or other interventions work in people. Each study is designed to test new methods of screening, prevention, diagnosis, or treatment of a disease. [NIH] Clomiphene: A stilbene derivative that functions both as a partial estrogen agonist and complete estrogen antagonist depending on the target tissue. It antagonizes the estrogen receptor thereby initiating or augmenting ovulation in anovulatory women. [NIH] Cloning: The production of a number of genetically identical individuals; in genetic engineering, a process for the efficient replication of a great number of identical DNA molecules. [NIH] Coagulation: 1. The process of clot formation. 2. In colloid chemistry, the solidification of a sol into a gelatinous mass; an alteration of a disperse phase or of a dissolved solid which causes the separation of the system into a liquid phase and an insoluble mass called the clot or curd. Coagulation is usually irreversible. 3. In surgery, the disruption of tissue by physical means to form an amorphous residuum, as in electrocoagulation and photocoagulation. [EU] Coal: A natural fuel formed by partial decomposition of vegetable matter under certain environmental conditions. [NIH] Codon: A set of three nucleotides in a protein coding sequence that specifies individual amino acids or a termination signal (codon, terminator). Most codons are universal, but some organisms do not produce the transfer RNAs (RNA, transfer) complementary to all codons. These codons are referred to as unassigned codons (codons, nonsense). [NIH] Coenzymes: Substances that are necessary for the action or enhancement of action of an enzyme. Many vitamins are coenzymes. [NIH] Cofactor: A substance, microorganism or environmental factor that activates or enhances the action of another entity such as a disease-causing agent. [NIH] Cognition: Intellectual or mental process whereby an organism becomes aware of or obtains knowledge. [NIH] Colitis: Inflammation of the colon. [NIH] Collagen: A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of skin, connective tissue, and the organic substance of bones and teeth. Different forms of collagen are produced in the body but all consist of three alpha-polypeptide chains arranged in a triple helix. Collagen is differentiated from other fibrous proteins, such as elastin, by the content of proline, hydroxyproline, and hydroxylysine; by the absence of tryptophan; and particularly by the high content of polar groups which are responsible for its swelling properties. [NIH] Collagen disease: A term previously used to describe chronic diseases of the connective tissue (e.g., rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis), but now is thought to be more appropriate for diseases associated with defects in collagen, which is a component of the connective tissue. [NIH] Collapse: 1. A state of extreme prostration and depression, with failure of circulation. 2. Abnormal falling in of the walls of any part of organ. [EU] Colloidal: Of the nature of a colloid. [EU] Colonoscopy: Endoscopic examination, therapy or surgery of the luminal surface of the colon. [NIH] Colorectal: Having to do with the colon or the rectum. [NIH] Colorectal Cancer: Cancer that occurs in the colon (large intestine) or the rectum (the end of

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the large intestine). A number of digestive diseases may increase a person's risk of colorectal cancer, including polyposis and Zollinger-Ellison Syndrome. [NIH] Combination Therapy: Association of 3 drugs to treat AIDS (AZT + DDC or DDI + protease inhibitor). [NIH] Complement: A term originally used to refer to the heat-labile factor in serum that causes immune cytolysis, the lysis of antibody-coated cells, and now referring to the entire functionally related system comprising at least 20 distinct serum proteins that is the effector not only of immune cytolysis but also of other biologic functions. Complement activation occurs by two different sequences, the classic and alternative pathways. The proteins of the classic pathway are termed 'components of complement' and are designated by the symbols C1 through C9. C1 is a calcium-dependent complex of three distinct proteins C1q, C1r and C1s. The proteins of the alternative pathway (collectively referred to as the properdin system) and complement regulatory proteins are known by semisystematic or trivial names. Fragments resulting from proteolytic cleavage of complement proteins are designated with lower-case letter suffixes, e.g., C3a. Inactivated fragments may be designated with the suffix 'i', e.g. C3bi. Activated components or complexes with biological activity are designated by a bar over the symbol e.g. C1 or C4b,2a. The classic pathway is activated by the binding of C1 to classic pathway activators, primarily antigen-antibody complexes containing IgM, IgG1, IgG3; C1q binds to a single IgM molecule or two adjacent IgG molecules. The alternative pathway can be activated by IgA immune complexes and also by nonimmunologic materials including bacterial endotoxins, microbial polysaccharides, and cell walls. Activation of the classic pathway triggers an enzymatic cascade involving C1, C4, C2 and C3; activation of the alternative pathway triggers a cascade involving C3 and factors B, D and P. Both result in the cleavage of C5 and the formation of the membrane attack complex. Complement activation also results in the formation of many biologically active complement fragments that act as anaphylatoxins, opsonins, or chemotactic factors. [EU] Computational Biology: A field of biology concerned with the development of techniques for the collection and manipulation of biological data, and the use of such data to make biological discoveries or predictions. This field encompasses all computational methods and theories applicable to molecular biology and areas of computer-based techniques for solving biological problems including manipulation of models and datasets. [NIH] Computed tomography: CT scan. A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized tomography and computerized axial tomography (CAT) scan. [NIH] Computerized axial tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called CAT scan, computed tomography (CT scan), or computerized tomography. [NIH] Computerized tomography: A series of detailed pictures of areas inside the body, taken from different angles; the pictures are created by a computer linked to an x-ray machine. Also called computerized axial tomography (CAT) scan and computed tomography (CT scan). [NIH] Conception: The onset of pregnancy, marked by implantation of the blastocyst; the formation of a viable zygote. [EU] Concomitant: Accompanying; accessory; joined with another. [EU] Conjugated: Acting or operating as if joined; simultaneous. [EU] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective

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tissue cells embedded in a large amount of extracellular matrix. [NIH] Connective Tissue: Tissue that supports and binds other tissues. It consists of connective tissue cells embedded in a large amount of extracellular matrix. [NIH] Consciousness: Sense of awareness of self and of the environment. [NIH] Constipation: Infrequent or difficult evacuation of feces. [NIH] Constriction: The act of constricting. [NIH] Consultation: A deliberation between two or more physicians concerning the diagnosis and the proper method of treatment in a case. [NIH] Consumption: Pulmonary tuberculosis. [NIH] Continuum: An area over which the vegetation or animal population is of constantly changing composition so that homogeneous, separate communities cannot be distinguished. [NIH]

Contraceptive: An agent that diminishes the likelihood of or prevents conception. [EU] Contraceptive Agents: Chemical substances that prevent or reduce the probability of conception. [NIH] Contraindications: Any factor or sign that it is unwise to pursue a certain kind of action or treatment, e. g. giving a general anesthetic to a person with pneumonia. [NIH] Control group: In a clinical trial, the group that does not receive the new treatment being studied. This group is compared to the group that receives the new treatment, to see if the new treatment works. [NIH] Controlled clinical trial: A clinical study that includes a comparison (control) group. The comparison group receives a placebo, another treatment, or no treatment at all. [NIH] Controlled study: An experiment or clinical trial that includes a comparison (control) group. [NIH]

Convulsions: A general term referring to sudden and often violent motor activity of cerebral or brainstem origin. Convulsions may also occur in the absence of an electrical cerebral discharge (e.g., in response to hypotension). [NIH] Coordination: Muscular or motor regulation or the harmonious cooperation of muscles or groups of muscles, in a complex action or series of actions. [NIH] Cor: The muscular organ that maintains the circulation of the blood. c. adiposum a heart that has undergone fatty degeneration or that has an accumulation of fat around it; called also fat or fatty, heart. c. arteriosum the left side of the heart, so called because it contains oxygenated (arterial) blood. c. biloculare a congenital anomaly characterized by failure of formation of the atrial and ventricular septums, the heart having only two chambers, a single atrium and a single ventricle, and a common atrioventricular valve. c. bovinum (L. 'ox heart') a greatly enlarged heart due to a hypertrophied left ventricle; called also c. taurinum and bucardia. c. dextrum (L. 'right heart') the right atrium and ventricle. c. hirsutum, c. villosum. c. mobile (obs.) an abnormally movable heart. c. pendulum a heart so movable that it seems to be hanging by the great blood vessels. c. pseudotriloculare biatriatum a congenital cardiac anomaly in which the heart functions as a three-chambered heart because of tricuspid atresia, the right ventricle being extremely small or rudimentary and the right atrium greatly dilated. Blood passes from the right to the left atrium and thence disease due to pulmonary hypertension secondary to disease of the lung, or its blood vessels, with hypertrophy of the right ventricle. [EU] Coronary: Encircling in the manner of a crown; a term applied to vessels; nerves, ligaments, etc. The term usually denotes the arteries that supply the heart muscle and, by extension, a pathologic involvement of them. [EU]

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Coronary Arteriosclerosis: Thickening and loss of elasticity of the coronary arteries. [NIH] Coronary heart disease: A type of heart disease caused by narrowing of the coronary arteries that feed the heart, which needs a constant supply of oxygen and nutrients carried by the blood in the coronary arteries. When the coronary arteries become narrowed or clogged by fat and cholesterol deposits and cannot supply enough blood to the heart, CHD results. [NIH] Coronary Thrombosis: Presence of a thrombus in a coronary artery, often causing a myocardial infarction. [NIH] Corpus: The body of the uterus. [NIH] Corpus Luteum: The yellow glandular mass formed in the ovary by an ovarian follicle that has ruptured and discharged its ovum. [NIH] Cortex: The outer layer of an organ or other body structure, as distinguished from the internal substance. [EU] Corticosteroid: Any of the steroids elaborated by the adrenal cortex (excluding the sex hormones of adrenal origin) in response to the release of corticotrophin (adrenocorticotropic hormone) by the pituitary gland, to any of the synthetic equivalents of these steroids, or to angiotensin II. They are divided, according to their predominant biological activity, into three major groups: glucocorticoids, chiefly influencing carbohydrate, fat, and protein metabolism; mineralocorticoids, affecting the regulation of electrolyte and water balance; and C19 androgens. Some corticosteroids exhibit both types of activity in varying degrees, and others exert only one type of effect. The corticosteroids are used clinically for hormonal replacement therapy, for suppression of ACTH secretion by the anterior pituitary, as antineoplastic, antiallergic, and anti-inflammatory agents, and to suppress the immune response. Called also adrenocortical hormone and corticoid. [EU] Corticotropin-Releasing Hormone: A neuropeptide released by the hypothalamus that stimulates the release of corticotropin by the anterior pituitary gland. [NIH] Cortisol: A steroid hormone secreted by the adrenal cortex as part of the body's response to stress. [NIH] Cross-Sectional Studies: Studies in which the presence or absence of disease or other health-related variables are determined in each member of the study population or in a representative sample at one particular time. This contrasts with longitudinal studies which are followed over a period of time. [NIH] Cultured cells: Animal or human cells that are grown in the laboratory. [NIH] Curative: Tending to overcome disease and promote recovery. [EU] Cutaneous: Having to do with the skin. [NIH] Cyclic: Pertaining to or occurring in a cycle or cycles; the term is applied to chemical compounds that contain a ring of atoms in the nucleus. [EU] Cyclophosphamide: Precursor of an alkylating nitrogen mustard antineoplastic and immunosuppressive agent that must be activated in the liver to form the active aldophosphamide. It is used in the treatment of lymphomas, leukemias, etc. Its side effect, alopecia, has been made use of in defleecing sheep. Cyclophosphamide may also cause sterility, birth defects, mutations, and cancer. [NIH] Cyproterone: An anti-androgen that, in the form of its acetate, also has progestational properties. It is used in the treatment of hypersexuality in males, as a palliative in prostatic carcinoma, and, in combination with estrogen, for the therapy of severe acne and hirsutism in females. [NIH]

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Cyproterone Acetate: An agent with anti-androgen and progestational properties. It shows competitive binding with dihydrotestosterone at androgen receptor sites. [NIH] Cysteine: A thiol-containing non-essential amino acid that is oxidized to form cystine. [NIH] Cytochrome: Any electron transfer hemoprotein having a mode of action in which the transfer of a single electron is effected by a reversible valence change of the central iron atom of the heme prosthetic group between the +2 and +3 oxidation states; classified as cytochromes a in which the heme contains a formyl side chain, cytochromes b, which contain protoheme or a closely similar heme that is not covalently bound to the protein, cytochromes c in which protoheme or other heme is covalently bound to the protein, and cytochromes d in which the iron-tetrapyrrole has fewer conjugated double bonds than the hemes have. Well-known cytochromes have been numbered consecutively within groups and are designated by subscripts (beginning with no subscript), e.g. cytochromes c, c1, C2, . New cytochromes are named according to the wavelength in nanometres of the absorption maximum of the a-band of the iron (II) form in pyridine, e.g., c-555. [EU] Cytokine: Small but highly potent protein that modulates the activity of many cell types, including T and B cells. [NIH] Cytoplasm: The protoplasm of a cell exclusive of that of the nucleus; it consists of a continuous aqueous solution (cytosol) and the organelles and inclusions suspended in it (phaneroplasm), and is the site of most of the chemical activities of the cell. [EU] Cytoskeletal Proteins: Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible. [NIH]

Cytoskeleton: The network of filaments, tubules, and interconnecting filamentous bridges which give shape, structure, and organization to the cytoplasm. [NIH] Cytotoxic: Cell-killing. [NIH] Dairy Products: Raw and processed or manufactured milk and milk-derived products. These are usually from cows (bovine) but are also from goats, sheep, reindeer, and water buffalo. [NIH] Data Collection: Systematic gathering of data for a particular purpose from various sources, including questionnaires, interviews, observation, existing records, and electronic devices. The process is usually preliminary to statistical analysis of the data. [NIH] Databases, Bibliographic: Extensive collections, reputedly complete, of references and citations to books, articles, publications, etc., generally on a single subject or specialized subject area. Databases can operate through automated files, libraries, or computer disks. The concept should be differentiated from factual databases which is used for collections of data and facts apart from bibliographic references to them. [NIH] De novo: In cancer, the first occurrence of cancer in the body. [NIH] Deamination: The removal of an amino group (NH2) from a chemical compound. [NIH] Decarboxylation: The removal of a carboxyl group, usually in the form of carbon dioxide, from a chemical compound. [NIH] Decompensation: Failure of compensation; cardiac decompensation is marked by dyspnea, venous engorgement, and edema. [EU] Degenerative: Undergoing degeneration : tending to degenerate; having the character of or involving degeneration; causing or tending to cause degeneration. [EU] Dehydroepiandrosterone: DHEA. A substance that is being studied as a cancer prevention drug. It belongs to the family of drugs called steroids. [NIH]

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Deletion: A genetic rearrangement through loss of segments of DNA (chromosomes), bringing sequences, which are normally separated, into close proximity. [NIH] Denaturation: Rupture of the hydrogen bonds by heating a DNA solution and then cooling it rapidly causes the two complementary strands to separate. [NIH] Dendritic: 1. Branched like a tree. 2. Pertaining to or possessing dendrites. [EU] Density: The logarithm to the base 10 of the opacity of an exposed and processed film. [NIH] Deoxyglucose: 2-Deoxy-D-arabino-hexose. An antimetabolite of glucose with antiviral activity. [NIH] Depolarization: The process or act of neutralizing polarity. In neurophysiology, the reversal of the resting potential in excitable cell membranes when stimulated, i.e., the tendency of the cell membrane potential to become positive with respect to the potential outside the cell. [EU] Depressive Disorder: An affective disorder manifested by either a dysphoric mood or loss of interest or pleasure in usual activities. The mood disturbance is prominent and relatively persistent. [NIH] Desensitization: The prevention or reduction of immediate hypersensitivity reactions by administration of graded doses of allergen; called also hyposensitization and immunotherapy. [EU] Desogestrel: A synthetic progestational hormone used often as the progestogenic component of combined oral contraceptive agents. [NIH] Deuterium: Deuterium. The stable isotope of hydrogen. It has one neutron and one proton in the nucleus. [NIH] Developed Countries: Countries that have reached a level of economic achievement through an increase of production, per capita income and consumption, and utilization of natural and human resources. [NIH] Developing Countries: Countries in the process of change directed toward economic growth, that is, an increase in production, per capita consumption, and income. The process of economic growth involves better utilization of natural and human resources, which results in a change in the social, political, and economic structures. [NIH] DEXA: A method (dual energy X-ray absortiometry) used to estimate total body fat and percent of body fat. Potential disadvantages include whole body radiation and the long time required for scanning while the subject lies on a hard table. [NIH] Diabetes Mellitus: A heterogeneous group of disorders that share glucose intolerance in common. [NIH] Diabetic Retinopathy: Retinopathy associated with diabetes mellitus, which may be of the background type, progressively characterized by microaneurysms, interretinal punctuate macular edema, or of the proliferative type, characterized by neovascularization of the retina and optic disk, which may project into the vitreous, proliferation of fibrous tissue, vitreous hemorrhage, and retinal detachment. [NIH] Diagnostic procedure: A method used to identify a disease. [NIH] Dialysate: A cleansing liquid used in the two major forms of dialysis--hemodialysis and peritoneal dialysis. [NIH] Dialyzer: A part of the hemodialysis machine. (See hemodialysis under dialysis.) The dialyzer has two sections separated by a membrane. One section holds dialysate. The other holds the patient's blood. [NIH] Diarrhea: Passage of excessively liquid or excessively frequent stools. [NIH] Diastolic: Of or pertaining to the diastole. [EU]

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Diencephalon: The paired caudal parts of the prosencephalon from which the thalamus, hypothalamus, epithalamus, and subthalamus are derived. [NIH] Dietary Fats: Fats present in food, especially in animal products such as meat, meat products, butter, ghee. They are present in lower amounts in nuts, seeds, and avocados. [NIH]

Dietary Fiber: The remnants of plant cell walls that are resistant to digestion by the alimentary enzymes of man. It comprises various polysaccharides and lignins. [NIH] Dietitian: An expert in nutrition who helps people plan what and how much food to eat. [NIH]

Diffusion: The tendency of a gas or solute to pass from a point of higher pressure or concentration to a point of lower pressure or concentration and to distribute itself throughout the available space; a major mechanism of biological transport. [NIH] Digestion: The process of breakdown of food for metabolism and use by the body. [NIH] Digestive system: The organs that take in food and turn it into products that the body can use to stay healthy. Waste products the body cannot use leave the body through bowel movements. The digestive system includes the salivary glands, mouth, esophagus, stomach, liver, pancreas, gallbladder, small and large intestines, and rectum. [NIH] Dihydrotestosterone: Anabolic agent. [NIH] Dilatation: The act of dilating. [NIH] Dilatation, Pathologic: The condition of an anatomical structure's being dilated beyond normal dimensions. [NIH] Dilated cardiomyopathy: Heart muscle disease that leads to enlargement of the heart's chambers, robbing the heart of its pumping ability. [NIH] Dilation: A process by which the pupil is temporarily enlarged with special eye drops (mydriatic); allows the eye care specialist to better view the inside of the eye. [NIH] Dilution: A diluted or attenuated medicine; in homeopathy, the diffusion of a given quantity of a medicinal agent in ten or one hundred times the same quantity of water. [NIH] Direct: 1. Straight; in a straight line. 2. Performed immediately and without the intervention of subsidiary means. [EU] Disinfectant: An agent that disinfects; applied particularly to agents used on inanimate objects. [EU] Disposition: A tendency either physical or mental toward certain diseases. [EU] Dissection: Cutting up of an organism for study. [NIH] Dissociation: 1. The act of separating or state of being separated. 2. The separation of a molecule into two or more fragments (atoms, molecules, ions, or free radicals) produced by the absorption of light or thermal energy or by solvation. 3. In psychology, a defense mechanism in which a group of mental processes are segregated from the rest of a person's mental activity in order to avoid emotional distress, as in the dissociative disorders (q.v.), or in which an idea or object is segregated from its emotional significance; in the first sense it is roughly equivalent to splitting, in the second, to isolation. 4. A defect of mental integration in which one or more groups of mental processes become separated off from normal consciousness and, thus separated, function as a unitary whole. [EU] Dissociative Disorders: Sudden temporary alterations in the normally integrative functions of consciousness. [NIH] Diuretic: A drug that increases the production of urine. [NIH] Dominance: In genetics, the full phenotypic expression of a gene in both heterozygotes and

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homozygotes. [EU] Dormancy: The period when an organism (i. e., a virus or a bacterium) is in the body but not producing any ill effects. [NIH] Dosage Forms: Completed forms of the pharmaceutical preparation in which prescribed doses of medication are included. They are designed to resist action by gastric fluids, prevent vomiting and nausea, reduce or alleviate the undesirable taste and smells associated with oral administration, achieve a high concentration of drug at target site, or produce a delayed or long-acting drug effect. They include capsules, liniments, ointments, pharmaceutical solutions, powders, tablets, etc. [NIH] Drive: A state of internal activity of an organism that is a necessary condition before a given stimulus will elicit a class of responses; e.g., a certain level of hunger (drive) must be present before food will elicit an eating response. [NIH] Drug Tolerance: Progressive diminution of the susceptibility of a human or animal to the effects of a drug, resulting from its continued administration. It should be differentiated from drug resistance wherein an organism, disease, or tissue fails to respond to the intended effectiveness of a chemical or drug. It should also be differentiated from maximum tolerated dose and no-observed-adverse-effect level. [NIH] Duodenum: The first part of the small intestine. [NIH] Dyslipidemia: Disorders in the lipoprotein metabolism; classified as hypercholesterolemia, hypertriglyceridemia, combined hyperlipidemia, and low levels of high-density lipoprotein (HDL) cholesterol. All of the dyslipidemias can be primary or secondary. Both elevated levels of low-density lipoprotein (LDL) cholesterol and low levels of HDL cholesterol predispose to premature atherosclerosis. [NIH] Dyspareunia: Painful sexual intercourse. [NIH] Dysphoric: A feeling of unpleasantness and discomfort. [NIH] Dysplasia: Cells that look abnormal under a microscope but are not cancer. [NIH] Dyspnea: Difficult or labored breathing. [NIH] Dystrophy: Any disorder arising from defective or faulty nutrition, especially the muscular dystrophies. [EU] Eclampsia: Onset of convulsions or coma in a previously diagnosed pre-eclamptic patient. [NIH]

Ectopic: Pertaining to or characterized by ectopia. [EU] Edema: Excessive amount of watery fluid accumulated in the intercellular spaces, most commonly present in subcutaneous tissue. [NIH] Effector: It is often an enzyme that converts an inactive precursor molecule into an active second messenger. [NIH] Efficacy: The extent to which a specific intervention, procedure, regimen, or service produces a beneficial result under ideal conditions. Ideally, the determination of efficacy is based on the results of a randomized control trial. [NIH] Eicosanoids: A class of oxygenated, endogenous, unsaturated fatty acids derived from arachidonic acid. They include prostaglandins, leukotrienes, thromboxanes, and hydroxyeicosatetraenoic acid compounds (HETE). They are hormone-like substances that act near the site of synthesis without altering functions throughout the body. [NIH] Elasticity: Resistance and recovery from distortion of shape. [NIH] Elastin: The protein that gives flexibility to tissues. [NIH]

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Elective: Subject to the choice or decision of the patient or physician; applied to procedures that are advantageous to the patient but not urgent. [EU] Electrolyte: A substance that dissociates into ions when fused or in solution, and thus becomes capable of conducting electricity; an ionic solute. [EU] Electrons: Stable elementary particles having the smallest known negative charge, present in all elements; also called negatrons. Positively charged electrons are called positrons. The numbers, energies and arrangement of electrons around atomic nuclei determine the chemical identities of elements. Beams of electrons are called cathode rays or beta rays, the latter being a high-energy biproduct of nuclear decay. [NIH] Electrophoresis: An electrochemical process in which macromolecules or colloidal particles with a net electric charge migrate in a solution under the influence of an electric current. [NIH]

Elementary Particles: Individual components of atoms, usually subatomic; subnuclear particles are usually detected only when the atomic nucleus decays and then only transiently, as most of them are unstable, often yielding pure energy without substance, i.e., radiation. [NIH] Embolism: Blocking of a blood vessel by a blood clot or foreign matter that has been transported from a distant site by the blood stream. [NIH] Embolus: Bit of foreign matter which enters the blood stream at one point and is carried until it is lodged or impacted in an artery and obstructs it. It may be a blood clot, an air bubble, fat or other tissue, or clumps of bacteria. [NIH] Embryo: The prenatal stage of mammalian development characterized by rapid morphological changes and the differentiation of basic structures. [NIH] Emollient: Softening or soothing; called also malactic. [EU] Endocrine System: The system of glands that release their secretions (hormones) directly into the circulatory system. In addition to the endocrine glands, included are the chromaffin system and the neurosecretory systems. [NIH] Endocrinology: A subspecialty of internal medicine concerned with the metabolism, physiology, and disorders of the endocrine system. [NIH] Endocytosis: Cellular uptake of extracellular materials within membrane-limited vacuoles or microvesicles. Endosomes play a central role in endocytosis. [NIH] Endometrial: Having to do with the endometrium (the layer of tissue that lines the uterus). [NIH]

Endometrium: The layer of tissue that lines the uterus. [NIH] Endopeptidases: A subclass of peptide hydrolases. They are classified primarily by their catalytic mechanism. Specificity is used only for identification of individual enzymes. They comprise the serine endopeptidases, EC 3.4.21; cysteine endopeptidases, EC 3.4.22; aspartic endopeptidases, EC 3.4.23, metalloendopeptidases, EC 3.4.24; and a group of enzymes yet to be assigned to any of the above sub-classes, EC 3.4.99. EC 3.4.-. [NIH] Endothelial cell: The main type of cell found in the inside lining of blood vessels, lymph vessels, and the heart. [NIH] Endothelium: A layer of epithelium that lines the heart, blood vessels (endothelium, vascular), lymph vessels (endothelium, lymphatic), and the serous cavities of the body. [NIH] Endothelium, Lymphatic: Unbroken cellular lining (intima) of the lymph vessels (e.g., the high endothelial lymphatic venules). It is more permeable than vascular endothelium, lacking selective absorption and functioning mainly to remove plasma proteins that have filtered through the capillaries into the tissue spaces. [NIH]

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Endothelium, Vascular: Single pavement layer of cells which line the luminal surface of the entire vascular system and regulate the transport of macromolecules and blood components from interstitium to lumen; this function has been most intensively studied in the blood capillaries. [NIH] Endothelium-derived: Small molecule that diffuses to the adjacent muscle layer and relaxes it. [NIH] Endotoxemia: A condition characterized by the presence of endotoxins in the blood. If endotoxemia is the result of gram-negative rod-shaped bacteria, shock may occur. [NIH] Endotoxic: Of, relating to, or acting as an endotoxin (= a heat-stable toxin, associated with the outer membranes of certain gram-negative bacteria. Endotoxins are not secreted and are released only when the cells are disrupted). [EU] Endotoxin: Toxin from cell walls of bacteria. [NIH] End-stage renal: Total chronic kidney failure. When the kidneys fail, the body retains fluid and harmful wastes build up. A person with ESRD needs treatment to replace the work of the failed kidneys. [NIH] Energy balance: Energy is the capacity of a body or a physical system for doing work. Energy balance is the state in which the total energy intake equals total energy needs. [NIH] Energy Intake: Total number of calories taken in daily whether ingested or by parenteral routes. [NIH] Environmental Exposure: The exposure to potentially harmful chemical, physical, or biological agents in the environment or to environmental factors that may include ionizing radiation, pathogenic organisms, or toxic chemicals. [NIH] Environmental Health: The science of controlling or modifying those conditions, influences, or forces surrounding man which relate to promoting, establishing, and maintaining health. [NIH]

Enzymatic: Phase where enzyme cuts the precursor protein. [NIH] Enzyme: A protein that speeds up chemical reactions in the body. [NIH] Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction. [NIH] Eosinophils: Granular leukocytes with a nucleus that usually has two lobes connected by a slender thread of chromatin, and cytoplasm containing coarse, round granules that are uniform in size and stainable by eosin. [NIH] Epidemic: Occurring suddenly in numbers clearly in excess of normal expectancy; said especially of infectious diseases but applied also to any disease, injury, or other healthrelated event occurring in such outbreaks. [EU] Epidemiological: Relating to, or involving epidemiology. [EU] Epigastric: Having to do with the upper middle area of the abdomen. [NIH] Epinephrine: The active sympathomimetic hormone from the adrenal medulla in most species. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. It is used in asthma and cardiac failure and to delay absorption of local anesthetics. [NIH] Epithelial: Refers to the cells that line the internal and external surfaces of the body. [NIH] Epithelial Cells: Cells that line the inner and outer surfaces of the body. [NIH] Epithelium: One or more layers of epithelial cells, supported by the basal lamina, which

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covers the inner or outer surfaces of the body. [NIH] Erythrocyte Indices: Quantification of size and cell hemoglobin content or concentration of the erythrocyte, usually derived from erythrocyte count, blood hemoglobin concentration, and hematocrit. Includes the mean cell volume (MCV), mean cell hemoglobin (MCH), and mean cell hemoglobin concentration (MCHC). Use also for cell diameter and thickness. [NIH] Erythrocytes: Red blood cells. Mature erythrocytes are non-nucleated, biconcave disks containing hemoglobin whose function is to transport oxygen. [NIH] Erythropoietin: Glycoprotein hormone, secreted chiefly by the kidney in the adult and the liver in the fetus, that acts on erythroid stem cells of the bone marrow to stimulate proliferation and differentiation. [NIH] Esophagitis: Inflammation, acute or chronic, of the esophagus caused by bacteria, chemicals, or trauma. [NIH] Esophagus: The muscular tube through which food passes from the throat to the stomach. [NIH]

Essential Tremor: A rhythmic, involuntary, purposeless, oscillating movement resulting from the alternate contraction and relaxation of opposing groups of muscles. [NIH] Esterification: The process of converting an acid into an alkyl or aryl derivative. Most frequently the process consists of the reaction of an acid with an alcohol in the presence of a trace of mineral acid as catalyst or the reaction of an acyl chloride with an alcohol. Esterification can also be accomplished by enzymatic processes. [NIH] Estradiol: The most potent mammalian estrogenic hormone. It is produced in the ovary, placenta, testis, and possibly the adrenal cortex. [NIH] Estrogen: One of the two female sex hormones. [NIH] Estrogen receptor: ER. Protein found on some cancer cells to which estrogen will attach. [NIH]

Estrogen Replacement Therapy: The use of hormonal agents with estrogen-like activity in postmenopausal or other estrogen-deficient women to alleviate effects of hormone deficiency, such as vasomotor symptoms, dyspareunia, and progressive development of osteoporosis. This may also include the use of progestational agents in combination therapy. [NIH]

Ethanol: A clear, colorless liquid rapidly absorbed from the gastrointestinal tract and distributed throughout the body. It has bactericidal activity and is used often as a topical disinfectant. It is widely used as a solvent and preservative in pharmaceutical preparations as well as serving as the primary ingredient in alcoholic beverages. [NIH] Ethnic Groups: A group of people with a common cultural heritage that sets them apart from others in a variety of social relationships. [NIH] Evacuation: An emptying, as of the bowels. [EU] Exhaustion: The feeling of weariness of mind and body. [NIH] Exocrine: Secreting outwardly, via a duct. [EU] Exocytosis: Cellular release of material within membrane-limited vesicles by fusion of the vesicles with the cell membrane. [NIH] Exogenous: Developed or originating outside the organism, as exogenous disease. [EU] Exon: The part of the DNA that encodes the information for the actual amino acid sequence of the protein. In many eucaryotic genes, the coding sequences consist of a series of exons alternating with intron sequences. [NIH] Expiration: The act of breathing out, or expelling air from the lungs. [EU]

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Extracellular: Outside a cell or cells. [EU] Extracellular Matrix: A meshwork-like substance found within the extracellular space and in association with the basement membrane of the cell surface. It promotes cellular proliferation and provides a supporting structure to which cells or cell lysates in culture dishes adhere. [NIH] Extracellular Space: Interstitial space between cells, occupied by fluid as well as amorphous and fibrous substances. [NIH] Extraction: The process or act of pulling or drawing out. [EU] Family Planning: Programs or services designed to assist the family in controlling reproduction by either improving or diminishing fertility. [NIH] Fasting Blood Glucose Test: A method for finding out how much glucose (sugar) is in the blood. The test can show if a person has diabetes. A blood sample is taken in a lab or doctor's office. The test is usually done in the morning before the person has eaten. The normal, nondiabetic range for blood glucose is from 70 to 110 mg/dl, depending on the type of blood being tested. If the level is 126 mg/dl or greater, it means the person has diabetes (except for newborns and some pregnant women). [NIH] Fat: Total lipids including phospholipids. [NIH] Fatigue: The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. [NIH]

Fatty acids: A major component of fats that are used by the body for energy and tissue development. [NIH] Fatty Liver: The buildup of fat in liver cells. The most common cause is alcoholism. Other causes include obesity, diabetes, and pregnancy. Also called steatosis. [NIH] Feces: The excrement discharged from the intestines, consisting of bacteria, cells exfoliated from the intestines, secretions, chiefly of the liver, and a small amount of food residue. [EU] Ferritin: An iron-containing protein complex that is formed by a combination of ferric iron with the protein apoferritin. [NIH] Fetus: The developing offspring from 7 to 8 weeks after conception until birth. [NIH] Fibrin: A protein derived from fibrinogen in the presence of thrombin, which forms part of the blood clot. [NIH] Fibrinogen: Plasma glycoprotein clotted by thrombin, composed of a dimer of three nonidentical pairs of polypeptide chains (alpha, beta, gamma) held together by disulfide bonds. Fibrinogen clotting is a sol-gel change involving complex molecular arrangements: whereas fibrinogen is cleaved by thrombin to form polypeptides A and B, the proteolytic action of other enzymes yields different fibrinogen degradation products. [NIH] Fibrinolysis: The natural enzymatic dissolution of fibrin. [NIH] Fibrinolytic: Pertaining to, characterized by, or causing the dissolution of fibrin by enzymatic action [EU] Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules. [NIH] Fibrosis: Any pathological condition where fibrous connective tissue invades any organ, usually as a consequence of inflammation or other injury. [NIH] Fine-needle aspiration: The removal of tissue or fluid with a needle for examination under a microscope. Also called needle biopsy. [NIH]

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Fistula: Abnormal communication most commonly seen between two internal organs, or between an internal organ and the surface of the body. [NIH] Fixation: 1. The act or operation of holding, suturing, or fastening in a fixed position. 2. The condition of being held in a fixed position. 3. In psychiatry, a term with two related but distinct meanings : (1) arrest of development at a particular stage, which like regression (return to an earlier stage), if temporary is a normal reaction to setbacks and difficulties but if protracted or frequent is a cause of developmental failures and emotional problems, and (2) a close and suffocating attachment to another person, especially a childhood figure, such as one's mother or father. Both meanings are derived from psychoanalytic theory and refer to 'fixation' of libidinal energy either in a specific erogenous zone, hence fixation at the oral, anal, or phallic stage, or in a specific object, hence mother or father fixation. 4. The use of a fixative (q.v.) to preserve histological or cytological specimens. 5. In chemistry, the process whereby a substance is removed from the gaseous or solution phase and localized, as in carbon dioxide fixation or nitrogen fixation. 6. In ophthalmology, direction of the gaze so that the visual image of the object falls on the fovea centralis. 7. In film processing, the chemical removal of all undeveloped salts of the film emulsion, leaving only the developed silver to form a permanent image. [EU] Flatus: Gas passed through the rectum. [NIH] Flutamide: An antiandrogen with about the same potency as cyproterone in rodent and canine species. [NIH] Fold: A plication or doubling of various parts of the body. [NIH] Foot Ulcer: Lesion on the surface of the skin of the foot, usually accompanied by inflammation. The lesion may become infected or necrotic and is frequently associated with diabetes or leprosy. [NIH] Forearm: The part between the elbow and the wrist. [NIH] Frontal Lobe: The anterior part of the cerebral hemisphere. [NIH] Fructose: A type of sugar found in many fruits and vegetables and in honey. Fructose is used to sweeten some diet foods. It is considered a nutritive sweetener because it has calories. [NIH] Gallbladder: The pear-shaped organ that sits below the liver. Bile is concentrated and stored in the gallbladder. [NIH] Gallstones: The solid masses or stones made of cholesterol or bilirubin that form in the gallbladder or bile ducts. [NIH] Ganglia: Clusters of multipolar neurons surrounded by a capsule of loosely organized connective tissue located outside the central nervous system. [NIH] Gas: Air that comes from normal breakdown of food. The gases are passed out of the body through the rectum (flatus) or the mouth (burp). [NIH] Gasoline: Volative flammable fuel (liquid hydrocarbons) derived from crude petroleum by processes such as distillation reforming, polymerization, etc. [NIH] Gastric: Having to do with the stomach. [NIH] Gastric Emptying: The evacuation of food from the stomach into the duodenum. [NIH] Gastrin: A hormone released after eating. Gastrin causes the stomach to produce more acid. [NIH]

Gastritis: Inflammation of the stomach. [EU] Gastrointestinal: Refers to the stomach and intestines. [NIH] Gastrointestinal tract: The stomach and intestines. [NIH]

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Gastroparesis: Nerve or muscle damage in the stomach. Causes slow digestion and emptying, vomiting, nausea, or bloating. Also called delayed gastric emptying. [NIH] Gelatin: A product formed from skin, white connective tissue, or bone collagen. It is used as a protein food adjuvant, plasma substitute, hemostatic, suspending agent in pharmaceutical preparations, and in the manufacturing of capsules and suppositories. [NIH] Gemfibrozil: A lipid-regulating agent that lowers elevated serum lipids primarily by decreasing serum triglycerides with a variable reduction in total cholesterol. These decreases occur primarily in the VLDL fraction and less frequently in the LDL fraction. Gemfibrozil increases HDL subfractions HDL2 and HDL3 as well as apolipoproteins A-I and A-II. Its mechanism of action has not been definitely established. [NIH] Gene: The functional and physical unit of heredity passed from parent to offspring. Genes are pieces of DNA, and most genes contain the information for making a specific protein. [NIH]

Gene Deletion: A genetic rearrangement through loss of segments of DNA or RNA, bringing sequences which are normally separated into close proximity. This deletion may be detected using cytogenetic techniques and can also be inferred from the phenotype, indicating a deletion at one specific locus. [NIH] Gene Expression: The phenotypic manifestation of a gene or genes by the processes of gene action. [NIH] Genetic Code: The specifications for how information, stored in nucleic acid sequence (base sequence), is translated into protein sequence (amino acid sequence). The start, stop, and order of amino acids of a protein is specified by consecutive triplets of nucleotides called codons (codon). [NIH] Genetic Engineering: Directed modification of the gene complement of a living organism by such techniques as altering the DNA, substituting genetic material by means of a virus, transplanting whole nuclei, transplanting cell hybrids, etc. [NIH] Genetic testing: Analyzing DNA to look for a genetic alteration that may indicate an increased risk for developing a specific disease or disorder. [NIH] Genetics: The biological science that deals with the phenomena and mechanisms of heredity. [NIH] Genotype: The genetic constitution of the individual; the characterization of the genes. [NIH] Germ Cells: The reproductive cells in multicellular organisms. [NIH] Gestation: The period of development of the young in viviparous animals, from the time of fertilization of the ovum until birth. [EU] Gestational: Psychosis attributable to or occurring during pregnancy. [NIH] Gestational Age: Age of the conceptus. In humans, this may be assessed by medical history, physical examination, early immunologic pregnancy tests, radiography, ultrasonography, and amniotic fluid analysis. [NIH] Gland: An organ that produces and releases one or more substances for use in the body. Some glands produce fluids that affect tissues or organs. Others produce hormones or participate in blood production. [NIH] Glomerular: Pertaining to or of the nature of a glomerulus, especially a renal glomerulus. [EU]

Glomerular Filtration Rate: The volume of water filtered out of plasma through glomerular capillary walls into Bowman's capsules per unit of time. It is considered to be equivalent to inulin clearance. [NIH]

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Glomeruli: Plural of glomerulus. [NIH] Glomerulus: A tiny set of looping blood vessels in the nephron where blood is filtered in the kidney. [NIH] Glucocorticoid: A compound that belongs to the family of compounds called corticosteroids (steroids). Glucocorticoids affect metabolism and have anti-inflammatory and immunosuppressive effects. They may be naturally produced (hormones) or synthetic (drugs). [NIH] Glucokinase: A group of enzymes that catalyzes the conversion of ATP and D-glucose to ADP and D-glucose 6-phosphate. They are found in invertebrates and microorganisms and are highly specific for glucose. (Enzyme Nomenclature, 1992) EC 2.7.1.2. [NIH] Gluconeogenesis: The process by which glucose is formed from a non-carbohydrate source. [NIH]

Glucose: D-Glucose. A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement. [NIH] Glucose Clamp Technique: Maintenance of a constant blood glucose level by perfusion or infusion with glucose or insulin. It is used for the study of metabolic rates (e.g., in glucose, lipid, amino acid metabolism) at constant glucose concentration. [NIH] Glucose Intolerance: A pathological state in which the fasting plasma glucose level is less than 140 mg per deciliter and the 30-, 60-, or 90-minute plasma glucose concentration following a glucose tolerance test exceeds 200 mg per deciliter. This condition is seen frequently in diabetes mellitus but also occurs with other diseases. [NIH] Glucose tolerance: The power of the normal liver to absorb and store large quantities of glucose and the effectiveness of intestinal absorption of glucose. The glucose tolerance test is a metabolic test of carbohydrate tolerance that measures active insulin, a hepatic function based on the ability of the liver to absorb glucose. The test consists of ingesting 100 grams of glucose into a fasting stomach; blood sugar should return to normal in 2 to 21 hours after ingestion. [NIH] Glucose Tolerance Test: Determination of whole blood or plasma sugar in a fasting state before and at prescribed intervals (usually 1/2 hr, 1 hr, 3 hr, 4 hr) after taking a specified amount (usually 100 gm orally) of glucose. [NIH] Glucuronic Acid: Derivatives of uronic acid found throughout the plant and animal kingdoms. They detoxify drugs and toxins by conjugating with them to form glucuronides in the liver which are more water-soluble metabolites that can be easily eliminated from the body. [NIH] Glutamic Acid: A non-essential amino acid naturally occurring in the L-form. Glutamic acid (glutamate) is the most common excitatory neurotransmitter in the central nervous system. [NIH]

Glutamine: A non-essential amino acid present abundantly throught the body and is involved in many metabolic processes. It is synthesized from glutamic acid and ammonia. It is the principal carrier of nitrogen in the body and is an important energy source for many cells. [NIH] Glutathione Peroxidase: An enzyme catalyzing the oxidation of 2 moles of glutathione in the presence of hydrogen peroxide to yield oxidized glutathione and water. EC 1.11.1.9. [NIH]

Glyburide: An antidiabetic sulfonylurea derivative with actions similar to those of chlorpropamide. [NIH]

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Glycerol: A trihydroxy sugar alcohol that is an intermediate in carbohydrate and lipid metabolism. It is used as a solvent, emollient, pharmaceutical agent, and sweetening agent. [NIH]

Glycerophospholipids: Derivatives of phosphatidic acid in which the hydrophobic regions are composed of two fatty acids and a polar alcohol is joined to the C-3 position of glycerol through a phosphodiester bond. They are named according to their polar head groups, such as phosphatidylcholine and phosphatidylethanolamine. [NIH] Glycine: A non-essential amino acid. It is found primarily in gelatin and silk fibroin and used therapeutically as a nutrient. It is also a fast inhibitory neurotransmitter. [NIH] Glycogen: A sugar stored in the liver and muscles. It releases glucose into the blood when cells need it for energy. Glycogen is the chief source of stored fuel in the body. [NIH] Glycogen Synthase: An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11. [NIH] Glycoprotein: A protein that has sugar molecules attached to it. [NIH] Glycosidic: Formed by elimination of water between the anomeric hydroxyl of one sugar and a hydroxyl of another sugar molecule. [NIH] Glycosylation: The chemical or biochemical addition of carbohydrate or glycosyl groups to other chemicals, especially peptides or proteins. Glycosyl transferases are used in this biochemical reaction. [NIH] Gonad: A sex organ, such as an ovary or a testicle, which produces the gametes in most multicellular animals. [NIH] Gonadal: Pertaining to a gonad. [EU] Gonadorelin: A decapeptide hormone released by the hypothalamus. It stimulates the synthesis and secretion of both follicle-stimulating hormone (FSH) and luteinizing hormone (LH) from the pituitary gland. [NIH] Gonadotropin: The water-soluble follicle stimulating substance, by some believed to originate in chorionic tissue, obtained from the serum of pregnant mares. It is used to supplement the action of estrogens. [NIH] Gout: Hereditary metabolic disorder characterized by recurrent acute arthritis, hyperuricemia and deposition of sodium urate in and around the joints, sometimes with formation of uric acid calculi. [NIH] Governing Board: The group in which legal authority is vested for the control of healthrelated institutions and organizations. [NIH] Grade: The grade of a tumor depends on how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. Grading systems are different for each type of cancer. [NIH] Graft: Healthy skin, bone, or other tissue taken from one part of the body and used to replace diseased or injured tissue removed from another part of the body. [NIH] Gram-negative: Losing the stain or decolorized by alcohol in Gram's method of staining, a primary characteristic of bacteria having a cell wall composed of a thin layer of peptidoglycan covered by an outer membrane of lipoprotein and lipopolysaccharide. [EU] Granulocytes: Leukocytes with abundant granules in the cytoplasm. They are divided into three groups: neutrophils, eosinophils, and basophils. [NIH] Growth: The progressive development of a living being or part of an organism from its earliest stage to maturity. [NIH] Growth factors: Substances made by the body that function to regulate cell division and cell

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survival. Some growth factors are also produced in the laboratory and used in biological therapy. [NIH] Guanylate Cyclase: An enzyme that catalyzes the conversion of GTP to 3',5'-cyclic GMP and pyrophosphate. It also acts on ITP and dGTP. (From Enzyme Nomenclature, 1992) EC 4.6.1.2. [NIH] Habitual: Of the nature of a habit; according to habit; established by or repeated by force of habit, customary. [EU] Half-Life: The time it takes for a substance (drug, radioactive nuclide, or other) to lose half of its pharmacologic, physiologic, or radiologic activity. [NIH] Headache: Pain in the cranial region that may occur as an isolated and benign symptom or as a manifestation of a wide variety of conditions including subarachnoid hemorrhage; craniocerebral trauma; central nervous system infections; intracranial hypertension; and other disorders. In general, recurrent headaches that are not associated with a primary disease process are referred to as headache disorders (e.g., migraine). [NIH] Health Behavior: Behaviors expressed by individuals to protect, maintain or promote their health status. For example, proper diet, and appropriate exercise are activities perceived to influence health status. Life style is closely associated with health behavior and factors influencing life style are socioeconomic, educational, and cultural. [NIH] Health Education: Education that increases the awareness and favorably influences the attitudes and knowledge relating to the improvement of health on a personal or community basis. [NIH] Health Promotion: Encouraging consumer behaviors most likely to optimize health potentials (physical and psychosocial) through health information, preventive programs, and access to medical care. [NIH] Health Status: The level of health of the individual, group, or population as subjectively assessed by the individual or by more objective measures. [NIH] Heart attack: A seizure of weak or abnormal functioning of the heart. [NIH] Heart failure: Loss of pumping ability by the heart, often accompanied by fatigue, breathlessness, and excess fluid accumulation in body tissues. [NIH] Heartbeat: One complete contraction of the heart. [NIH] Hematocrit: Measurement of the volume of packed red cells in a blood specimen by centrifugation. The procedure is performed using a tube with graduated markings or with automated blood cell counters. It is used as an indicator of erythrocyte status in disease. For example, anemia shows a low hematocrit, polycythemia, high values. [NIH] Hemochromatosis: A disease that occurs when the body absorbs too much iron. The body stores the excess iron in the liver, pancreas, and other organs. May cause cirrhosis of the liver. Also called iron overload disease. [NIH] Hemodialysis: The use of a machine to clean wastes from the blood after the kidneys have failed. The blood travels through tubes to a dialyzer, which removes wastes and extra fluid. The cleaned blood then flows through another set of tubes back into the body. [NIH] Hemodynamics: The movements of the blood and the forces involved in systemic or regional blood circulation. [NIH] Hemoglobin: One of the fractions of glycosylated hemoglobin A1c. Glycosylated hemoglobin is formed when linkages of glucose and related monosaccharides bind to hemoglobin A and its concentration represents the average blood glucose level over the previous several weeks. HbA1c levels are used as a measure of long-term control of plasma

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glucose (normal, 4 to 6 percent). In controlled diabetes mellitus, the concentration of glycosylated hemoglobin A is within the normal range, but in uncontrolled cases the level may be 3 to 4 times the normal conentration. Generally, complications are substantially lower among patients with Hb levels of 7 percent or less than in patients with HbA1c levels of 9 percent or more. [NIH] Hemoglobinuria: The presence of free hemoglobin in the urine. [NIH] Hemorrhage: Bleeding or escape of blood from a vessel. [NIH] Hemostasis: The process which spontaneously arrests the flow of blood from vessels carrying blood under pressure. It is accomplished by contraction of the vessels, adhesion and aggregation of formed blood elements, and the process of blood or plasma coagulation. [NIH]

Heparin: Heparinic acid. A highly acidic mucopolysaccharide formed of equal parts of sulfated D-glucosamine and D-glucuronic acid with sulfaminic bridges. The molecular weight ranges from six to twenty thousand. Heparin occurs in and is obtained from liver, lung, mast cells, etc., of vertebrates. Its function is unknown, but it is used to prevent blood clotting in vivo and vitro, in the form of many different salts. [NIH] Hepatic: Refers to the liver. [NIH] Hepatitis: Inflammation of the liver and liver disease involving degenerative or necrotic alterations of hepatocytes. [NIH] Hepatocyte: A liver cell. [NIH] Hepatoma: A liver tumor. [NIH] Hereditary: Of, relating to, or denoting factors that can be transmitted genetically from one generation to another. [NIH] Heredity: 1. The genetic transmission of a particular quality or trait from parent to offspring. 2. The genetic constitution of an individual. [EU] Heritability: The proportion of observed variation in a particular trait that can be attributed to inherited genetic factors in contrast to environmental ones. [NIH] Heterozygotes: Having unlike alleles at one or more corresponding loci on homologous chromosomes. [NIH] Hexokinase: An enzyme that catalyzes the conversion of ATP and a D-hexose to ADP and a D-hexose 6-phosphate. D-Glucose, D-mannose, D-fructose, sorbitol, and D-glucosamine can act as acceptors; ITP and dATP can act as donors. The liver isoenzyme has sometimes been called glucokinase. (From Enzyme Nomenclature, 1992) EC 2.7.1.1. [NIH] Hirsutism: Excess hair in females and children with an adult male pattern of distribution. The concept does not include hypertrichosis, which is localized or generalized excess hair. [NIH]

Histamine: 1H-Imidazole-4-ethanamine. A depressor amine derived by enzymatic decarboxylation of histidine. It is a powerful stimulant of gastric secretion, a constrictor of bronchial smooth muscle, a vasodilator, and also a centrally acting neurotransmitter. [NIH] Histocompatibility: The degree of antigenic similarity between the tissues of different individuals, which determines the acceptance or rejection of allografts. [NIH] Histocompatibility Antigens: A group of antigens that includes both the major and minor histocompatibility antigens. The former are genetically determined by the major histocompatibility complex. They determine tissue type for transplantation and cause allograft rejections. The latter are systems of allelic alloantigens that can cause weak transplant rejection. [NIH]

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Homeostasis: The processes whereby the internal environment of an organism tends to remain balanced and stable. [NIH] Homogeneous: Consisting of or composed of similar elements or ingredients; of a uniform quality throughout. [EU] Homologous: Corresponding in structure, position, origin, etc., as (a) the feathers of a bird and the scales of a fish, (b) antigen and its specific antibody, (c) allelic chromosomes. [EU] Homozygotes: An individual having a homozygous gene pair. [NIH] Hormonal: Pertaining to or of the nature of a hormone. [EU] Hormone: A substance in the body that regulates certain organs. Hormones such as gastrin help in breaking down food. Some hormones come from cells in the stomach and small intestine. [NIH] Hormone Replacement Therapy: Therapeutic use of hormones to alleviate the effects of hormone deficiency. [NIH] Hormone therapy: Treatment of cancer by removing, blocking, or adding hormones. Also called endocrine therapy. [NIH] Host: Any animal that receives a transplanted graft. [NIH] Hybrid: Cross fertilization between two varieties or, more usually, two species of vines, see also crossing. [NIH] Hybridomas: Cells artificially created by fusion of activated lymphocytes with neoplastic cells. The resulting hybrid cells are cloned and produce pure or "monoclonal" antibodies or T-cell products, identical to those produced by the immunologically competent parent, and continually grow and divide as the neoplastic parent. [NIH] Hydrocortisone: The main glucocorticoid secreted by the adrenal cortex. Its synthetic counterpart is used, either as an injection or topically, in the treatment of inflammation, allergy, collagen diseases, asthma, adrenocortical deficiency, shock, and some neoplastic conditions. [NIH] Hydrogen: The first chemical element in the periodic table. It has the atomic symbol H, atomic number 1, and atomic weight 1. It exists, under normal conditions, as a colorless, odorless, tasteless, diatomic gas. Hydrogen ions are protons. Besides the common H1 isotope, hydrogen exists as the stable isotope deuterium and the unstable, radioactive isotope tritium. [NIH] Hydrogen Peroxide: A strong oxidizing agent used in aqueous solution as a ripening agent, bleach, and topical anti-infective. It is relatively unstable and solutions deteriorate over time unless stabilized by the addition of acetanilide or similar organic materials. [NIH] Hydrolysis: The process of cleaving a chemical compound by the addition of a molecule of water. [NIH] Hydrophobic: Not readily absorbing water, or being adversely affected by water, as a hydrophobic colloid. [EU] Hydroxylysine: A hydroxylated derivative of the amino acid lysine that is present in certain collagens. [NIH] Hydroxyproline: A hydroxylated form of the imino acid proline. A deficiency in ascorbic acid can result in impaired hydroxyproline formation. [NIH] Hyperandrogenism: A state characterized or caused by an excessive secretion of androgens by the adrenal cortex, ovaries, or testes. The clinical significance in males is negligible, so the term is used most commonly with reference to the female. The common manifestations in women are hirsutism and virilism. It is often caused by ovarian disease (particularly the

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polycystic ovary syndrome) and by adrenal diseases (particularly adrenal gland hyperfunction). [NIH] Hypercholesterolemia: Abnormally high levels of cholesterol in the blood. [NIH] Hyperglycaemia: Abnormally increased content of sugar in the blood. [EU] Hyperglycemia: Abnormally high blood sugar. [NIH] Hyperlipidemia: An excess of lipids in the blood. [NIH] Hyperlipoproteinemia: Metabolic disease characterized by elevated plasma cholesterol and/or triglyceride levels. The inherited form is attributed to a single gene mechanism. [NIH] Hyperphagia: Ingestion of a greater than optimal quantity of food. [NIH] Hyperplasia: An increase in the number of cells in a tissue or organ, not due to tumor formation. It differs from hypertrophy, which is an increase in bulk without an increase in the number of cells. [NIH] Hypersensitivity: Altered reactivity to an antigen, which can result in pathologic reactions upon subsequent exposure to that particular antigen. [NIH] Hypertension: Persistently high arterial blood pressure. Currently accepted threshold levels are 140 mm Hg systolic and 90 mm Hg diastolic pressure. [NIH] Hypertrichosis: Localized or generalized excess hair. The concept does not include hirsutism, which is excess hair in females and children with an adult male pattern of distribution. [NIH] Hypertriglyceridemia: Condition of elevated triglyceride concentration in the blood; an inherited form occurs in familial hyperlipoproteinemia IIb and hyperlipoproteinemia type IV. It has been linked to higher risk of heart disease and arteriosclerosis. [NIH] Hypertrophy: General increase in bulk of a part or organ, not due to tumor formation, nor to an increase in the number of cells. [NIH] Hyperuricaemia: Excess of uric acid or urates in the blood; it is a prerequisite for the development or gout and may lead to renal disease. Called also uricacidaemia and, formerly, lithemia. [EU] Hyperuricemia: A buildup of uric acid (a byproduct of metabolism) in the blood; a side effect of some anticancer drugs. [NIH] Hypoglycemia: Abnormally low blood sugar [NIH] Hypoglycemic: An orally active drug that produces a fall in blood glucose concentration. [NIH]

Hypoglycemic Agents: Agents which lower the blood glucose level. [NIH] Hypogonadism: Condition resulting from or characterized by abnormally decreased functional activity of the gonads, with retardation of growth and sexual development. [NIH] Hypolipidemic: A drug that lowers abnormally high plasma concentrations of cholesterol or triglycerides or both. [NIH] Hypotension: Abnormally low blood pressure. [NIH] Hypothalamic: Of or involving the hypothalamus. [EU] Hypothalamus: Ventral part of the diencephalon extending from the region of the optic chiasm to the caudal border of the mammillary bodies and forming the inferior and lateral walls of the third ventricle. [NIH] Hypoxia: Reduction of oxygen supply to tissue below physiological levels despite adequate perfusion of the tissue by blood. [EU]

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Iatrogenic: Resulting from the activity of physicians. Originally applied to disorders induced in the patient by autosuggestion based on the physician's examination, manner, or discussion, the term is now applied to any adverse condition in a patient occurring as the result of treatment by a physician or surgeon, especially to infections acquired by the patient during the course of treatment. [EU] Id: The part of the personality structure which harbors the unconscious instinctive desires and strivings of the individual. [NIH] Ileum: The lower end of the small intestine. [NIH] Imaging procedures: Methods of producing pictures of areas inside the body. [NIH] Imidazole: C3H4N2. The ring is present in polybenzimidazoles. [NIH] Immune response: The activity of the immune system against foreign substances (antigens). [NIH]

Immune system: The organs, cells, and molecules responsible for the recognition and disposal of foreign ("non-self") material which enters the body. [NIH] Immunization: Deliberate stimulation of the host's immune response. Active immunization involves administration of antigens or immunologic adjuvants. Passive immunization involves administration of immune sera or lymphocytes or their extracts (e.g., transfer factor, immune RNA) or transplantation of immunocompetent cell producing tissue (thymus or bone marrow). [NIH] Immunodeficiency: The decreased ability of the body to fight infection and disease. [NIH] Immunofluorescence: A technique for identifying molecules present on the surfaces of cells or in tissues using a highly fluorescent substance coupled to a specific antibody. [NIH] Immunogenic: Producing immunity; evoking an immune response. [EU] Immunoglobulin: A protein that acts as an antibody. [NIH] Immunologic: The ability of the antibody-forming system to recall a previous experience with an antigen and to respond to a second exposure with the prompt production of large amounts of antibody. [NIH] Immunosuppressive: Describes the ability to lower immune system responses. [NIH] Immunotherapy: Manipulation of the host's immune system in treatment of disease. It includes both active and passive immunization as well as immunosuppressive therapy to prevent graft rejection. [NIH] Impairment: In the context of health experience, an impairment is any loss or abnormality of psychological, physiological, or anatomical structure or function. [NIH] In vitro: In the laboratory (outside the body). The opposite of in vivo (in the body). [NIH] In vivo: In the body. The opposite of in vitro (outside the body or in the laboratory). [NIH] Incision: A cut made in the body during surgery. [NIH] Incontinence: Inability to control the flow of urine from the bladder (urinary incontinence) or the escape of stool from the rectum (fecal incontinence). [NIH] Indicative: That indicates; that points out more or less exactly; that reveals fairly clearly. [EU] Indinavir: A potent and specific HIV protease inhibitor that appears to have good oral bioavailability. [NIH] Induction: The act or process of inducing or causing to occur, especially the production of a specific morphogenetic effect in the developing embryo through the influence of evocators or organizers, or the production of anaesthesia or unconsciousness by use of appropriate agents. [EU]

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Infantile: Pertaining to an infant or to infancy. [EU] Infarction: A pathological process consisting of a sudden insufficient blood supply to an area, which results in necrosis of that area. It is usually caused by a thrombus, an embolus, or a vascular torsion. [NIH] Infection: 1. Invasion and multiplication of microorganisms in body tissues, which may be clinically unapparent or result in local cellular injury due to competitive metabolism, toxins, intracellular replication, or antigen-antibody response. The infection may remain localized, subclinical, and temporary if the body's defensive mechanisms are effective. A local infection may persist and spread by extension to become an acute, subacute, or chronic clinical infection or disease state. A local infection may also become systemic when the microorganisms gain access to the lymphatic or vascular system. 2. An infectious disease. [EU]

Infertility: The diminished or absent ability to conceive or produce an offspring while sterility is the complete inability to conceive or produce an offspring. [NIH] Inflammation: A pathological process characterized by injury or destruction of tissues caused by a variety of cytologic and chemical reactions. It is usually manifested by typical signs of pain, heat, redness, swelling, and loss of function. [NIH] Infusion: A method of putting fluids, including drugs, into the bloodstream. Also called intravenous infusion. [NIH] Ingestion: Taking into the body by mouth [NIH] Initiation: Mutation induced by a chemical reactive substance causing cell changes; being a step in a carcinogenic process. [NIH] Inorganic: Pertaining to substances not of organic origin. [EU] Inositol: An isomer of glucose that has traditionally been considered to be a B vitamin although it has an uncertain status as a vitamin and a deficiency syndrome has not been identified in man. (From Martindale, The Extra Pharmacopoeia, 30th ed, p1379) Inositol phospholipids are important in signal transduction. [NIH] Inpatients: Persons admitted to health facilities which provide board and room, for the purpose of observation, care, diagnosis or treatment. [NIH] Insight: The capacity to understand one's own motives, to be aware of one's own psychodynamics, to appreciate the meaning of symbolic behavior. [NIH] Insomnia: Difficulty in going to sleep or getting enough sleep. [NIH] Insulator: Material covering the metal conductor of the lead. It is usually polyurethane or silicone. [NIH] Insulin: A protein hormone secreted by beta cells of the pancreas. Insulin plays a major role in the regulation of glucose metabolism, generally promoting the cellular utilization of glucose. It is also an important regulator of protein and lipid metabolism. Insulin is used as a drug to control insulin-dependent diabetes mellitus. [NIH] Insulin-dependent diabetes mellitus: A disease characterized by high levels of blood glucose resulting from defects in insulin secretion, insulin action, or both. Autoimmune, genetic, and environmental factors are involved in the development of type I diabetes. [NIH] Insulin-like: Muscular growth factor. [NIH] Interleukin-1: A soluble factor produced by monocytes, macrophages, and other cells which activates T-lymphocytes and potentiates their response to mitogens or antigens. IL-1 consists of two distinct forms, IL-1 alpha and IL-1 beta which perform the same functions but are distinct proteins. The biological effects of IL-1 include the ability to replace macrophage

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requirements for T-cell activation. The factor is distinct from interleukin-2. [NIH] Interleukin-2: Chemical mediator produced by activated T lymphocytes and which regulates the proliferation of T cells, as well as playing a role in the regulation of NK cell activity. [NIH] Interleukin-6: Factor that stimulates the growth and differentiation of human B-cells and is also a growth factor for hybridomas and plasmacytomas. It is produced by many different cells including T-cells, monocytes, and fibroblasts. [NIH] Intermittent: Occurring at separated intervals; having periods of cessation of activity. [EU] Internal Medicine: A medical specialty concerned with the diagnosis and treatment of diseases of the internal organ systems of adults. [NIH] Interstitial: Pertaining to or situated between parts or in the interspaces of a tissue. [EU] Intestinal: Having to do with the intestines. [NIH] Intestine: A long, tube-shaped organ in the abdomen that completes the process of digestion. There is both a large intestine and a small intestine. Also called the bowel. [NIH] Intracellular: Inside a cell. [NIH] Intrahepatic: Within the liver. [NIH] Intramuscular: IM. Within or into muscle. [NIH] Intravenous: IV. Into a vein. [NIH] Intrinsic: Situated entirely within or pertaining exclusively to a part. [EU] Inulin: A starch found in the tubers and roots of many plants. Since it is hydrolyzable to fructose, it is classified as a fructosan. It has been used in physiologic investigation for determination of the rate of glomerular function. [NIH] Invasive: 1. Having the quality of invasiveness. 2. Involving puncture or incision of the skin or insertion of an instrument or foreign material into the body; said of diagnostic techniques. [EU]

Invertebrates: Animals that have no spinal column. [NIH] Involuntary: Reaction occurring without intention or volition. [NIH] Ion Transport: The movement of ions across energy-transducing cell membranes. Transport can be active or passive. Passive ion transport (facilitated diffusion) derives its energy from the concentration gradient of the ion itself and allows the transport of a single solute in one direction (uniport). Active ion transport is usually coupled to an energy-yielding chemical or photochemical reaction such as ATP hydrolysis. This form of primary active transport is called an ion pump. Secondary active transport utilizes the voltage and ion gradients produced by the primary transport to drive the cotransport of other ions or molecules. These may be transported in the same (symport) or opposite (antiport) direction. [NIH] Ions: An atom or group of atoms that have a positive or negative electric charge due to a gain (negative charge) or loss (positive charge) of one or more electrons. Atoms with a positive charge are known as cations; those with a negative charge are anions. [NIH] Irritable Bowel Syndrome: A disorder that comes and goes. Nerves that control the muscles in the GI tract are too active. The GI tract becomes sensitive to food, stool, gas, and stress. Causes abdominal pain, bloating, and constipation or diarrhea. Also called spastic colon or mucous colitis. [NIH] Ischemia: Deficiency of blood in a part, due to functional constriction or actual obstruction of a blood vessel. [EU] Islet: Cell producing insulin in pancreas. [NIH]

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Isoenzyme: Different forms of an enzyme, usually occurring in different tissues. The isoenzymes of a particular enzyme catalyze the same reaction but they differ in some of their properties. [NIH] Isoflavones: 3-Phenylchromones. Isomeric form of flavones in which the benzene group is attached to the 3 position of the benzopyran ring instead of the 2 position. [NIH] Joint: The point of contact between elements of an animal skeleton with the parts that surround and support it. [NIH] Kb: A measure of the length of DNA fragments, 1 Kb = 1000 base pairs. The largest DNA fragments are up to 50 kilobases long. [NIH] Ketone Bodies: Chemicals that the body makes when there is not enough insulin in the blood and it must break down fat for its energy. Ketone bodies can poison and even kill body cells. When the body does not have the help of insulin, the ketones build up in the blood and then "spill" over into the urine so that the body can get rid of them. The body can also rid itself of one type of ketone, called acetone, through the lungs. This gives the breath a fruity odor. Ketones that build up in the body for a long time lead to serious illness and coma. [NIH] Ketosis: A condition of having ketone bodies build up in body tissues and fluids. The signs of ketosis are nausea, vomiting, and stomach pain. Ketosis can lead to ketoacidosis. [NIH] Kidney Disease: Any one of several chronic conditions that are caused by damage to the cells of the kidney. People who have had diabetes for a long time may have kidney damage. Also called nephropathy. [NIH] Kidney Failure: The inability of a kidney to excrete metabolites at normal plasma levels under conditions of normal loading, or the inability to retain electrolytes under conditions of normal intake. In the acute form (kidney failure, acute), it is marked by uremia and usually by oliguria or anuria, with hyperkalemia and pulmonary edema. The chronic form (kidney failure, chronic) is irreversible and requires hemodialysis. [NIH] Kinetic: Pertaining to or producing motion. [EU] Lactation: The period of the secretion of milk. [EU] Large Intestine: The part of the intestine that goes from the cecum to the rectum. The large intestine absorbs water from stool and changes it from a liquid to a solid form. The large intestine is 5 feet long and includes the appendix, cecum, colon, and rectum. Also called colon. [NIH] Latent: Phoria which occurs at one distance or another and which usually has no troublesome effect. [NIH] Least-Squares Analysis: A principle of estimation in which the estimates of a set of parameters in a statistical model are those quantities minimizing the sum of squared differences between the observed values of a dependent variable and the values predicted by the model. [NIH] Lens: The transparent, double convex (outward curve on both sides) structure suspended between the aqueous and vitreous; helps to focus light on the retina. [NIH] Leprosy: A chronic granulomatous infection caused by Mycobacterium leprae. The granulomatous lesions are manifested in the skin, the mucous membranes, and the peripheral nerves. Two polar or principal types are lepromatous and tuberculoid. [NIH] Leptin: A 16-kD peptide hormone secreted from white adipocytes and implicated in the regulation of food intake and energy balance. Leptin provides the key afferent signal from fat cells in the feedback system that controls body fat stores. [NIH]

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Lesion: An area of abnormal tissue change. [NIH] Lethal: Deadly, fatal. [EU] Leucocyte: All the white cells of the blood and their precursors (myeloid cell series, lymphoid cell series) but commonly used to indicate granulocytes exclusive of lymphocytes. [NIH]

Leukemia: Cancer of blood-forming tissue. [NIH] Leukocytes: White blood cells. These include granular leukocytes (basophils, eosinophils, and neutrophils) as well as non-granular leukocytes (lymphocytes and monocytes). [NIH] Leukotrienes: A family of biologically active compounds derived from arachidonic acid by oxidative metabolism through the 5-lipoxygenase pathway. They participate in host defense reactions and pathophysiological conditions such as immediate hypersensitivity and inflammation. They have potent actions on many essential organs and systems, including the cardiovascular, pulmonary, and central nervous system as well as the gastrointestinal tract and the immune system. [NIH] Leuprolide: A potent and long acting analog of naturally occurring gonadotropin-releasing hormone (gonadorelin). Its action is similar to gonadorelin, which regulates the synthesis and release of pituitary gonadotropins. [NIH] Libido: The psychic drive or energy associated with sexual instinct in the broad sense (pleasure and love-object seeking). It may also connote the psychic energy associated with instincts in general that motivate behavior. [NIH] Library Services: Services offered to the library user. They include reference and circulation. [NIH]

Ligament: A band of fibrous tissue that connects bones or cartilages, serving to support and strengthen joints. [EU] Ligands: A RNA simulation method developed by the MIT. [NIH] Likelihood Functions: Functions constructed from a statistical model and a set of observed data which give the probability of that data for various values of the unknown model parameters. Those parameter values that maximize the probability are the maximum likelihood estimates of the parameters. [NIH] Linear Models: Statistical models in which the value of a parameter for a given value of a factor is assumed to be equal to a + bx, where a and b are constants. The models predict a linear regression. [NIH] Linkage: The tendency of two or more genes in the same chromosome to remain together from one generation to the next more frequently than expected according to the law of independent assortment. [NIH] Linkage Disequilibrium: Nonrandom association of linked genes. This is the tendency of the alleles of two separate but already linked loci to be found together more frequently than would be expected by chance alone. [NIH] Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. It is produced by glands on the tongue and by the pancreas and initiates the digestion of dietary fats. (From Dorland, 27th ed) EC 3.1.1.3. [NIH] Lipid: Fat. [NIH] Lipid A: Lipid A is the biologically active component of lipopolysaccharides. It shows strong endotoxic activity and exhibits immunogenic properties. [NIH] Lipid Peroxidation: Peroxidase catalyzed oxidation of lipids using hydrogen peroxide as an

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electron acceptor. [NIH] Lipodystrophy: A collection of rare conditions resulting from defective fat metabolism and characterized by atrophy of the subcutaneous fat. They include total, congenital or acquired, partial, abdominal infantile, and localized lipodystrophy. [NIH] Lipolysis: The hydrolysis of lipids. [NIH] Lipopolysaccharide: Substance consisting of polysaccaride and lipid. [NIH] Lipoprotein: Any of the lipid-protein complexes in which lipids are transported in the blood; lipoprotein particles consist of a spherical hydrophobic core of triglycerides or cholesterol esters surrounded by an amphipathic monolayer of phospholipids, cholesterol, and apolipoproteins; the four principal classes are high-density, low-density, and very-lowdensity lipoproteins and chylomicrons. [EU] Lipoprotein Lipase: An enzyme of the hydrolase class that catalyzes the reaction of triacylglycerol and water to yield diacylglycerol and a fatty acid anion. The enzyme hydrolyzes triacylglycerols in chylomicrons, very-low-density lipoproteins, low-density lipoproteins, and diacylglycerols. It occurs on capillary endothelial surfaces, especially in mammary, muscle, and adipose tissue. Genetic deficiency of the enzyme causes familial hyperlipoproteinemia Type I. (Dorland, 27th ed) EC 3.1.1.34. [NIH] Lipoprotein(a): A family of lipoprotein particles varying in density and size depending on the protein-lipid ratio and the protein composition. These particles consist of apolipoprotein B-100 covalently linked to apolipoprotein-a by one or two disulfide bonds. There is a correlation between high plasma levels of this lipoprotein and increased risk for atherosclerotic cardiovascular disease. [NIH] Liposarcoma: A rare cancer of the fat cells. [NIH] Lipoxygenase: An enzyme of the oxidoreductase class that catalyzes reactions between linoleate and other fatty acids and oxygen to form hydroperoxy-fatty acid derivatives. Related enzymes in this class include the arachidonate lipoxygenases, arachidonate 5lipoxygenase, arachidonate 12-lipoxygenase, and arachidonate 15-lipoxygenase. EC 1.13.11.12. [NIH] Liver: A large, glandular organ located in the upper abdomen. The liver cleanses the blood and aids in digestion by secreting bile. [NIH] Liver scan: An image of the liver created on a computer screen or on film. A radioactive substance is injected into a blood vessel and travels through the bloodstream. It collects in the liver, especially in abnormal areas, and can be detected by the scanner. [NIH] Lobe: A portion of an organ such as the liver, lung, breast, or brain. [NIH] Localization: The process of determining or marking the location or site of a lesion or disease. May also refer to the process of keeping a lesion or disease in a specific location or site. [NIH] Localized: Cancer which has not metastasized yet. [NIH] Logistic Models: Statistical models which describe the relationship between a qualitative dependent variable (that is, one which can take only certain discrete values, such as the presence or absence of a disease) and an independent variable. A common application is in epidemiology for estimating an individual's risk (probability of a disease) as a function of a given risk factor. [NIH] Longitudinal Studies: Studies in which variables relating to an individual or group of individuals are assessed over a period of time. [NIH] Longitudinal study: Also referred to as a "cohort study" or "prospective study"; the analytic

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method of epidemiologic study in which subsets of a defined population can be identified who are, have been, or in the future may be exposed or not exposed, or exposed in different degrees, to a factor or factors hypothesized to influence the probability of occurrence of a given disease or other outcome. The main feature of this type of study is to observe large numbers of subjects over an extended time, with comparisons of incidence rates in groups that differ in exposure levels. [NIH] Loop: A wire usually of platinum bent at one end into a small loop (usually 4 mm inside diameter) and used in transferring microorganisms. [NIH] Low-density lipoprotein: Lipoprotein that contains most of the cholesterol in the blood. LDL carries cholesterol to the tissues of the body, including the arteries. A high level of LDL increases the risk of heart disease. LDL typically contains 60 to 70 percent of the total serum cholesterol and both are directly correlated with CHD risk. [NIH] Lupus: A form of cutaneous tuberculosis. It is seen predominantly in women and typically involves the nasal, buccal, and conjunctival mucosa. [NIH] Lymph: The almost colorless fluid that travels through the lymphatic system and carries cells that help fight infection and disease. [NIH] Lymph node: A rounded mass of lymphatic tissue that is surrounded by a capsule of connective tissue. Also known as a lymph gland. Lymph nodes are spread out along lymphatic vessels and contain many lymphocytes, which filter the lymphatic fluid (lymph). [NIH]

Lymphatic: The tissues and organs, including the bone marrow, spleen, thymus, and lymph nodes, that produce and store cells that fight infection and disease. [NIH] Lymphocyte: A white blood cell. Lymphocytes have a number of roles in the immune system, including the production of antibodies and other substances that fight infection and diseases. [NIH] Lymphoid: Referring to lymphocytes, a type of white blood cell. Also refers to tissue in which lymphocytes develop. [NIH] Lymphoma: A general term for various neoplastic diseases of the lymphoid tissue. [NIH] Macrophage: A type of white blood cell that surrounds and kills microorganisms, removes dead cells, and stimulates the action of other immune system cells. [NIH] Magnetic Resonance Imaging: Non-invasive method of demonstrating internal anatomy based on the principle that atomic nuclei in a strong magnetic field absorb pulses of radiofrequency energy and emit them as radiowaves which can be reconstructed into computerized images. The concept includes proton spin tomographic techniques. [NIH] Magnetic Resonance Spectroscopy: Spectroscopic method of measuring the magnetic moment of elementary particles such as atomic nuclei, protons or electrons. It is employed in clinical applications such as NMR Tomography (magnetic resonance imaging). [NIH] Major Histocompatibility Complex: The genetic region which contains the loci of genes which determine the structure of the serologically defined (SD) and lymphocyte-defined (LD) transplantation antigens, genes which control the structure of the immune responseassociated (Ia) antigens, the immune response (Ir) genes which control the ability of an animal to respond immunologically to antigenic stimuli, and genes which determine the structure and/or level of the first four components of complement. [NIH] Malabsorption: Impaired intestinal absorption of nutrients. [EU] Malignancy: A cancerous tumor that can invade and destroy nearby tissue and spread to other parts of the body. [NIH] Malignant: Cancerous; a growth with a tendency to invade and destroy nearby tissue and

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spread to other parts of the body. [NIH] Malnutrition: A condition caused by not eating enough food or not eating a balanced diet. [NIH]

Mammary: Pertaining to the mamma, or breast. [EU] Mammogram: An x-ray of the breast. [NIH] Manifest: Being the part or aspect of a phenomenon that is directly observable : concretely expressed in behaviour. [EU] Mannitol: A diuretic and renal diagnostic aid related to sorbitol. It has little significant energy value as it is largely eliminated from the body before any metabolism can take place. It can be used to treat oliguria associated with kidney failure or other manifestations of inadequate renal function and has been used for determination of glomerular filtration rate. Mannitol is also commonly used as a research tool in cell biological studies, usually to control osmolarity. [NIH] Meat: The edible portions of any animal used for food including domestic mammals (the major ones being cattle, swine, and sheep) along with poultry, fish, shellfish, and game. [NIH]

Medial: Lying near the midsaggital plane of the body; opposed to lateral. [NIH] Mediate: Indirect; accomplished by the aid of an intervening medium. [EU] Mediator: An object or substance by which something is mediated, such as (1) a structure of the nervous system that transmits impulses eliciting a specific response; (2) a chemical substance (transmitter substance) that induces activity in an excitable tissue, such as nerve or muscle; or (3) a substance released from cells as the result of the interaction of antigen with antibody or by the action of antigen with a sensitized lymphocyte. [EU] Medicament: A medicinal substance or agent. [EU] MEDLINE: An online database of MEDLARS, the computerized bibliographic Medical Literature Analysis and Retrieval System of the National Library of Medicine. [NIH] Melanin: The substance that gives the skin its color. [NIH] Melanocytes: Epidermal dendritic pigment cells which control long-term morphological color changes by alteration in their number or in the amount of pigment they produce and store in the pigment containing organelles called melanosomes. Melanophores are larger cells which do not exist in mammals. [NIH] Melanoma: A form of skin cancer that arises in melanocytes, the cells that produce pigment. Melanoma usually begins in a mole. [NIH] Melanosis: Disorders of increased melanin pigmentation that develop without preceding inflammatory disease. [NIH] Melanosomes: Melanin-containing organelles found in melanocytes and melanophores. [NIH]

Membrane: A very thin layer of tissue that covers a surface. [NIH] Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors. [NIH] Memory: Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. [NIH] Meninges: The three membranes that cover and protect the brain and spinal cord. [NIH]

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Menopause: Permanent cessation of menstruation. [NIH] Menstrual Cycle: The period of the regularly recurring physiologic changes in the endometrium occurring during the reproductive period in human females and some primates and culminating in partial sloughing of the endometrium (menstruation). [NIH] Menstruation: The normal physiologic discharge through the vagina of blood and mucosal tissues from the nonpregnant uterus. [NIH] Mental Disorders: Psychiatric illness or diseases manifested by breakdowns in the adaptational process expressed primarily as abnormalities of thought, feeling, and behavior producing either distress or impairment of function. [NIH] Mental Health: The state wherein the person is well adjusted. [NIH] Mental Processes: Conceptual functions or thinking in all its forms. [NIH] Mentors: Senior professionals who provide guidance, direction and support to those persons desirous of improvement in academic positions, administrative positions or other career development situations. [NIH] Mesenteric: Pertaining to the mesentery : a membranous fold attaching various organs to the body wall. [EU] Mesentery: A layer of the peritoneum which attaches the abdominal viscera to the abdominal wall and conveys their blood vessels and nerves. [NIH] Metabolic disorder: A condition in which normal metabolic processes are disrupted, usually because of a missing enzyme. [NIH] Metabolite: Any substance produced by metabolism or by a metabolic process. [EU] Metastasis: The spread of cancer from one part of the body to another. Tumors formed from cells that have spread are called "secondary tumors" and contain cells that are like those in the original (primary) tumor. The plural is metastases. [NIH] Methionine: A sulfur containing essential amino acid that is important in many body functions. It is a chelating agent for heavy metals. [NIH] MI: Myocardial infarction. Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Microbe: An organism which cannot be observed with the naked eye; e. g. unicellular animals, lower algae, lower fungi, bacteria. [NIH] Microbiology: The study of microorganisms such as fungi, bacteria, algae, archaea, and viruses. [NIH] Microcalcifications: Tiny deposits of calcium in the breast that cannot be felt but can be detected on a mammogram. A cluster of these very small specks of calcium may indicate that cancer is present. [NIH] Microorganism: An organism that can be seen only through a microscope. Microorganisms include bacteria, protozoa, algae, and fungi. Although viruses are not considered living organisms, they are sometimes classified as microorganisms. [NIH] Midaxillary line: An imaginary vertical line that passes midway between the anterior and posterior axillary (armpit) folds. [NIH] Millimeter: A measure of length. A millimeter is approximately 26-times smaller than an inch. [NIH] Mineralocorticoid: 1. Any of the group of C21 corticosteroids, principally aldosterone, predominantly involved in the regulation of electrolyte and water balance through their

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effect on ion transport in epithelial cells of the renal tubules, resulting in retention of sodium and loss of potassium; some also possess varying degrees of glucocorticoid activity. Their secretion is regulated principally by plasma volume, serum potassium concentration and angiotensin II, and to a lesser extent by anterior pituitary ACTH. 2. Of, pertaining to, having the properties of, or resembling a mineralocorticoid. [EU] Minor Histocompatibility Antigens: Allelic alloantigens often responsible for weak graft rejection in cases when (major) histocompatibility has been established by standard tests. In the mouse they are coded by more than 500 genes at up to 30 minor histocompatibility loci. The most well-known minor histocompatibility antigen in mammals is the H-Y antigen. [NIH]

Minority Groups: A subgroup having special characteristics within a larger group, often bound together by special ties which distinguish it from the larger group. [NIH] Miscarriage: Spontaneous expulsion of the products of pregnancy before the middle of the second trimester. [NIH] Mitochondria: Parts of a cell where aerobic production (also known as cell respiration) takes place. [NIH] Mitochondrial Swelling: Increase in volume of mitochondria due to an influx of fluid; it occurs in hypotonic solutions due to osmotic pressure and in isotonic solutions as a result of altered permeability of the membranes of respiring mitochondria. [NIH] Mitosis: A method of indirect cell division by means of which the two daughter nuclei normally receive identical complements of the number of chromosomes of the somatic cells of the species. [NIH] Mobilization: The process of making a fixed part or stored substance mobile, as by separating a part from surrounding structures to make it accessible for an operative procedure or by causing release into the circulation for body use of a substance stored in the body. [EU] Modeling: A treatment procedure whereby the therapist presents the target behavior which the learner is to imitate and make part of his repertoire. [NIH] Modification: A change in an organism, or in a process in an organism, that is acquired from its own activity or environment. [NIH] Modulator: A specific inductor that brings out characteristics peculiar to a definite region. [EU]

Molecular: Of, pertaining to, or composed of molecules : a very small mass of matter. [EU] Molecular Structure: The location of the atoms, groups or ions relative to one another in a molecule, as well as the number, type and location of covalent bonds. [NIH] Molecule: A chemical made up of two or more atoms. The atoms in a molecule can be the same (an oxygen molecule has two oxygen atoms) or different (a water molecule has two hydrogen atoms and one oxygen atom). Biological molecules, such as proteins and DNA, can be made up of many thousands of atoms. [NIH] Monitor: An apparatus which automatically records such physiological signs as respiration, pulse, and blood pressure in an anesthetized patient or one undergoing surgical or other procedures. [NIH] Monoclonal: An antibody produced by culturing a single type of cell. It therefore consists of a single species of immunoglobulin molecules. [NIH] Monocytes: Large, phagocytic mononuclear leukocytes produced in the vertebrate bone marrow and released into the blood; contain a large, oval or somewhat indented nucleus surrounded by voluminous cytoplasm and numerous organelles. [NIH]

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Monogenic: A human disease caused by a mutation in a single gene. [NIH] Mononuclear: A cell with one nucleus. [NIH] Monotherapy: A therapy which uses only one drug. [EU] Morphological: Relating to the configuration or the structure of live organs. [NIH] Motility: The ability to move spontaneously. [EU] Motion Sickness: Sickness caused by motion, as sea sickness, train sickness, car sickness, and air sickness. [NIH] Mucosa: A mucous membrane, or tunica mucosa. [EU] Multicenter study: A clinical trial that is carried out at more than one medical institution. [NIH]

Multiple sclerosis: A disorder of the central nervous system marked by weakness, numbness, a loss of muscle coordination, and problems with vision, speech, and bladder control. Multiple sclerosis is thought to be an autoimmune disease in which the body's immune system destroys myelin. Myelin is a substance that contains both protein and fat (lipid) and serves as a nerve insulator and helps in the transmission of nerve signals. [NIH] Muscle Fibers: Large single cells, either cylindrical or prismatic in shape, that form the basic unit of muscle tissue. They consist of a soft contractile substance enclosed in a tubular sheath. [NIH] Muscular Atrophy: Derangement in size and number of muscle fibers occurring with aging, reduction in blood supply, or following immobilization, prolonged weightlessness, malnutrition, and particularly in denervation. [NIH] Muscular Dystrophies: A general term for a group of inherited disorders which are characterized by progressive degeneration of skeletal muscles. [NIH] Mutagenesis: Process of generating genetic mutations. It may occur spontaneously or be induced by mutagens. [NIH] Mutagens: Chemical agents that increase the rate of genetic mutation by interfering with the function of nucleic acids. A clastogen is a specific mutagen that causes breaks in chromosomes. [NIH] Mydriatic: 1. Dilating the pupil. 2. Any drug that dilates the pupil. [EU] Myelin: The fatty substance that covers and protects nerves. [NIH] Myocardial infarction: Gross necrosis of the myocardium as a result of interruption of the blood supply to the area; it is almost always caused by atherosclerosis of the coronary arteries, upon which coronary thrombosis is usually superimposed. [NIH] Myocardial Ischemia: A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary arteriosclerosis), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Severe interruption of the blood supply to the myocardial tissue may result in necrosis of cardiac muscle (myocardial infarction). [NIH] Myocardial Reperfusion: Generally, restoration of blood supply to heart tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. Reperfusion can be induced to treat ischemia. Methods include chemical dissolution of an occluding thrombus, administration of vasodilator drugs, angioplasty, catheterization, and artery bypass graft surgery. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing myocardial reperfusion injury. [NIH]

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Myocardial Reperfusion Injury: Functional, metabolic, or structural changes in ischemic heart muscle thought to result from reperfusion to the ischemic areas. Changes can be fatal to muscle cells and may include edema with explosive cell swelling and disintegration, sarcolemma disruption, fragmentation of mitochondria, contraction band necrosis, enzyme washout, and calcium overload. Other damage may include hemorrhage and ventricular arrhythmias. One possible mechanism of damage is thought to be oxygen free radicals. Treatment currently includes the introduction of scavengers of oxygen free radicals, and injury is thought to be prevented by warm blood cardioplegic infusion prior to reperfusion. [NIH]

Myocardium: The muscle tissue of the heart composed of striated, involuntary muscle known as cardiac muscle. [NIH] Myofibrils: Highly organized bundles of actin, myosin, and other proteins in the cytoplasm of skeletal and cardiac muscle cells that contract by a sliding filament mechanism. [NIH] Myotonic Dystrophy: A condition presenting muscle weakness and wasting which may be progressive. [NIH] Myristate: Pharmacological activator of protein kinase C. [NIH] Naive: Used to describe an individual who has never taken a certain drug or class of drugs (e. g., AZT-naive, antiretroviral-naive), or to refer to an undifferentiated immune system cell. [NIH] Natural selection: A part of the evolutionary process resulting in the survival and reproduction of the best adapted individuals. [NIH] Nausea: An unpleasant sensation in the stomach usually accompanied by the urge to vomit. Common causes are early pregnancy, sea and motion sickness, emotional stress, intense pain, food poisoning, and various enteroviruses. [NIH] NCI: National Cancer Institute. NCI, part of the National Institutes of Health of the United States Department of Health and Human Services, is the federal government's principal agency for cancer research. NCI conducts, coordinates, and funds cancer research, training, health information dissemination, and other programs with respect to the cause, diagnosis, prevention, and treatment of cancer. Access the NCI Web site at http://cancer.gov. [NIH] Necrosis: A pathological process caused by the progressive degradative action of enzymes that is generally associated with severe cellular trauma. It is characterized by mitochondrial swelling, nuclear flocculation, uncontrolled cell lysis, and ultimately cell death. [NIH] Need: A state of tension or dissatisfaction felt by an individual that impels him to action toward a goal he believes will satisfy the impulse. [NIH] Needle biopsy: The removal of tissue or fluid with a needle for examination under a microscope. Also called fine-needle aspiration. [NIH] Neonatal: Pertaining to the first four weeks after birth. [EU] Neoplasia: Abnormal and uncontrolled cell growth. [NIH] Neoplastic: Pertaining to or like a neoplasm (= any new and abnormal growth); pertaining to neoplasia (= the formation of a neoplasm). [EU] Nephrology: A subspecialty of internal medicine concerned with the anatomy, physiology, and pathology of the kidney. [NIH] Nephropathy: Disease of the kidneys. [EU] Nerve: A cordlike structure of nervous tissue that connects parts of the nervous system with other tissues of the body and conveys nervous impulses to, or away from, these tissues. [NIH] Nervous System: The entire nerve apparatus composed of the brain, spinal cord, nerves and

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ganglia. [NIH] Neural: 1. Pertaining to a nerve or to the nerves. 2. Situated in the region of the spinal axis, as the neutral arch. [EU] Neuromuscular: Pertaining to muscles and nerves. [EU] Neuromuscular Junction: The synapse between a neuron and a muscle. [NIH] Neuronal: Pertaining to a neuron or neurons (= conducting cells of the nervous system). [EU] Neurons: The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. [NIH] Neuropathy: A problem in any part of the nervous system except the brain and spinal cord. Neuropathies can be caused by infection, toxic substances, or disease. [NIH] Neuropeptide: A member of a class of protein-like molecules made in the brain. Neuropeptides consist of short chains of amino acids, with some functioning as neurotransmitters and some functioning as hormones. [NIH] Neurotransmitters: Endogenous signaling molecules that alter the behavior of neurons or effector cells. Neurotransmitter is used here in its most general sense, including not only messengers that act directly to regulate ion channels, but also those that act through second messenger systems, and those that act at a distance from their site of release. Included are neuromodulators, neuroregulators, neuromediators, and neurohumors, whether or not acting at synapses. [NIH] Neutrophils: Granular leukocytes having a nucleus with three to five lobes connected by slender threads of chromatin, and cytoplasm containing fine inconspicuous granules and stainable by neutral dyes. [NIH] Niacin: Water-soluble vitamin of the B complex occurring in various animal and plant tissues. Required by the body for the formation of coenzymes NAD and NADP. Has pellagra-curative, vasodilating, and antilipemic properties. [NIH] Nicotine: Nicotine is highly toxic alkaloid. It is the prototypical agonist at nicotinic cholinergic receptors where it dramatically stimulates neurons and ultimately blocks synaptic transmission. Nicotine is also important medically because of its presence in tobacco smoke. [NIH] Nitric Oxide: A free radical gas produced endogenously by a variety of mammalian cells. It is synthesized from arginine by a complex reaction, catalyzed by nitric oxide synthase. Nitric oxide is endothelium-derived relaxing factor. It is released by the vascular endothelium and mediates the relaxation induced by some vasodilators such as acetylcholine and bradykinin. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic guanylate cyclase and thus elevates intracellular levels of cyclic GMP. [NIH]

Nitrogen: An element with the atomic symbol N, atomic number 7, and atomic weight 14. Nitrogen exists as a diatomic gas and makes up about 78% of the earth's atmosphere by volume. It is a constituent of proteins and nucleic acids and found in all living cells. [NIH] Norepinephrine: Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers and of the diffuse projection system in the brain arising from the locus ceruleus. It is also found in plants and is used pharmacologically as a sympathomimetic. [NIH] Normotensive: 1. Characterized by normal tone, tension, or pressure, as by normal blood

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pressure. 2. A person with normal blood pressure. [EU] Nuclear: A test of the structure, blood flow, and function of the kidneys. The doctor injects a mildly radioactive solution into an arm vein and uses x-rays to monitor its progress through the kidneys. [NIH] Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with nucleoproteins which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus. [NIH] Nuclei: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nucleic acid: Either of two types of macromolecule (DNA or RNA) formed by polymerization of nucleotides. Nucleic acids are found in all living cells and contain the information (genetic code) for the transfer of genetic information from one generation to the next. [NIH] Nucleoproteins: Proteins conjugated with nucleic acids. [NIH] Nucleus: A body of specialized protoplasm found in nearly all cells and containing the chromosomes. [NIH] Nutritional Status: State of the body in relation to the consumption and utilization of nutrients. [NIH] Octreotide: A potent, long-acting somatostatin octapeptide analog which has a wide range of physiological actions. It inhibits growth hormone secretion, is effective in the treatment of hormone-secreting tumors from various organs, and has beneficial effects in the management of many pathological states including diabetes mellitus, orthostatic hypertension, hyperinsulinism, hypergastrinemia, and small bowel fistula. [NIH] Ointments: Semisolid preparations used topically for protective emollient effects or as a vehicle for local administration of medications. Ointment bases are various mixtures of fats, waxes, animal and plant oils and solid and liquid hydrocarbons. [NIH] Oligo: Chemical and mineral elements that exist in minimal (oligo) quantities in the body, in foods, in the air, in soil; name applied to any element observed as a microconstituent of plant or animal tissue and of beneficial, harmful, or even doubtful significance. [NIH] Oligomenorrhea: Abnormally infrequent menstruation. [NIH] Oliguria: Clinical manifestation of the urinary system consisting of a decrease in the amount of urine secreted. [NIH] Oncogene: A gene that normally directs cell growth. If altered, an oncogene can promote or allow the uncontrolled growth of cancer. Alterations can be inherited or caused by an environmental exposure to carcinogens. [NIH] Opacity: Degree of density (area most dense taken for reading). [NIH] Optic Chiasm: The X-shaped structure formed by the meeting of the two optic nerves. At the optic chiasm the fibers from the medial part of each retina cross to project to the other side of the brain while the lateral retinal fibers continue on the same side. As a result each half of the brain receives information about the contralateral visual field from both eyes. [NIH]

Optic Disk: The portion of the optic nerve seen in the fundus with the ophthalmoscope. It is formed by the meeting of all the retinal ganglion cell axons as they enter the optic nerve. [NIH]

Organelles: Specific particles of membrane-bound organized living substances present in eukaryotic cells, such as the mitochondria; the golgi apparatus; endoplasmic reticulum; lysomomes; plastids; and vacuoles. [NIH]

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Orlistat: A lipase inhibitor used for weight loss. Lipase is an enzyme found in the bowel that assists in lipid absorption by the body. Orlistat blocks this enzyme, reducing the amount of fat the body absorbs by about 30 percent. It is known colloquially as a "fat blocker." Because more oily fat is left in the bowel to be excreted, Orlistat can cause an oily anal leakage and fecal incontinence. Orlistat may not be suitable for people with bowel conditions such as irritable bowel syndrome or Crohn's disease. [NIH] Orthostatic: Pertaining to or caused by standing erect. [EU] Osmolarity: The concentration of osmotically active particles expressed in terms of osmoles of solute per litre of solution. [EU] Osmotic: Pertaining to or of the nature of osmosis (= the passage of pure solvent from a solution of lesser to one of greater solute concentration when the two solutions are separated by a membrane which selectively prevents the passage of solute molecules, but is permeable to the solvent). [EU] Osteoporosis: Reduction of bone mass without alteration in the composition of bone, leading to fractures. Primary osteoporosis can be of two major types: postmenopausal osteoporosis and age-related (or senile) osteoporosis. [NIH] Outpatient: A patient who is not an inmate of a hospital but receives diagnosis or treatment in a clinic or dispensary connected with the hospital. [NIH] Ovarian Cysts: General term for cysts and cystic diseases of the ovary. [NIH] Ovaries: The pair of female reproductive glands in which the ova, or eggs, are formed. The ovaries are located in the pelvis, one on each side of the uterus. [NIH] Ovary: Either of the paired glands in the female that produce the female germ cells and secrete some of the female sex hormones. [NIH] Overexpress: An excess of a particular protein on the surface of a cell. [NIH] Overweight: An excess of body weight but not necessarily body fat; a body mass index of 25 to 29.9 kg/m2. [NIH] Ovulation: The discharge of a secondary oocyte from a ruptured graafian follicle. [NIH] Ovum: A female germ cell extruded from the ovary at ovulation. [NIH] Oxidation: The act of oxidizing or state of being oxidized. Chemically it consists in the increase of positive charges on an atom or the loss of negative charges. Most biological oxidations are accomplished by the removal of a pair of hydrogen atoms (dehydrogenation) from a molecule. Such oxidations must be accompanied by reduction of an acceptor molecule. Univalent o. indicates loss of one electron; divalent o., the loss of two electrons. [EU]

Oxidative metabolism: A chemical process in which oxygen is used to make energy from carbohydrates (sugars). Also known as aerobic respiration, cell respiration, or aerobic metabolism. [NIH] Oxidative Stress: A disturbance in the prooxidant-antioxidant balance in favor of the former, leading to potential damage. Indicators of oxidative stress include damaged DNA bases, protein oxidation products, and lipid peroxidation products (Sies, Oxidative Stress, 1991, pxv-xvi). [NIH] Oxygen Consumption: The oxygen consumption is determined by calculating the difference between the amount of oxygen inhaled and exhaled. [NIH] Palliative: 1. Affording relief, but not cure. 2. An alleviating medicine. [EU] Pancreas: A mixed exocrine and endocrine gland situated transversely across the posterior abdominal wall in the epigastric and hypochondriac regions. The endocrine portion is

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comprised of the Islets of Langerhans, while the exocrine portion is a compound acinar gland that secretes digestive enzymes. [NIH] Pancreatic: Having to do with the pancreas. [NIH] Pancreatic cancer: Cancer of the pancreas, a salivary gland of the abdomen. [NIH] Pancreatitis: Acute or chronic inflammation of the pancreas, which may be asymptomatic or symptomatic, and which is due to autodigestion of a pancreatic tissue by its own enzymes. It is caused most often by alcoholism or biliary tract disease; less commonly it may be associated with hyperlipaemia, hyperparathyroidism, abdominal trauma (accidental or operative injury), vasculitis, or uraemia. [EU] Paralysis: Loss of ability to move all or part of the body. [NIH] Parathyroid: 1. Situated beside the thyroid gland. 2. One of the parathyroid glands. 3. A sterile preparation of the water-soluble principle(s) of the parathyroid glands, ad-ministered parenterally as an antihypocalcaemic, especially in the treatment of acute hypoparathyroidism with tetany. [EU] Parathyroid Glands: Two small paired endocrine glands in the region of the thyroid gland. They secrete parathyroid hormone and are concerned with the metabolism of calcium and phosphorus. [NIH] Parathyroid hormone: A substance made by the parathyroid gland that helps the body store and use calcium. Also called parathormone, parathyrin, or PTH. [NIH] Parenteral: Not through the alimentary canal but rather by injection through some other route, as subcutaneous, intramuscular, intraorbital, intracapsular, intraspinal, intrasternal, intravenous, etc. [EU] Paroxysmal: Recurring in paroxysms (= spasms or seizures). [EU] Particle: A tiny mass of material. [EU] Pathogenesis: The cellular events and reactions that occur in the development of disease. [NIH]

Pathologic: 1. Indicative of or caused by a morbid condition. 2. Pertaining to pathology (= branch of medicine that treats the essential nature of the disease, especially the structural and functional changes in tissues and organs of the body caused by the disease). [EU] Pathologic Processes: The abnormal mechanisms and forms involved in the dysfunctions of tissues and organs. [NIH] Pathologies: The study of abnormality, especially the study of diseases. [NIH] Pathophysiology: Altered functions in an individual or an organ due to disease. [NIH] Patient Compliance: Voluntary cooperation of the patient in following a prescribed regimen. [NIH] Patient Education: The teaching or training of patients concerning their own health needs. [NIH]

Pelvic: Pertaining to the pelvis. [EU] Penicillin: An antibiotic drug used to treat infection. [NIH] Peptide: Any compound consisting of two or more amino acids, the building blocks of proteins. Peptides are combined to make proteins. [NIH] Percutaneous: Performed through the skin, as injection of radiopacque material in radiological examination, or the removal of tissue for biopsy accomplished by a needle. [EU] Perfusion: Bathing an organ or tissue with a fluid. In regional perfusion, a specific area of the body (usually an arm or a leg) receives high doses of anticancer drugs through a blood

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vessel. Such a procedure is performed to treat cancer that has not spread. [NIH] Pericardium: The fibroserous sac surrounding the heart and the roots of the great vessels. [NIH]

Perimenopausal: The time of a woman's life when menstrual periods become irregular. Refers to the time near menopause. [NIH] Peripheral Nervous System: The nervous system outside of the brain and spinal cord. The peripheral nervous system has autonomic and somatic divisions. The autonomic nervous system includes the enteric, parasympathetic, and sympathetic subdivisions. The somatic nervous system includes the cranial and spinal nerves and their ganglia and the peripheral sensory receptors. [NIH] Peripheral Vascular Disease: Disease in the large blood vessels of the arms, legs, and feet. People who have had diabetes for a long time may get this because major blood vessels in their arms, legs, and feet are blocked and these limbs do not receive enough blood. The signs of PVD are aching pains in the arms, legs, and feet (especially when walking) and foot sores that heal slowly. Although people with diabetes cannot always avoid PVD, doctors say they have a better chance of avoiding it if they take good care of their feet, do not smoke, and keep both their blood pressure and diabetes under good control. [NIH] Peritoneal: Having to do with the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Peritoneal Dialysis: Dialysis fluid being introduced into and removed from the peritoneal cavity as either a continuous or an intermittent procedure. [NIH] Pharmaceutical Preparations: Drugs intended for human or veterinary use, presented in their finished dosage form. Included here are materials used in the preparation and/or formulation of the finished dosage form. [NIH] Pharmaceutical Solutions: Homogeneous liquid preparations that contain one or more chemical substances dissolved, i.e., molecularly dispersed, in a suitable solvent or mixture of mutually miscible solvents. For reasons of their ingredients, method of preparation, or use, they do not fall into another group of products. [NIH] Pharmacists: Those persons legally qualified by education and training to engage in the practice of pharmacy. [NIH] Pharmacologic: Pertaining to pharmacology or to the properties and reactions of drugs. [EU] Pharmacotherapy: A regimen of using appetite suppressant medications to manage obesity by decreasing appetite or increasing the feeling of satiety. These medications decrease appetite by increasing serotonin or catecholamine—two brain chemicals that affect mood and appetite. [NIH] Phenotype: The outward appearance of the individual. It is the product of interactions between genes and between the genotype and the environment. This includes the killer phenotype, characteristic of yeasts. [NIH] Phenyl: Ingredient used in cold and flu remedies. [NIH] Phenylalanine: An aromatic amino acid that is essential in the animal diet. It is a precursor of melanin, dopamine, noradrenalin, and thyroxine. [NIH] Phlebotomy: The letting of blood from a vein. Although it is one of the techniques used in drawing blood to be used in diagnostic procedures, in modern medicine, it is used commonly in the treatment of erythrocytosis, hemochromocytosis, polycythemia vera, and porphyria cutanea tarda. Its historical counterpart is bloodletting. (From Cecil Textbook of Medicine, 19th ed & Wintrobe's Clinical Hematology, 9th ed) Venipuncture is not only for the letting of blood from a vein but also for the injecting of a drug into the vein for

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diagnostic analysis. [NIH] Phorbol: Class of chemicals that promotes the development of tumors. [NIH] Phosphates: Inorganic salts of phosphoric acid. [NIH] Phosphodiesterase: Effector enzyme that regulates the levels of a second messenger, the cyclic GMP. [NIH] Phospholipases: A class of enzymes that catalyze the hydrolysis of phosphoglycerides or glycerophosphatidates. EC 3.1.-. [NIH] Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides; glycerophospholipids) or sphingosine (sphingolipids). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system. [NIH] Phosphorus: A non-metallic element that is found in the blood, muscles, nevers, bones, and teeth, and is a component of adenosine triphosphate (ATP; the primary energy source for the body's cells.) [NIH] Phosphorylase: An enzyme of the transferase class that catalyzes the phosphorylysis of a terminal alpha-1,4-glycosidic bond at the non-reducing end of a glycogen molecule, releasing a glucose 1-phosphate residue. Phosphorylase should be qualified by the natural substance acted upon. EC 2.4.1.1. [NIH] Phosphorylate: Attached to a phosphate group. [NIH] Phosphorylated: Attached to a phosphate group. [NIH] Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. [NIH] Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis. [NIH] Physical Examination: Systematic and thorough inspection of the patient for physical signs of disease or abnormality. [NIH] Physiologic: Having to do with the functions of the body. When used in the phrase "physiologic age," it refers to an age assigned by general health, as opposed to calendar age. [NIH]

Physiology: The science that deals with the life processes and functions of organismus, their cells, tissues, and organs. [NIH] Pigment: A substance that gives color to tissue. Pigments are responsible for the color of skin, eyes, and hair. [NIH] Pigmentation: Coloration or discoloration of a part by a pigment. [NIH] Pilot study: The initial study examining a new method or treatment. [NIH] Pituitary Gland: A small, unpaired gland situated in the sella turcica tissue. It is connected to the hypothalamus by a short stalk. [NIH] Placenta: A highly vascular fetal organ through which the fetus absorbs oxygen and other nutrients and excretes carbon dioxide and other wastes. It begins to form about the eighth day of gestation when the blastocyst adheres to the decidua. [NIH] Plants: Multicellular, eukaryotic life forms of the kingdom Plantae. They are characterized by a mainly photosynthetic mode of nutrition; essentially unlimited growth at localized regions of cell divisions (meristems); cellulose within cells providing rigidity; the absence of

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organs of locomotion; absense of nervous and sensory systems; and an alteration of haploid and diploid generations. [NIH] Plaque: A clear zone in a bacterial culture grown on an agar plate caused by localized destruction of bacterial cells by a bacteriophage. The concentration of infective virus in a fluid can be estimated by applying the fluid to a culture and counting the number of. [NIH] Plasma: The clear, yellowish, fluid part of the blood that carries the blood cells. The proteins that form blood clots are in plasma. [NIH] Plasma cells: A type of white blood cell that produces antibodies. [NIH] Plasma protein: One of the hundreds of different proteins present in blood plasma, including carrier proteins ( such albumin, transferrin, and haptoglobin), fibrinogen and other coagulation factors, complement components, immunoglobulins, enzyme inhibitors, precursors of substances such as angiotension and bradykinin, and many other types of proteins. [EU] Plasma Volume: Volume of plasma in the circulation. It is usually measured by indicator dilution techniques. [NIH] Plasmapheresis: Procedure whereby plasma is separated and extracted from anticoagulated whole blood and the red cells retransfused to the donor. Plasmapheresis is also employed for therapeutic use. [NIH] Plasmin: A product of the lysis of plasminogen (profibrinolysin) by plasminogen activators. It is composed of two polypeptide chains, light (B) and heavy (A), with a molecular weight of 75,000. It is the major proteolytic enzyme involved in blood clot retraction or the lysis of fibrin and quickly inactivated by antiplasmins. EC 3.4.21.7. [NIH] Plasminogen: Precursor of fibrinolysin (plasmin). It is a single-chain beta-globulin of molecular weight 80-90,000 found mostly in association with fibrinogen in plasma; plasminogen activators change it to fibrinolysin. It is used in wound debriding and has been investigated as a thrombolytic agent. [NIH] Plasminogen Activators: A heterogeneous group of proteolytic enzymes that convert plasminogen to plasmin. They are concentrated in the lysosomes of most cells and in the vascular endothelium, particularly in the vessels of the microcirculation. EC 3.4.21.-. [NIH] Plasticity: In an individual or a population, the capacity for adaptation: a) through gene changes (genetic plasticity) or b) through internal physiological modifications in response to changes of environment (physiological plasticity). [NIH] Platelet Activation: A series of progressive, overlapping events triggered by exposure of the platelets to subendothelial tissue. These events include shape change, adhesiveness, aggregation, and release reactions. When carried through to completion, these events lead to the formation of a stable hemostatic plug. [NIH] Platelet Aggregation: The attachment of platelets to one another. This clumping together can be induced by a number of agents (e.g., thrombin, collagen) and is part of the mechanism leading to the formation of a thrombus. [NIH] Platelets: A type of blood cell that helps prevent bleeding by causing blood clots to form. Also called thrombocytes. [NIH] Platinum: Platinum. A heavy, soft, whitish metal, resembling tin, atomic number 78, atomic weight 195.09, symbol Pt. (From Dorland, 28th ed) It is used in manufacturing equipment for laboratory and industrial use. It occurs as a black powder (platinum black) and as a spongy substance (spongy platinum) and may have been known in Pliny's time as "alutiae". [NIH]

Point Mutation: A mutation caused by the substitution of one nucleotide for another. This

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results in the DNA molecule having a change in a single base pair. [NIH] Poisoning: A condition or physical state produced by the ingestion, injection or inhalation of, or exposure to a deleterious agent. [NIH] Polycystic: An inherited disorder characterized by many grape-like clusters of fluid-filled cysts that make both kidneys larger over time. These cysts take over and destroy working kidney tissue. PKD may cause chronic renal failure and end-stage renal disease. [NIH] Polycystic Ovary Syndrome: Clinical symptom complex characterized by oligomenorrhea or amenorrhea, anovulation, and regularly associated with bilateral polycystic ovaries. [NIH] Polymerase: An enzyme which catalyses the synthesis of DNA using a single DNA strand as a template. The polymerase copies the template in the 5'-3'direction provided that sufficient quantities of free nucleotides, dATP and dTTP are present. [NIH] Polymorphic: Occurring in several or many forms; appearing in different forms at different stages of development. [EU] Polymorphism: The occurrence together of two or more distinct forms in the same population. [NIH] Polypeptide: A peptide which on hydrolysis yields more than two amino acids; called tripeptides, tetrapeptides, etc. according to the number of amino acids contained. [EU] Polyposis: The development of numerous polyps (growths that protrude from a mucous membrane). [NIH] Polysaccharide: A type of carbohydrate. It contains sugar molecules that are linked together chemically. [NIH] Polyunsaturated fat: An unsaturated fat found in greatest amounts in foods derived from plants, including safflower, sunflower, corn, and soybean oils. [NIH] Porphyria: A group of disorders characterized by the excessive production of porphyrins or their precursors that arises from abnormalities in the regulation of the porphyrin-heme pathway. The porphyrias are usually divided into three broad groups, erythropoietic, hepatic, and erythrohepatic, according to the major sites of abnormal porphyrin synthesis. [NIH]

Porphyria Cutanea Tarda: A form of hepatic porphyria (porphyria, hepatic) characterized by photosensitivity resulting in bullae that rupture easily to form shallow ulcers. This condition occurs in two forms: a sporadic, nonfamilial form that begins in middle age and has normal amounts of uroporphyrinogen decarboxylase with diminished activity in the liver; and a familial form in which there is an autosomal dominant inherited deficiency of uroporphyrinogen decarboxylase in the liver and red blood cells. [NIH] Posterior: Situated in back of, or in the back part of, or affecting the back or dorsal surface of the body. In lower animals, it refers to the caudal end of the body. [EU] Postmenopausal: Refers to the time after menopause. Menopause is the time in a woman's life when menstrual periods stop permanently; also called "change of life." [NIH] Postnatal: Occurring after birth, with reference to the newborn. [EU] Postprandial: Occurring after dinner, or after a meal; postcibal. [EU] Postprandial Blood Glucose: Blood taken 1-2 hours after eating to see the amount of glucose (sugar) in the blood. [NIH] Postsynaptic: Nerve potential generated by an inhibitory hyperpolarizing stimulation. [NIH] Post-translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH]

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Potassium: An element that is in the alkali group of metals. It has an atomic symbol K, atomic number 19, and atomic weight 39.10. It is the chief cation in the intracellular fluid of muscle and other cells. Potassium ion is a strong electrolyte and it plays a significant role in the regulation of fluid volume and maintenance of the water-electrolyte balance. [NIH] Potentiates: A degree of synergism which causes the exposure of the organism to a harmful substance to worsen a disease already contracted. [NIH] Potentiation: An overall effect of two drugs taken together which is greater than the sum of the effects of each drug taken alone. [NIH] Practice Guidelines: Directions or principles presenting current or future rules of policy for the health care practitioner to assist him in patient care decisions regarding diagnosis, therapy, or related clinical circumstances. The guidelines may be developed by government agencies at any level, institutions, professional societies, governing boards, or by the convening of expert panels. The guidelines form a basis for the evaluation of all aspects of health care and delivery. [NIH] Pravastatin: An antilipemic fungal metabolite isolated from cultures of Nocardia autotrophica. It acts as a competitive inhibitor of HMG CoA reductase (hydroxymethylglutaryl CoA reductases). [NIH] Precancerous: A term used to describe a condition that may (or is likely to) become cancer. Also called premalignant. [NIH] Precursor: Something that precedes. In biological processes, a substance from which another, usually more active or mature substance is formed. In clinical medicine, a sign or symptom that heralds another. [EU] Predisposition: A latent susceptibility to disease which may be activated under certain conditions, as by stress. [EU] Preeclampsia: A toxaemia of late pregnancy characterized by hypertension, edema, and proteinuria, when convulsions and coma are associated, it is called eclampsia. [EU] Pre-Eclampsia: Development of hypertension with proteinuria, edema, or both, due to pregnancy or the influence of a recent pregnancy. It occurs after the 20th week of gestation, but it may develop before this time in the presence of trophoblastic disease. [NIH] Pre-eclamptic: A syndrome characterized by hypertension, albuminuria, and generalized oedema, occurring only in pregnancy. [NIH] Pregnancy Tests: Tests to determine whether or not an individual is pregnant. [NIH] Premenopausal: Refers to the time before menopause. Menopause is the time of life when a women's menstrual periods stop permanently; also called "change of life." [NIH] Prenatal: Existing or occurring before birth, with reference to the fetus. [EU] Prenatal Diagnosis: Determination of the nature of a pathological condition or disease in the postimplantation embryo, fetus, or pregnant female before birth. [NIH] Prevalence: The total number of cases of a given disease in a specified population at a designated time. It is differentiated from incidence, which refers to the number of new cases in the population at a given time. [NIH] Primary endpoint: The main result that is measured at the end of a study to see if a given treatment worked (e.g., the number of deaths or the difference in survival between the treatment group and the control group). What the primary endpoint will be is decided before the study begins. [NIH] Primary Prevention: Prevention of disease or mental disorders in susceptible individuals or populations through promotion of health, including mental health, and specific protection,

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as in immunization, as distinguished from the prevention of complications or after-effects of existing disease. [NIH] Prodrug: A substance that gives rise to a pharmacologically active metabolite, although not itself active (i. e. an inactive precursor). [NIH] Progesterone: Pregn-4-ene-3,20-dione. The principal progestational hormone of the body, secreted by the corpus luteum, adrenal cortex, and placenta. Its chief function is to prepare the uterus for the reception and development of the fertilized ovum. It acts as an antiovulatory agent when administered on days 5-25 of the menstrual cycle. [NIH] Progression: Increase in the size of a tumor or spread of cancer in the body. [NIH] Progressive: Advancing; going forward; going from bad to worse; increasing in scope or severity. [EU] Proline: A non-essential amino acid that is synthesized from glutamic acid. It is an essential component of collagen and is important for proper functioning of joints and tendons. [NIH] Promoter: A chemical substance that increases the activity of a carcinogenic process. [NIH] Prone: Having the front portion of the body downwards. [NIH] Prophylaxis: An attempt to prevent disease. [NIH] Proportional: Being in proportion : corresponding in size, degree, or intensity, having the same or a constant ratio; of, relating to, or used in determining proportions. [EU] Prospective Studies: Observation of a population for a sufficient number of persons over a sufficient number of years to generate incidence or mortality rates subsequent to the selection of the study group. [NIH] Prospective study: An epidemiologic study in which a group of individuals (a cohort), all free of a particular disease and varying in their exposure to a possible risk factor, is followed over a specific amount of time to determine the incidence rates of the disease in the exposed and unexposed groups. [NIH] Prostaglandin: Any of a group of components derived from unsaturated 20-carbon fatty acids, primarily arachidonic acid, via the cyclooxygenase pathway that are extremely potent mediators of a diverse group of physiologic processes. The abbreviation for prostaglandin is PG; specific compounds are designated by adding one of the letters A through I to indicate the type of substituents found on the hydrocarbon skeleton and a subscript (1, 2 or 3) to indicate the number of double bonds in the hydrocarbon skeleton e.g., PGE2. The predominant naturally occurring prostaglandins all have two double bonds and are synthesized from arachidonic acid (5,8,11,14-eicosatetraenoic acid) by the pathway shown in the illustration. The 1 series and 3 series are produced by the same pathway with fatty acids having one fewer double bond (8,11,14-eicosatrienoic acid or one more double bond (5,8,11,14,17-eicosapentaenoic acid) than arachidonic acid. The subscript a or ß indicates the configuration at C-9 (a denotes a substituent below the plane of the ring, ß, above the plane). The naturally occurring PGF's have the a configuration, e.g., PGF2a. All of the prostaglandins act by binding to specific cell-surface receptors causing an increase in the level of the intracellular second messenger cyclic AMP (and in some cases cyclic GMP also). The effect produced by the cyclic AMP increase depends on the specific cell type. In some cases there is also a positive feedback effect. Increased cyclic AMP increases prostaglandin synthesis leading to further increases in cyclic AMP. [EU] Prostaglandins A: (13E,15S)-15-Hydroxy-9-oxoprosta-10,13-dien-1-oic acid (PGA(1)); (5Z,13E,15S)-15-hydroxy-9-oxoprosta-5,10,13-trien-1-oic acid (PGA(2)); (5Z,13E,15S,17Z)-15hydroxy-9-oxoprosta-5,10,13,17-tetraen-1-oic acid (PGA(3)). A group of naturally occurring secondary prostaglandins derived from PGE. PGA(1) and PGA(2) as well as their 19-

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hydroxy derivatives are found in many organs and tissues. [NIH] Prostate: A gland in males that surrounds the neck of the bladder and the urethra. It secretes a substance that liquifies coagulated semen. It is situated in the pelvic cavity behind the lower part of the pubic symphysis, above the deep layer of the triangular ligament, and rests upon the rectum. [NIH] Protease: Proteinase (= any enzyme that catalyses the splitting of interior peptide bonds in a protein). [EU] Protease Inhibitors: Compounds which inhibit or antagonize biosynthesis or actions of proteases (endopeptidases). [NIH] Protein C: A vitamin-K dependent zymogen present in the blood, which, upon activation by thrombin and thrombomodulin exerts anticoagulant properties by inactivating factors Va and VIIIa at the rate-limiting steps of thrombin formation. [NIH] Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. Quaternary protein structure describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain). [NIH] Protein S: The vitamin K-dependent cofactor of activated protein C. Together with protein C, it inhibits the action of factors VIIIa and Va. A deficiency in protein S can lead to recurrent venous and arterial thrombosis. [NIH] Proteins: Polymers of amino acids linked by peptide bonds. The specific sequence of amino acids determines the shape and function of the protein. [NIH] Proteinuria: The presence of protein in the urine, indicating that the kidneys are not working properly. [NIH] Proteolytic: 1. Pertaining to, characterized by, or promoting proteolysis. 2. An enzyme that promotes proteolysis (= the splitting of proteins by hydrolysis of the peptide bonds with formation of smaller polypeptides). [EU] Protocol: The detailed plan for a clinical trial that states the trial's rationale, purpose, drug or vaccine dosages, length of study, routes of administration, who may participate, and other aspects of trial design. [NIH] Protons: Stable elementary particles having the smallest known positive charge, found in the nuclei of all elements. The proton mass is less than that of a neutron. A proton is the nucleus of the light hydrogen atom, i.e., the hydrogen ion. [NIH] Psychology: The science dealing with the study of mental processes and behavior in man and animals. [NIH] Psychomotor: Pertaining to motor effects of cerebral or psychic activity. [EU] Puberty: The period during which the secondary sex characteristics begin to develop and the capability of sexual reproduction is attained. [EU] Public Health: Branch of medicine concerned with the prevention and control of disease and disability, and the promotion of physical and mental health of the population on the international, national, state, or municipal level. [NIH] Public Policy: A course or method of action selected, usually by a government, from among alternatives to guide and determine present and future decisions. [NIH] Publishing: "The business or profession of the commercial production and issuance of literature" (Webster's 3d). It includes the publisher, publication processes, editing and editors. Production may be by conventional printing methods or by electronic publishing. [NIH]

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Pulmonary: Relating to the lungs. [NIH] Pulmonary Artery: The short wide vessel arising from the conus arteriosus of the right ventricle and conveying unaerated blood to the lungs. [NIH] Pulmonary hypertension: Abnormally high blood pressure in the arteries of the lungs. [NIH] Pulse: The rhythmical expansion and contraction of an artery produced by waves of pressure caused by the ejection of blood from the left ventricle of the heart as it contracts. [NIH]

Pupil: The aperture in the iris through which light passes. [NIH] Purifying: Respiratory equipment whose function is to remove contaminants from otherwise wholesome air. [NIH] Purines: A series of heterocyclic compounds that are variously substituted in nature and are known also as purine bases. They include adenine and guanine, constituents of nucleic acids, as well as many alkaloids such as caffeine and theophylline. Uric acid is the metabolic end product of purine metabolism. [NIH] Quality of Life: A generic concept reflecting concern with the modification and enhancement of life attributes, e.g., physical, political, moral and social environment. [NIH] Race: A population within a species which exhibits general similarities within itself, but is both discontinuous and distinct from other populations of that species, though not sufficiently so as to achieve the status of a taxon. [NIH] Radiation: Emission or propagation of electromagnetic energy (waves/rays), or the waves/rays themselves; a stream of electromagnetic particles (electrons, neutrons, protons, alpha particles) or a mixture of these. The most common source is the sun. [NIH] Radiation therapy: The use of high-energy radiation from x-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. Radiation may come from a machine outside the body (external-beam radiation therapy), or it may come from radioactive material placed in the body in the area near cancer cells (internal radiation therapy, implant radiation, or brachytherapy). Systemic radiation therapy uses a radioactive substance, such as a radiolabeled monoclonal antibody, that circulates throughout the body. Also called radiotherapy. [NIH] Radioactive: Giving off radiation. [NIH] Radiography: Examination of any part of the body for diagnostic purposes by means of roentgen rays, recording the image on a sensitized surface (such as photographic film). [NIH] Radioisotope: An unstable element that releases radiation as it breaks down. Radioisotopes can be used in imaging tests or as a treatment for cancer. [NIH] Radiological: Pertaining to radiodiagnostic and radiotherapeutic procedures, and interventional radiology or other planning and guiding medical radiology. [NIH] Radiology: A specialty concerned with the use of x-ray and other forms of radiant energy in the diagnosis and treatment of disease. [NIH] Raloxifene: A second generation selective estrogen receptor modulator (SERM) used to prevent osteoporosis in postmenopausal women. It has estrogen agonist effects on bone and cholesterol metabolism but behaves as a complete estrogen antagonist on mammary gland and uterine tissue. [NIH] Ramipril: A long-acting angiotensin-converting enzyme inhibitor. It is a prodrug that is transformed in the liver to its active metabolite ramiprilat. [NIH] Randomized: Describes an experiment or clinical trial in which animal or human subjects are assigned by chance to separate groups that compare different treatments. [NIH]

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Randomized clinical trial: A study in which the participants are assigned by chance to separate groups that compare different treatments; neither the researchers nor the participants can choose which group. Using chance to assign people to groups means that the groups will be similar and that the treatments they receive can be compared objectively. At the time of the trial, it is not known which treatment is best. It is the patient's choice to be in a randomized trial. [NIH] Receptor: A molecule inside or on the surface of a cell that binds to a specific substance and causes a specific physiologic effect in the cell. [NIH] Receptor, Insulin: A cell surface receptor for insulin. It is comprised of a tetramer of two alpha and two beta subunits which are derived from cleavage of a single precusor protein. The receptor contains an intrinsic tyrosine kinase domain that is located within the beta subunit. Activation of the receptor by insulin results in numerous metabolic changes including increased uptake of glucose into the liver, muscle, and adipose tissue. EC 2.7.11.-. [NIH]

Receptors, Serotonin: Cell-surface proteins that bind serotonin and trigger intracellular changes which influence the behavior of cells. Several types of serotonin receptors have been recognized which differ in their pharmacology, molecular biology, and mode of action. [NIH] Recombinant: A cell or an individual with a new combination of genes not found together in either parent; usually applied to linked genes. [EU] Reconstitution: 1. A type of regeneration in which a new organ forms by the rearrangement of tissues rather than from new formation at an injured surface. 2. The restoration to original form of a substance previously altered for preservation and storage, as the restoration to a liquid state of blood serum or plasma that has been dried and stored. [EU] Rectum: The last 8 to 10 inches of the large intestine. [NIH] Red blood cells: RBCs. Cells that carry oxygen to all parts of the body. Also called erythrocytes. [NIH] Red Nucleus: A pinkish-yellow portion of the midbrain situated in the rostral mesencephalic tegmentum. It receives a large projection from the contralateral half of the cerebellum via the superior cerebellar peduncle and a projection from the ipsilateral motor cortex. [NIH] Reductase: Enzyme converting testosterone to dihydrotestosterone. [NIH] Refer: To send or direct for treatment, aid, information, de decision. [NIH] Refraction: A test to determine the best eyeglasses or contact lenses to correct a refractive error (myopia, hyperopia, or astigmatism). [NIH] Refractory: Not readily yielding to treatment. [EU] Regeneration: The natural renewal of a structure, as of a lost tissue or part. [EU] Regimen: A treatment plan that specifies the dosage, the schedule, and the duration of treatment. [NIH] Regression Analysis: Procedures for finding the mathematical function which best describes the relationship between a dependent variable and one or more independent variables. In linear regression (see linear models) the relationship is constrained to be a straight line and least-squares analysis is used to determine the best fit. In logistic regression (see logistic models) the dependent variable is qualitative rather than continuously variable and likelihood functions are used to find the best relationship. In multiple regression the dependent variable is considered to depend on more than a single independent variable. [NIH]

Renal failure: Progressive renal insufficiency and uremia, due to irreversible and

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progressive renal glomerular tubular or interstitial disease. [NIH] Renin: An enzyme which is secreted by the kidney and is formed from prorenin in plasma and kidney. The enzyme cleaves the Leu-Leu bond in angiotensinogen to generate angiotensin I. EC 3.4.23.15. (Formerly EC 3.4.99.19). [NIH] Reperfusion: Restoration of blood supply to tissue which is ischemic due to decrease in normal blood supply. The decrease may result from any source including atherosclerotic obstruction, narrowing of the artery, or surgical clamping. It is primarily a procedure for treating infarction or other ischemia, by enabling viable ischemic tissue to recover, thus limiting further necrosis. However, it is thought that reperfusion can itself further damage the ischemic tissue, causing reperfusion injury. [NIH] Reperfusion Injury: Functional, metabolic, or structural changes, including necrosis, in ischemic tissues thought to result from reperfusion to ischemic areas of the tissue. The most common instance is myocardial reperfusion injury. [NIH] Respiration: The act of breathing with the lungs, consisting of inspiration, or the taking into the lungs of the ambient air, and of expiration, or the expelling of the modified air which contains more carbon dioxide than the air taken in (Blakiston's Gould Medical Dictionary, 4th ed.). This does not include tissue respiration (= oxygen consumption) or cell respiration (= cell respiration). [NIH] Resting metabolic rate: RMR accounts for 65 to 75 percent of daily energy expenditure and represents the minimum energy needed to maintain all physiological cell functions in the resting state. The principal determinant of RMR is lean body mass (LBM). Obese subjects have a higher RMR in absolute terms than lean individuals, an equivalent RMR when corrected for LBM and per unit surface area, and a lower RMR when expressed per kilogram of body weight. Obese persons require more energy for any given activity because of a larger mass, but they tend to be more sedentary than lean subjects. [NIH] Restoration: Broad term applied to any inlay, crown, bridge or complete denture which restores or replaces loss of teeth or oral tissues. [NIH] Retina: The ten-layered nervous tissue membrane of the eye. It is continuous with the optic nerve and receives images of external objects and transmits visual impulses to the brain. Its outer surface is in contact with the choroid and the inner surface with the vitreous body. The outer-most layer is pigmented, whereas the inner nine layers are transparent. [NIH] Retinal: 1. Pertaining to the retina. 2. The aldehyde of retinol, derived by the oxidative enzymatic splitting of absorbed dietary carotene, and having vitamin A activity. In the retina, retinal combines with opsins to form visual pigments. One isomer, 11-cis retinal combines with opsin in the rods (scotopsin) to form rhodopsin, or visual purple. Another, all-trans retinal (trans-r.); visual yellow; xanthopsin) results from the bleaching of rhodopsin by light, in which the 11-cis form is converted to the all-trans form. Retinal also combines with opsins in the cones (photopsins) to form the three pigments responsible for colour vision. Called also retinal, and retinene1. [EU] Retinoblastoma: An eye cancer that most often occurs in children younger than 5 years. It occurs in hereditary and nonhereditary (sporadic) forms. [NIH] Retinoid: Vitamin A or a vitamin A-like compound. [NIH] Retinopathy: 1. Retinitis (= inflammation of the retina). 2. Retinosis (= degenerative, noninflammatory condition of the retina). [EU] Retroperitoneal: Having to do with the area outside or behind the peritoneum (the tissue that lines the abdominal wall and covers most of the organs in the abdomen). [NIH] Reverse Transcriptase Inhibitors: Inhibitors of reverse transcriptase (RNA-directed DNA

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polymerase), an enzyme that synthesizes DNA on an RNA template. [NIH] Rheumatism: A group of disorders marked by inflammation or pain in the connective tissue structures of the body. These structures include bone, cartilage, and fat. [NIH] Rheumatoid: Resembling rheumatism. [EU] Rheumatoid arthritis: A form of arthritis, the cause of which is unknown, although infection, hypersensitivity, hormone imbalance and psychologic stress have been suggested as possible causes. [NIH] Ribose: A pentose active in biological systems usually in its D-form. [NIH] Ribosome: A granule of protein and RNA, synthesized in the nucleolus and found in the cytoplasm of cells. Ribosomes are the main sites of protein synthesis. Messenger RNA attaches to them and there receives molecules of transfer RNA bearing amino acids. [NIH] Risk factor: A habit, trait, condition, or genetic alteration that increases a person's chance of developing a disease. [NIH] Rod: A reception for vision, located in the retina. [NIH] Rosiglitazone: A drug taken to help reduce the amount of sugar in the blood. Rosiglitazone helps make insulin more effective and improves regulation of blood sugar. It belongs to the family of drugs called thiazolidinediones. [NIH] Sagittal: The line of direction passing through the body from back to front, or any vertical plane parallel to the medial plane of the body and inclusive of that plane; often restricted to the medial plane, the plane of the sagittal suture. [NIH] Salicylate: Non-steroidal anti-inflammatory drugs. [NIH] Salicylic: A tuberculosis drug. [NIH] Salicylic Acids: Derivatives and salts of salicylic acid. [NIH] Salivary: The duct that convey saliva to the mouth. [NIH] Salivary glands: Glands in the mouth that produce saliva. [NIH] Sampling Studies: Studies in which a number of subjects are selected from all subjects in a defined population. Conclusions based on sample results may be attributed only to the population sampled. [NIH] Saponins: Sapogenin glycosides. A type of glycoside widely distributed in plants. Each consists of a sapogenin as the aglycon moiety, and a sugar. The sapogenin may be a steroid or a triterpene and the sugar may be glucose, galactose, a pentose, or a methylpentose. Sapogenins are poisonous towards the lower forms of life and are powerful hemolytics when injected into the blood stream able to dissolve red blood cells at even extreme dilutions. [NIH] Sarcolemma: The plasma membrane of a smooth, striated, or cardiac muscle fiber. [NIH] Satiation: Full gratification of a need or desire followed by a state of relative insensitivity to that particular need or desire. [NIH] Saturate: Means fatty acids without double bond. [NIH] Saturated fat: A type of fat found in greatest amounts in foods from animals, such as fatty cuts of meat, poultry with the skin, whole-milk dairy products, lard, and in some vegetable oils, including coconut, palm kernel, and palm oils. Saturated fat raises blood cholesterol more than anything else eaten. On a Step I Diet, no more than 8 to 10 percent of total calories should come from saturated fat, and in the Step II Diet, less than 7 percent of the day's total calories should come from saturated fat. [NIH] Scans: Pictures of structures inside the body. Scans often used in diagnosing, staging, and

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monitoring disease include liver scans, bone scans, and computed tomography (CT) or computerized axial tomography (CAT) scans and magnetic resonance imaging (MRI) scans. In liver scanning and bone scanning, radioactive substances that are injected into the bloodstream collect in these organs. A scanner that detects the radiation is used to create pictures. In CT scanning, an x-ray machine linked to a computer is used to produce detailed pictures of organs inside the body. MRI scans use a large magnet connected to a computer to create pictures of areas inside the body. [NIH] Sclerosis: A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. [NIH] Screening: Checking for disease when there are no symptoms. [NIH] Secondary tumor: Cancer that has spread from the organ in which it first appeared to another organ. For example, breast cancer cells may spread (metastasize) to the lungs and cause the growth of a new tumor. When this happens, the disease is called metastatic breast cancer, and the tumor in the lungs is called a secondary tumor. Also called secondary cancer. [NIH] Secretion: 1. The process of elaborating a specific product as a result of the activity of a gland; this activity may range from separating a specific substance of the blood to the elaboration of a new chemical substance. 2. Any substance produced by secretion. [EU] Secretory: Secreting; relating to or influencing secretion or the secretions. [NIH] Sedentary: 1. Sitting habitually; of inactive habits. 2. Pertaining to a sitting posture. [EU] Seizures: Clinical or subclinical disturbances of cortical function due to a sudden, abnormal, excessive, and disorganized discharge of brain cells. Clinical manifestations include abnormal motor, sensory and psychic phenomena. Recurrent seizures are usually referred to as epilepsy or "seizure disorder." [NIH] Selective estrogen receptor modulator: SERM. A drug that acts like estrogen on some tissues, but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are SERMs. [NIH] Semen: The thick, yellowish-white, viscid fluid secretion of male reproductive organs discharged upon ejaculation. In addition to reproductive organ secretions, it contains spermatozoa and their nutrient plasma. [NIH] Senile: Relating or belonging to old age; characteristic of old age; resulting from infirmity of old age. [NIH] Sensitization: 1. Administration of antigen to induce a primary immune response; priming; immunization. 2. Exposure to allergen that results in the development of hypersensitivity. 3. The coating of erythrocytes with antibody so that they are subject to lysis by complement in the presence of homologous antigen, the first stage of a complement fixation test. [EU] Sepsis: The presence of bacteria in the bloodstream. [NIH] Septic: Produced by or due to decomposition by microorganisms; putrefactive. [EU] Sequencing: The determination of the order of nucleotides in a DNA or RNA chain. [NIH] Serine: A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from glycine or threonine. It is involved in the biosynthesis of purines, pyrimidines, and other amino acids. [NIH] Serotonin: A biochemical messenger and regulator, synthesized from the essential amino acid L-tryptophan. In humans it is found primarily in the central nervous system, gastrointestinal tract, and blood platelets. Serotonin mediates several important physiological functions including neurotransmission, gastrointestinal motility, hemostasis,

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and cardiovascular integrity. Multiple receptor families (receptors, serotonin) explain the broad physiological actions and distribution of this biochemical mediator. [NIH] Serous: Having to do with serum, the clear liquid part of blood. [NIH] Serum: The clear liquid part of the blood that remains after blood cells and clotting proteins have been removed. [NIH] Sex Characteristics: Those characteristics that distinguish one sex from the other. The primary sex characteristics are the ovaries and testes and their related hormones. Secondary sex characteristics are those which are masculine or feminine but not directly related to reproduction. [NIH] Sex Determination: The biological characteristics which distinguish human beings as female or male. [NIH] Sex Hormone-Binding Globulin: A glycoprotein migrating as a beta-globulin. Its molecular weight, 52,000 or 95,000-115,000, indicates that it exists as a dimer. The protein binds testosterone, dihydrotestosterone, and estradiol in the plasma. Sex hormone-binding protein has the same amino acid sequence as androgen-binding protein. They differ by their sites of synthesis and post-translational oligosacaccharide modifications. [NIH] Shedding: Release of infectious particles (e. g., bacteria, viruses) into the environment, for example by sneezing, by fecal excretion, or from an open lesion. [NIH] Shivering: Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. [NIH] Shock: The general bodily disturbance following a severe injury; an emotional or moral upset occasioned by some disturbing or unexpected experience; disruption of the circulation, which can upset all body functions: sometimes referred to as circulatory shock. [NIH]

Sibutramine: A drug used for the management of obesity that helps reduce food intake and is indicated for weight loss and maintenance of weight loss when used in conjunction with a reduced-calorie diet. It works to suppress the appetite primarily by inhibiting the reuptake of the neurotransmitters norepinephrine and serotonin. Side effects include dry mouth, headache, constipation, insomnia, and a slight increase in average blood pressure. In some patients it causes a higher blood pressure increase. [NIH] Side effect: A consequence other than the one(s) for which an agent or measure is used, as the adverse effects produced by a drug, especially on a tissue or organ system other than the one sought to be benefited by its administration. [EU] Signal Transduction: The intercellular or intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GABA-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptormediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway. [NIH] Skeletal: Having to do with the skeleton (boney part of the body). [NIH] Skeleton: The framework that supports the soft tissues of vertebrate animals and protects

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many of their internal organs. The skeletons of vertebrates are made of bone and/or cartilage. [NIH] Skull: The skeleton of the head including the bones of the face and the bones enclosing the brain. [NIH] Sleep apnea: A serious, potentially life-threatening breathing disorder characterized by repeated cessation of breathing due to either collapse of the upper airway during sleep or absence of respiratory effort. [NIH] Small intestine: The part of the digestive tract that is located between the stomach and the large intestine. [NIH] Smooth muscle: Muscle that performs automatic tasks, such as constricting blood vessels. [NIH]

Sneezing: Sudden, forceful, involuntary expulsion of air from the nose and mouth caused by irritation to the mucous membranes of the upper respiratory tract. [NIH] Social Environment: The aggregate of social and cultural institutions, forms, patterns, and processes that influence the life of an individual or community. [NIH] Sodium: An element that is a member of the alkali group of metals. It has the atomic symbol Na, atomic number 11, and atomic weight 23. With a valence of 1, it has a strong affinity for oxygen and other nonmetallic elements. Sodium provides the chief cation of the extracellular body fluids. Its salts are the most widely used in medicine. (From Dorland, 27th ed) Physiologically the sodium ion plays a major role in blood pressure regulation, maintenance of fluid volume, and electrolyte balance. [NIH] Sodium Channels: Cell membrane glycoproteins selective for sodium ions. Fast sodium current is associated with the action potential in neural membranes. [NIH] Soft tissue: Refers to muscle, fat, fibrous tissue, blood vessels, or other supporting tissue of the body. [NIH] Solitary Nucleus: Gray matter located in the dorsomedial part of the medulla oblongata associated with the solitary tract. The solitary nucleus receives inputs from most organ systems including the terminations of the facial, glossopharyngeal, and vagus nerves. It is a major coordinator of autonomic nervous system regulation of cardiovascular, respiratory, gustatory, gastrointestinal, and chemoreceptive aspects of homeostasis. The solitary nucleus is also notable for the large number of neurotransmitters which are found therein. [NIH] Solvent: 1. Dissolving; effecting a solution. 2. A liquid that dissolves or that is capable of dissolving; the component of a solution that is present in greater amount. [EU] Somatic: 1. Pertaining to or characteristic of the soma or body. 2. Pertaining to the body wall in contrast to the viscera. [EU] Somatostatin: A polypeptide hormone produced in the hypothalamus, and other tissues and organs. It inhibits the release of human growth hormone, and also modulates important physiological functions of the kidney, pancreas, and gastrointestinal tract. Somatostatin receptors are widely expressed throughout the body. Somatostatin also acts as a neurotransmitter in the central and peripheral nervous systems. [NIH] Sorbitol: A polyhydric alcohol with about half the sweetness of sucrose. Sorbitol occurs naturally and is also produced synthetically from glucose. It was formerly used as a diuretic and may still be used as a laxative and in irrigating solutions for some surgical procedures. It is also used in many manufacturing processes, as a pharmaceutical aid, and in several research applications. [NIH] Soybean Oil: Oil from soybean or soybean plant. [NIH] Spastic: 1. Of the nature of or characterized by spasms. 2. Hypertonic, so that the muscles

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are stiff and the movements awkward. 3. A person exhibiting spasticity, such as occurs in spastic paralysis or in cerebral palsy. [EU] Specialist: In medicine, one who concentrates on 1 special branch of medical science. [NIH] Species: A taxonomic category subordinate to a genus (or subgenus) and superior to a subspecies or variety, composed of individuals possessing common characters distinguishing them from other categories of individuals of the same taxonomic level. In taxonomic nomenclature, species are designated by the genus name followed by a Latin or Latinized adjective or noun. [EU] Specificity: Degree of selectivity shown by an antibody with respect to the number and types of antigens with which the antibody combines, as well as with respect to the rates and the extents of these reactions. [NIH] Spectrum: A charted band of wavelengths of electromagnetic vibrations obtained by refraction and diffraction. By extension, a measurable range of activity, such as the range of bacteria affected by an antibiotic (antibacterial s.) or the complete range of manifestations of a disease. [EU] Sperm: The fecundating fluid of the male. [NIH] Spinal cord: The main trunk or bundle of nerves running down the spine through holes in the spinal bone (the vertebrae) from the brain to the level of the lower back. [NIH] Spleen: An organ that is part of the lymphatic system. The spleen produces lymphocytes, filters the blood, stores blood cells, and destroys old blood cells. It is located on the left side of the abdomen near the stomach. [NIH] Sporadic: Neither endemic nor epidemic; occurring occasionally in a random or isolated manner. [EU] Stabilization: The creation of a stable state. [EU] Staging: Performing exams and tests to learn the extent of the cancer within the body, especially whether the disease has spread from the original site to other parts of the body. [NIH]

Stagnation: The slowing down or stoppage of the flowing of any fluid. [NIH] Statistically significant: Describes a mathematical measure of difference between groups. The difference is said to be statistically significant if it is greater than what might be expected to happen by chance alone. [NIH] Steatosis: Fatty degeneration. [EU] Steel: A tough, malleable, iron-based alloy containing up to, but no more than, two percent carbon and often other metals. It is used in medicine and dentistry in implants and instrumentation. [NIH] Stem Cells: Relatively undifferentiated cells of the same lineage (family type) that retain the ability to divide and cycle throughout postnatal life to provide cells that can become specialized and take the place of those that die or are lost. [NIH] Stent: A device placed in a body structure (such as a blood vessel or the gastrointestinal tract) to provide support and keep the structure open. [NIH] Sterile: Unable to produce children. [NIH] Sterility: 1. The inability to produce offspring, i.e., the inability to conceive (female s.) or to induce conception (male s.). 2. The state of being aseptic, or free from microorganisms. [EU] Steroid: A group name for lipids that contain a hydrogenated cyclopentanoperhydrophenanthrene ring system. Some of the substances included in this group are progesterone, adrenocortical hormones, the gonadal hormones, cardiac aglycones,

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bile acids, sterols (such as cholesterol), toad poisons, saponins, and some of the carcinogenic hydrocarbons. [EU] Stimulus: That which can elicit or evoke action (response) in a muscle, nerve, gland or other excitable issue, or cause an augmenting action upon any function or metabolic process. [NIH] Stomach: An organ of digestion situated in the left upper quadrant of the abdomen between the termination of the esophagus and the beginning of the duodenum. [NIH] Stool: The waste matter discharged in a bowel movement; feces. [NIH] Strand: DNA normally exists in the bacterial nucleus in a helix, in which two strands are coiled together. [NIH] Stress: Forcibly exerted influence; pressure. Any condition or situation that causes strain or tension. Stress may be either physical or psychologic, or both. [NIH] Stroke: Sudden loss of function of part of the brain because of loss of blood flow. Stroke may be caused by a clot (thrombosis) or rupture (hemorrhage) of a blood vessel to the brain. [NIH] Stroke Volume: The amount of blood pumped out of the heart per beat not to be confused with cardiac output (volume/time). [NIH] Stromal: Large, veil-like cell in the bone marrow. [NIH] Stromal Cells: Connective tissue cells of an organ found in the loose connective tissue. These are most often associated with the uterine mucosa and the ovary as well as the hematopoietic system and elsewhere. [NIH] Subacute: Somewhat acute; between acute and chronic. [EU] Subclinical: Without clinical manifestations; said of the early stage(s) of an infection or other disease or abnormality before symptoms and signs become apparent or detectable by clinical examination or laboratory tests, or of a very mild form of an infection or other disease or abnormality. [EU] Subcutaneous: Beneath the skin. [NIH] Substance P: An eleven-amino acid neurotransmitter that appears in both the central and peripheral nervous systems. It is involved in transmission of pain, causes rapid contractions of the gastrointestinal smooth muscle, and modulates inflammatory and immune responses. [NIH]

Substrate: A substance upon which an enzyme acts. [EU] Sulfur: An element that is a member of the chalcogen family. It has an atomic symbol S, atomic number 16, and atomic weight 32.066. It is found in the amino acids cysteine and methionine. [NIH] Superoxide: Derivative of molecular oxygen that can damage cells. [NIH] Suppression: A conscious exclusion of disapproved desire contrary with repression, in which the process of exclusion is not conscious. [NIH] Sympathetic Nervous System: The thoracolumbar division of the autonomic nervous system. Sympathetic preganglionic fibers originate in neurons of the intermediolateral column of the spinal cord and project to the paravertebral and prevertebral ganglia, which in turn project to target organs. The sympathetic nervous system mediates the body's response to stressful situations, i.e., the fight or flight reactions. It often acts reciprocally to the parasympathetic system. [NIH] Symphysis: A secondary cartilaginous joint. [NIH] Symptomatic: Having to do with symptoms, which are signs of a condition or disease. [NIH] Synaptic: Pertaining to or affecting a synapse (= site of functional apposition between

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neurons, at which an impulse is transmitted from one neuron to another by electrical or chemical means); pertaining to synapsis (= pairing off in point-for-point association of homologous chromosomes from the male and female pronuclei during the early prophase of meiosis). [EU] Synaptic Transmission: The communication from a neuron to a target (neuron, muscle, or secretory cell) across a synapse. In chemical synaptic transmission, the presynaptic neuron releases a neurotransmitter that diffuses across the synaptic cleft and binds to specific synaptic receptors. These activated receptors modulate ion channels and/or secondmessenger systems to influence the postsynaptic cell. Electrical transmission is less common in the nervous system, and, as in other tissues, is mediated by gap junctions. [NIH] Synergistic: Acting together; enhancing the effect of another force or agent. [EU] Systemic: Affecting the entire body. [NIH] Systemic lupus erythematosus: SLE. A chronic inflammatory connective tissue disease marked by skin rashes, joint pain and swelling, inflammation of the kidneys, inflammation of the fibrous tissue surrounding the heart (i.e., the pericardium), as well as other problems. Not all affected individuals display all of these problems. May be referred to as lupus. [NIH] Systolic: Indicating the maximum arterial pressure during contraction of the left ventricle of the heart. [EU] Systolic blood pressure: The maximum pressure in the artery produced as the heart contracts and blood begins to flow. [NIH] Telangiectasia: The permanent enlargement of blood vessels, causing redness in the skin or mucous membranes. [NIH] Temporal: One of the two irregular bones forming part of the lateral surfaces and base of the skull, and containing the organs of hearing. [NIH] Terminator: A DNA sequence sited at the end of a transcriptional unit that signals the end of transcription. [NIH] Testicles: The two egg-shaped glands found inside the scrotum. They produce sperm and male hormones. Also called testes. [NIH] Testicular: Pertaining to a testis. [EU] Testis: Either of the paired male reproductive glands that produce the male germ cells and the male hormones. [NIH] Testosterone: A hormone that promotes the development and maintenance of male sex characteristics. [NIH] Tetany: 1. Hyperexcitability of nerves and muscles due to decrease in concentration of extracellular ionized calcium, which may be associated with such conditions as parathyroid hypofunction, vitamin D deficiency, and alkalosis or result from ingestion of alkaline salts; it is characterized by carpopedal spasm, muscular twitching and cramps, laryngospasm with inspiratory stridor, hyperreflexia and choreiform movements. 2. Tetanus. [EU] Thalamic: Cell that reaches the lateral nucleus of amygdala. [NIH] Thalamic Diseases: Disorders of the centrally located thalamus, which integrates a wide range of cortical and subcortical information. Manifestations include sensory loss, movement disorders; ataxia, pain syndromes, visual disorders, a variety of neuropsychological conditions, and coma. Relatively common etiologies include cerebrovascular disorders; craniocerebral trauma; brain neoplasms; brain hypoxia; intracranial hemorrhages; and infectious processes. [NIH] Therapeutics: The branch of medicine which is concerned with the treatment of diseases,

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palliative or curative. [NIH] Thermal: Pertaining to or characterized by heat. [EU] Thermogenesis: The generation of heat in order to maintain body temperature. The uncoupled oxidation of fatty acids contained within brown adipose tissue and shivering are examples of thermogenesis in mammals. [NIH] Thigh: A leg; in anatomy, any elongated process or part of a structure more or less comparable to a leg. [NIH] Third Ventricle: A narrow cleft inferior to the corpus callosum, within the diencephalon, between the paired thalami. Its floor is formed by the hypothalamus, its anterior wall by the lamina terminalis, and its roof by ependyma. It communicates with the fourth ventricle by the cerebral aqueduct, and with the lateral ventricles by the interventricular foramina. [NIH] Thorax: A part of the trunk between the neck and the abdomen; the chest. [NIH] Threonine: An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins. [NIH] Threshold: For a specified sensory modality (e. g. light, sound, vibration), the lowest level (absolute threshold) or smallest difference (difference threshold, difference limen) or intensity of the stimulus discernible in prescribed conditions of stimulation. [NIH] Thrombin: An enzyme formed from prothrombin that converts fibrinogen to fibrin. (Dorland, 27th ed) EC 3.4.21.5. [NIH] Thrombolytic: 1. Dissolving or splitting up a thrombus. 2. A thrombolytic agent. [EU] Thrombomodulin: A cell surface glycoprotein of endothelial cells that binds thrombin and serves as a cofactor in the activation of protein C and its regulation of blood coagulation. [NIH]

Thrombosis: The formation or presence of a blood clot inside a blood vessel. [NIH] Thromboxanes: Physiologically active compounds found in many organs of the body. They are formed in vivo from the prostaglandin endoperoxides and cause platelet aggregation, contraction of arteries, and other biological effects. Thromboxanes are important mediators of the actions of polyunsaturated fatty acids transformed by cyclooxygenase. [NIH] Thrombus: An aggregation of blood factors, primarily platelets and fibrin with entrapment of cellular elements, frequently causing vascular obstruction at the point of its formation. Some authorities thus differentiate thrombus formation from simple coagulation or clot formation. [EU] Thyroid: A gland located near the windpipe (trachea) that produces thyroid hormone, which helps regulate growth and metabolism. [NIH] Thyroid Gland: A highly vascular endocrine gland consisting of two lobes, one on either side of the trachea, joined by a narrow isthmus; it produces the thyroid hormones which are concerned in regulating the metabolic rate of the body. [NIH] Thyroid Hormones: Hormones secreted by the thyroid gland. [NIH] Thyrotropin: A peptide hormone secreted by the anterior pituitary. It promotes the growth of the thyroid gland and stimulates the synthesis of thyroid hormones and the release of thyroxine by the thyroid gland. [NIH] Thyroxine: An amino acid of the thyroid gland which exerts a stimulating effect on thyroid metabolism. [NIH] Time Factors: Elements of limited time intervals, contributing to particular results or situations. [NIH]

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Tissue: A group or layer of cells that are alike in type and work together to perform a specific function. [NIH] Tissue Plasminogen Activator: A proteolytic enzyme in the serine protease family found in many tissues which converts plasminogen to plasmin. It has fibrin-binding activity and is immunologically different from urinary plasminogen activator. The primary sequence, composed of 527 amino acids, is identical in both the naturally occurring and synthetic proteases. EC 3.4.21.68. [NIH] Tolerance: 1. The ability to endure unusually large doses of a drug or toxin. 2. Acquired drug tolerance; a decreasing response to repeated constant doses of a drug or the need for increasing doses to maintain a constant response. [EU] Tomography: Imaging methods that result in sharp images of objects located on a chosen plane and blurred images located above or below the plane. [NIH] Topical: On the surface of the body. [NIH] Torpor: State of mental and motor inactivity with partial insensibility, stagnation of function, without losing consciousness. [NIH] Torsion: A twisting or rotation of a bodily part or member on its axis. [NIH] Toxaemia: 1. The condition resulting from the spread of bacterial products (toxins) by the bloodstream. 2. A condition resulting from metabolic disturbances, e.g. toxaemia of pregnancy. [EU] Toxic: Having to do with poison or something harmful to the body. Toxic substances usually cause unwanted side effects. [NIH] Toxicity: The quality of being poisonous, especially the degree of virulence of a toxic microbe or of a poison. [EU] Toxicology: The science concerned with the detection, chemical composition, and pharmacologic action of toxic substances or poisons and the treatment and prevention of toxic manifestations. [NIH] Toxins: Specific, characterizable, poisonous chemicals, often proteins, with specific biological properties, including immunogenicity, produced by microbes, higher plants, or animals. [NIH] Trace element: Substance or element essential to plant or animal life, but present in extremely small amounts. [NIH] Tracer: A substance (such as a radioisotope) used in imaging procedures. [NIH] Trachea: The cartilaginous and membranous tube descending from the larynx and branching into the right and left main bronchi. [NIH] Traction: The act of pulling. [NIH] Transcriptase: An enzyme which catalyses the synthesis of a complementary mRNA molecule from a DNA template in the presence of a mixture of the four ribonucleotides (ATP, UTP, GTP and CTP). [NIH] Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process. [NIH] Transduction: The transfer of genes from one cell to another by means of a viral (in the case of bacteria, a bacteriophage) vector or a vector which is similar to a virus particle (pseudovirion). [NIH] Transfection: The uptake of naked or purified DNA into cells, usually eukaryotic. It is analogous to bacterial transformation. [NIH]

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Transferases: Transferases are enzymes transferring a group, for example, the methyl group or a glycosyl group, from one compound (generally regarded as donor) to another compound (generally regarded as acceptor). The classification is based on the scheme "donor:acceptor group transferase". (Enzyme Nomenclature, 1992) EC 2. [NIH] Translation: The process whereby the genetic information present in the linear sequence of ribonucleotides in mRNA is converted into a corresponding sequence of amino acids in a protein. It occurs on the ribosome and is unidirectional. [NIH] Translational: The cleavage of signal sequence that directs the passage of the protein through a cell or organelle membrane. [NIH] Translocating: The attachment of a fragment of one chromosome to a non-homologous chromosome. [NIH] Translocation: The movement of material in solution inside the body of the plant. [NIH] Transmitter: A chemical substance which effects the passage of nerve impulses from one cell to the other at the synapse. [NIH] Transplantation: Transference of a tissue or organ, alive or dead, within an individual, between individuals of the same species, or between individuals of different species. [NIH] Trauma: Any injury, wound, or shock, must frequently physical or structural shock, producing a disturbance. [NIH] Trauma Centers: Specialized hospital facilities which provide diagnostic and therapeutic services for trauma patients. [NIH] Triad: Trivalent. [NIH] Tricuspid Atresia: Absence of the orifice between the right atrium and ventricle, with the presence of an atrial defect through which all the systemic venous return reaches the left heart. As a result, there is left ventricular hypertrophy because the right ventricle is absent or not functional. [NIH] Triglyceride: A lipid carried through the blood stream to tissues. Most of the body's fat tissue is in the form of triglycerides, stored for use as energy. Triglycerides are obtained primarily from fat in foods. [NIH] Troglitazone: A drug used in diabetes treatment that is being studied for its effect on reducing the risk of cancer cell growth in fat tissue. [NIH] Truncal: The bilateral dissection of the abdominal branches of the vagus nerve. [NIH] Tryptophan: An essential amino acid that is necessary for normal growth in infants and for nitrogen balance in adults. It is a precursor serotonin and niacin. [NIH] Tuberculosis: Any of the infectious diseases of man and other animals caused by species of Mycobacterium. [NIH] Tuberous Sclerosis: A rare congenital disease in which the essential pathology is the appearance of multiple tumors in the cerebrum and in other organs, such as the heart or kidneys. [NIH] Tumor marker: A substance sometimes found in an increased amount in the blood, other body fluids, or tissues and which may mean that a certain type of cancer is in the body. Examples of tumor markers include CA 125 (ovarian cancer), CA 15-3 (breast cancer), CEA (ovarian, lung, breast, pancreas, and gastrointestinal tract cancers), and PSA (prostate cancer). Also called biomarker. [NIH] Tumor Necrosis Factor: Serum glycoprotein produced by activated macrophages and other mammalian mononuclear leukocytes which has necrotizing activity against tumor cell lines and increases ability to reject tumor transplants. It mimics the action of endotoxin but differs

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from it. It has a molecular weight of less than 70,000 kDa. [NIH] Type 2 diabetes: Usually characterized by a gradual onset with minimal or no symptoms of metabolic disturbance and no requirement for exogenous insulin. The peak age of onset is 50 to 60 years. Obesity and possibly a genetic factor are usually present. [NIH] Tyramine: An indirect sympathomimetic. Tyramine does not directly activate adrenergic receptors, but it can serve as a substrate for adrenergic uptake systems and monoamine oxidase so it prolongs the actions of adrenergic transmitters. It also provokes transmitter release from adrenergic terminals. Tyramine may be a neurotransmitter in some invertebrate nervous systems. [NIH] Tyrosine: A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine, thyroid hormones, and melanin. [NIH] Ultrasonography: The visualization of deep structures of the body by recording the reflections of echoes of pulses of ultrasonic waves directed into the tissues. Use of ultrasound for imaging or diagnostic purposes employs frequencies ranging from 1.6 to 10 megahertz. [NIH] Umbilical Arteries: Either of a pair of arteries originating from the internal iliac artery and passing through the umbilical cord to carry blood from the fetus to the placenta. [NIH] Umbilical Cord: The flexible structure, giving passage to the umbilical arteries and vein, which connects the embryo or fetus to the placenta. [NIH] Unconscious: Experience which was once conscious, but was subsequently rejected, as the "personal unconscious". [NIH] Uracil: An anticancer drug that belongs to the family of drugs called alkylating agents. [NIH] Uraemia: 1. An excess in the blood of urea, creatinine, and other nitrogenous end products of protein and amino acids metabolism; more correctly referred to as azotemia. 2. In current usage the entire constellation of signs and symptoms of chronic renal failure, including nausea, vomiting anorexia, a metallic taste in the mouth, a uraemic odour of the breath, pruritus, uraemic frost on the skin, neuromuscular disorders, pain and twitching in the muscles, hypertension, edema, mental confusion, and acid-base and electrolyte imbalances. [EU]

Urea: A compound (CO(NH2)2), formed in the liver from ammonia produced by the deamination of amino acids. It is the principal end product of protein catabolism and constitutes about one half of the total urinary solids. [NIH] Uremia: The illness associated with the buildup of urea in the blood because the kidneys are not working effectively. Symptoms include nausea, vomiting, loss of appetite, weakness, and mental confusion. [NIH] Urethra: The tube through which urine leaves the body. It empties urine from the bladder. [NIH]

Uric: A kidney stone that may result from a diet high in animal protein. When the body breaks down this protein, uric acid levels rise and can form stones. [NIH] Uridine Diphosphate: A uracil nucleotide containing a pyrophosphate group esterified to C5 of the sugar moiety. [NIH] Urinary: Having to do with urine or the organs of the body that produce and get rid of urine. [NIH] Urinary Plasminogen Activator: A proteolytic enzyme that converts plasminogen to plasmin where the preferential cleavage is between arginine and valine. It was isolated originally from human urine, but is found in most tissues of most vertebrates. EC 3.4.21.73. [NIH]

Dictionary 317

Urine: Fluid containing water and waste products. Urine is made by the kidneys, stored in the bladder, and leaves the body through the urethra. [NIH] Uterus: The small, hollow, pear-shaped organ in a woman's pelvis. This is the organ in which a fetus develops. Also called the womb. [NIH] Vaccine: A substance or group of substances meant to cause the immune system to respond to a tumor or to microorganisms, such as bacteria or viruses. [NIH] Vacuoles: Any spaces or cavities within a cell. They may function in digestion, storage, secretion, or excretion. [NIH] Vagus Nerve: The 10th cranial nerve. The vagus is a mixed nerve which contains somatic afferents (from skin in back of the ear and the external auditory meatus), visceral afferents (from the pharynx, larynx, thorax, and abdomen), parasympathetic efferents (to the thorax and abdomen), and efferents to striated muscle (of the larynx and pharynx). [NIH] Valproic Acid: A fatty acid with anticonvulsant properties used in the treatment of epilepsy. The mechanisms of its therapeutic actions are not well understood. It may act by increasing GABA levels in the brain or by altering the properties of voltage dependent sodium channels. [NIH] Vascular: Pertaining to blood vessels or indicative of a copious blood supply. [EU] Vasculitis: Inflammation of a blood vessel. [NIH] Vasodilatation: A state of increased calibre of the blood vessels. [EU] Vasodilation: Physiological dilation of the blood vessels without anatomic change. For dilation with anatomic change, dilatation, pathologic or aneurysm (or specific aneurysm) is used. [NIH] Vasodilators: Any nerve or agent which induces dilatation of the blood vessels. [NIH] Vasomotor: 1. Affecting the calibre of a vessel, especially of a blood vessel. 2. Any element or agent that effects the calibre of a blood vessel. [EU] Vector: Plasmid or other self-replicating DNA molecule that transfers DNA between cells in nature or in recombinant DNA technology. [NIH] Vein: Vessel-carrying blood from various parts of the body to the heart. [NIH] Venous: Of or pertaining to the veins. [EU] Venous blood: Blood that has given up its oxygen to the tissues and carries carbon dioxide back for gas exchange. [NIH] Ventricle: One of the two pumping chambers of the heart. The right ventricle receives oxygen-poor blood from the right atrium and pumps it to the lungs through the pulmonary artery. The left ventricle receives oxygen-rich blood from the left atrium and pumps it to the body through the aorta. [NIH] Ventricular: Pertaining to a ventricle. [EU] Venules: The minute vessels that collect blood from the capillary plexuses and join together to form veins. [NIH] Very low-density lipoprotein: The lipoprotein particles that initially leave the liver, carrying cholesterol and lipid. VLDLs contain 10 to 15 percent of the total serum cholesterol along with most of the triglycerides in the fasting serum; VLDLs are precursors of LDL, and some forms of VLDL, particularly VLDL remnants, appear to be atherogenic. [NIH] Veterinary Medicine: The medical science concerned with the prevention, diagnosis, and treatment of diseases in animals. [NIH] Viral: Pertaining to, caused by, or of the nature of virus. [EU]

318

Insulin Resistance

Virilism: Development of masculine traits in the female. [NIH] Virulence: The degree of pathogenicity within a group or species of microorganisms or viruses as indicated by case fatality rates and/or the ability of the organism to invade the tissues of the host. [NIH] Virus: Submicroscopic organism that causes infectious disease. In cancer therapy, some viruses may be made into vaccines that help the body build an immune response to, and kill, tumor cells. [NIH] Visceral: , from viscus a viscus) pertaining to a viscus. [EU] Visceral Afferents: The sensory fibers innervating the viscera. [NIH] Visceral fat: One of the three compartments of abdominal fat. Retroperitoneal and subcutaneous are the other two compartments. [NIH] Vitamin A: A substance used in cancer prevention; it belongs to the family of drugs called retinoids. [NIH] Vitreous Hemorrhage: Hemorrhage into the vitreous body. [NIH] Vitro: Descriptive of an event or enzyme reaction under experimental investigation occurring outside a living organism. Parts of an organism or microorganism are used together with artificial substrates and/or conditions. [NIH] Vivo: Outside of or removed from the body of a living organism. [NIH] Waist circumference: To define the level at which the waist circumference is measured, a bony landmark is first located and marked. The subject stands, and the technician, positioned to the right of the subject, palpates the upper hip bone to locate the right ileum. Just above the uppermost lateral border of the right ileum, a horizontal mark is drawn and then crossed with a vertical mark on the midaxillary line. The measuring tape is then placed around the trunk, at the level of the mark on the right side, making sure that it is on a level horizontal plane on all sides. The tape is then tightened slightly without compressing the skin and underlying subcutaneous tissues. The measure is recorded in centimeters to the nearest millimeter. [NIH] Weight Gain: Increase in body weight over existing weight. [NIH] Weight Lifting: A sport in which weights are lifted competitively or as an exercise. [NIH] White blood cell: A type of cell in the immune system that helps the body fight infection and disease. White blood cells include lymphocytes, granulocytes, macrophages, and others. [NIH]

Windpipe: A rigid tube, 10 cm long, extending from the cricoid cartilage to the upper border of the fifth thoracic vertebra. [NIH] Xenograft: The cells of one species transplanted to another species. [NIH] X-ray: High-energy radiation used in low doses to diagnose diseases and in high doses to treat cancer. [NIH] Yeasts: A general term for single-celled rounded fungi that reproduce by budding. Brewers' and bakers' yeasts are Saccharomyces cerevisiae; therapeutic dried yeast is dried yeast. [NIH] Zymogen: Inactive form of an enzyme which can then be converted to the active form, usually by excision of a polypeptide, e. g. trypsinogen is the zymogen of trypsin. [NIH]

319

INDEX 3 3-dimensional, 42, 245, 302 A Abdomen, 148, 245, 254, 255, 269, 282, 285, 295, 296, 305, 310, 311, 313, 317 Abdominal fat, 4, 18, 46, 79, 118, 181, 245, 258, 318 Abdominal Pain, 245, 282 Aberrant, 197, 245 Ablate, 191, 245 Ablation, 245, 248 Acanthosis Nigricans, 5, 33, 42, 73, 108, 123, 149, 245 Acceptor, 245, 285, 294, 315 Acetylcholine, 199, 245, 259, 292 Acne, 69, 245, 263 Actin, 22, 245, 291 Acyl, 23, 35, 189, 245, 270 Adaptation, 245, 298 Adenine, 245, 303 Adenosine, 183, 245, 297 Adenylate Kinase, 181, 246 Adipocytes, 17, 21, 29, 30, 31, 34, 41, 47, 56, 64, 66, 67, 68, 77, 137, 163, 164, 168, 246, 283 Adjustment, 4, 7, 9, 12, 19, 245, 246 Adolescence, 9, 33, 38, 61, 144, 212, 246 Adrenal Cortex, 246, 247, 263, 270, 278, 301 Adrenal Glands, 160, 246 Adrenal insufficiency, 22, 246 Adrenergic, 60, 170, 246, 269, 316 Adverse Effect, 26, 210, 246, 308 Aerobic, 18, 28, 60, 75, 149, 246, 289, 294 Aerobic Exercise, 18, 60, 75, 246 Aerobic Metabolism, 246, 294 Aerobic Respiration, 246, 294 Afferent, 22, 246, 283 Affinity, 246, 247, 309 Age Factors, 4, 247 Age of Onset, 28, 247, 316 Agonist, 48, 66, 82, 214, 247, 260, 292, 303 Airway, 247, 309 Albumin, 29, 247, 298 Aldosterone, 53, 66, 126, 247, 288 Algorithms, 247, 254 Alimentary, 247, 266, 295 Alkaline, 247, 248, 256, 312

Alkaloid, 247, 292 Alleles, 60, 164, 247, 277, 284 Allergen, 247, 265, 307 Allograft, 247, 277 Alopecia, 247, 263 Alpha-1, 66, 247, 297 Alternative medicine, 214, 247 Ameliorating, 196, 247 Amenorrhea, 45, 247, 249, 299 Amino Acid Sequence, 166, 190, 247, 249, 250, 270, 273, 308 Amino Acid Substitution, 58, 248 Amlodipine, 92, 248 Ammonia, 248, 274, 316 Amnion, 248 Amniotic Fluid, 27, 248, 273 Amphetamine, 248, 254 Anabolic, 57, 216, 248, 266 Anaesthesia, 248, 280 Anal, 248, 272, 285, 294 Analgesic, 248 Analog, 32, 210, 248, 284, 293 Analogous, 248, 314 Analysis of Variance, 65, 248 Anatomical, 67, 248, 252, 266, 280, 307 Androgen suppression, 149, 248 Androgen-Binding Protein, 248, 308 Androgens, 7, 40, 46, 69, 246, 249, 251, 263, 278 Anemia, 227, 249, 276 Aneurysm, 249, 317 Angina, 7, 140, 248, 249 Angina Pectoris, 248, 249 Angiopathy, 162, 165, 249 Angiotensin converting enzyme inhibitor, 165, 205, 249 Angiotensinogen, 249, 305 Animal model, 24, 25, 30, 31, 67, 70, 73, 74, 75, 133, 161, 185, 186, 204, 249 Anions, 247, 249, 282 Anorexia, 196, 197, 249, 316 Anorexia Nervosa, 197, 249 Anovulation, 23, 40, 46, 61, 69, 249, 299 Antagonism, 67, 71, 191, 249 Anterior Cerebral Artery, 249, 259 Anthropometric measurements, 7, 249 Anthropometry, 33, 43, 60, 250 Antiallergic, 250, 263

320

Insulin Resistance

Antibacterial, 250, 310 Antibiotic, 158, 249, 250, 255, 295, 310 Antibodies, 159, 160, 166, 173, 199, 250, 252, 278, 286, 298 Antibody, 67, 246, 250, 261, 278, 280, 281, 287, 289, 303, 307, 310 Anticoagulant, 188, 250, 302 Anticonvulsant, 250, 256, 317 Antidepressant, 174, 250 Antidiabetic, 154, 155, 171, 250, 274 Antidiabetic Agent, 154, 155, 171, 250 Antigen, 78, 126, 246, 250, 261, 278, 279, 280, 281, 287, 289, 307 Antihypertensive, 5, 204, 250 Anti-inflammatory, 250, 251, 263, 274, 306 Anti-Inflammatory Agents, 250, 251, 263 Antimetabolite, 250, 265 Antineoplastic, 250, 263 Antioxidant, 217, 250, 294 Antipyretic, 250 Antiviral, 250, 265 Apnea, 250 Apnoea, 113, 250 Apolipoproteins, 251, 273, 285 Apoptosis, 41, 43, 157, 179, 251 Appetite Regulation, 178, 196, 251 Aqueous, 251, 253, 264, 278, 283 Arachidonic Acid, 188, 251, 267, 284, 301 Arginine, 251, 292, 316 Aromatase, 125, 251 Aromatic, 251, 254, 296 Arterial, 125, 154, 159, 169, 251, 259, 262, 279, 302, 312 Arteries, 249, 251, 252, 254, 255, 262, 263, 286, 288, 290, 303, 313, 316 Arterioles, 251, 254, 256, 290 Arteriolosclerosis, 251 Arteriosclerosis, 89, 94, 96, 158, 159, 165, 169, 182, 189, 251, 279 Aspirin, 47, 160, 251 Asymptomatic, 21, 251, 295 Ataxia, 226, 227, 251, 312 Atherogenic, 11, 25, 252, 317 Atrial, 252, 262, 315 Atrioventricular, 252, 262 Atrium, 252, 262, 315, 317 Atrophy, 226, 252, 285 Attenuated, 4, 252, 266 Atypical, 36, 171, 252 Autoantibodies, 132, 160, 252 Autoantigens, 252 Autodigestion, 252, 295

Autoimmune disease, 158, 160, 162, 173, 174, 252, 290 Autoimmunity, 160, 252 Autonomic, 19, 91, 245, 252, 292, 296, 309, 311 Autonomic Nervous System, 91, 252, 296, 309, 311 Autosuggestion, 252, 280 Axillary, 252, 255, 288 Axillary Artery, 252, 255 B Bacteria, 245, 250, 252, 253, 268, 269, 270, 271, 275, 288, 307, 308, 310, 314, 317 Bacterial Translocation, 191, 252 Bactericidal, 253, 270 Bacteriophage, 253, 298, 314 Bacterium, 253, 267 Basal Ganglia, 252, 253 Basal Ganglia Diseases, 252, 253 Base, 24, 60, 61, 245, 253, 265, 273, 283, 299, 312, 316 Basement Membrane, 253, 271 Basophils, 253, 275, 284 Benzene, 188, 253, 283 Bilateral, 253, 299, 315 Bile, 253, 272, 285, 311 Bile Ducts, 253, 272 Biliary, 253, 256, 295 Biliary Tract, 253, 256, 295 Bilirubin, 247, 253, 272 Bioavailability, 253, 280 Biochemical, 20, 47, 53, 57, 184, 247, 250, 253, 275, 307 Biogenesis, 32, 253 Biogenic Amines, 146, 254 Biological therapy, 254, 276 Biomarkers, 63, 93, 254 Biopsy, 27, 70, 141, 254, 295 Biosynthesis, 40, 159, 189, 251, 254, 302, 307 Biotechnology, 76, 79, 214, 223, 225, 226, 227, 254 Biotin, 72, 254 Bladder, 254, 280, 290, 302, 316, 317 Bloating, 254, 273, 282 Blood Cell Count, 254, 276 Blood Coagulation, 254, 256, 313 Blood Platelets, 254, 307 Body Composition, 4, 9, 14, 18, 28, 49, 61, 104, 119, 254 Body Fluids, 160, 254, 255, 309, 315 Body Image, 45, 255

Index 321

Body Mass Index, 6, 12, 14, 45, 62, 197, 217, 255, 294 Bolus, 59, 255 Bolus infusion, 255 Bolus injection, 59, 255 Bone Marrow, 25, 68, 253, 255, 270, 280, 286, 289, 311 Bone Marrow Transplantation, 68, 255 Bone scan, 255, 307 Bowel, 248, 255, 266, 282, 293, 294, 311 Bowel Movement, 255, 266, 311 Brachial, 21, 35, 46, 140, 255 Brachial Artery, 21, 35, 46, 140, 255 Bradykinin, 255, 292, 298 Branch, 132, 241, 255, 295, 302, 310, 312 Breakdown, 160, 255, 266, 272 Broad-spectrum, 61, 255 Buccal, 255, 286 Bulimia, 197, 255 Burns, 56, 131, 162, 255 Burns, Electric, 255 C Cachexia, 196, 197, 256 Calcification, 93, 251, 256 Calcium, 76, 136, 163, 164, 178, 205, 248, 256, 261, 288, 291, 295, 308, 312 Calcium channel blocker, 248, 256 Calcium Channels, 164, 178, 256 Calcium Signaling, 178, 256 Calculi, 256, 275 Calmodulin, 186, 256 Caloric intake, 43, 75, 148, 256 Calpain, 125, 256 Capillary, 111, 255, 256, 273, 285, 317 Capsules, 256, 267, 273 Carbamazepine, 134, 256 Carbon Dioxide, 257, 264, 272, 297, 305, 317 Carcinogenesis, 137, 257, 259, 297 Carcinogenic, 253, 257, 281, 301, 311 Carcinogens, 257, 259, 293 Carcinoma, 95, 257, 263 Cardiac, 18, 19, 54, 193, 212, 214, 256, 257, 262, 264, 269, 290, 291, 306, 310, 311 Cardiac Output, 54, 257, 311 Cardiomyopathy, 19, 192, 193, 257 Cardiorespiratory, 246, 257 Carnitine, 35, 181, 257 Carrier Proteins, 257, 298 Catabolism, 56, 257 Cataracts, 171, 192, 193, 257 Catecholamine, 257, 296

Catheters, 140, 257 Caudal, 257, 266, 279, 299 Causal, 3, 48, 54, 169, 257 Cause of Death, 159, 172, 257 Caveolae, 21, 67, 257, 258 Caveolins, 21, 258 Cecum, 43, 258, 283 Cell Death, 251, 258, 291 Cell Differentiation, 22, 79, 258, 308 Cell Division, 226, 252, 258, 275, 289, 297 Cell membrane, 40, 256, 257, 258, 265, 270, 282, 297, 309 Cell Membrane Structures, 257, 258 Cell proliferation, 251, 258, 308 Cell Respiration, 246, 258, 289, 294, 305 Cell Size, 31, 258 Cell Survival, 258, 276 Central fat distribution, 22, 258 Central Nervous System, 22, 245, 248, 252, 253, 256, 258, 272, 274, 276, 284, 290, 307 Cerebellar, 252, 258, 304 Cerebral, 166, 249, 252, 253, 258, 259, 262, 269, 272, 302, 310, 313 Cerebral Infarction, 166, 259 Cerebrospinal, 174, 259 Cerebrospinal fluid, 174, 259 Cerebrovascular, 158, 198, 253, 257, 259, 312 Cerebrum, 258, 259, 315 Chemopreventive, 60, 259 Cholesterol Esters, 259, 285 Cholinergic, 259, 292 Chromatin, 251, 259, 269, 292 Chromium, 136, 217, 259 Chromosomal, 33, 42, 50, 75, 259 Chromosome, 33, 51, 75, 125, 199, 259, 284, 315 Chronic Disease, 132, 176, 197, 215, 256, 259, 260 Chronic renal, 92, 259, 299, 316 Chylomicrons, 259, 285 Clamp, 8, 23, 25, 27, 35, 38, 46, 47, 48, 56, 59, 61, 64, 75, 140, 142, 259 Cleave, 190, 259 Clinical Medicine, 5, 124, 130, 202, 203, 259, 300 Clinical study, 259, 262 Clinical trial, 11, 16, 46, 139, 145, 146, 150, 223, 259, 260, 262, 290, 302, 303 Clomiphene, 87, 260 Cloning, 33, 58, 254, 260 Coagulation, 254, 260, 277, 298, 313

322

Insulin Resistance

Coal, 253, 260 Codon, 78, 260, 273 Coenzymes, 260, 292 Cofactor, 260, 302, 313 Cognition, 176, 260 Colitis, 260, 282 Collagen, 92, 253, 260, 271, 273, 278, 298, 301 Collagen disease, 260, 278 Collapse, 177, 255, 260, 309 Colloidal, 247, 260, 268 Colonoscopy, 43, 260 Colorectal, 43, 137, 260 Colorectal Cancer, 43, 260 Combination Therapy, 26, 155, 210, 261, 270 Complement, 261, 273, 286, 298, 307 Computational Biology, 223, 225, 261 Computed tomography, 50, 261, 307 Computerized axial tomography, 261, 307 Computerized tomography, 261 Conception, 261, 262, 271, 310 Concomitant, 14, 20, 28, 55, 194, 195, 261 Conjugated, 121, 132, 261, 264, 293 Connective Tissue, 255, 260, 261, 262, 271, 272, 273, 286, 306, 311, 312 Consciousness, 248, 262, 266, 314 Constipation, 216, 262, 282, 308 Constriction, 262, 282 Consultation, 142, 262 Consumption, 3, 41, 63, 115, 262, 265, 293, 294 Continuum, 28, 262 Contraceptive, 262, 265 Contraceptive Agents, 262, 265 Contraindications, ii, 262 Control group, 42, 142, 262, 300 Controlled clinical trial, 45, 262 Controlled study, 92, 262 Convulsions, 250, 262, 267, 300 Coordination, 262, 290 Cor, 148, 262, 263 Coronary Arteriosclerosis, 146, 263, 290 Coronary heart disease, 14, 15, 22, 37, 59, 132, 144, 163, 198, 201, 202, 205, 208, 257, 258, 263 Coronary Thrombosis, 263, 288, 290 Corpus, 263, 301, 313 Corpus Luteum, 263, 301 Cortex, 252, 263, 304 Corticosteroid, 120, 263

Corticotropin-Releasing Hormone, 148, 263 Cortisol, 22, 100, 106, 247, 263 Cross-Sectional Studies, 6, 263 Cultured cells, 33, 57, 69, 72, 263 Curative, 195, 263, 292, 313 Cutaneous, 5, 80, 263, 286 Cyclic, 173, 256, 263, 276, 292, 297, 301 Cyclophosphamide, 132, 263 Cyproterone, 100, 263, 264, 272 Cyproterone Acetate, 100, 264 Cysteine, 256, 264, 268, 311 Cytochrome, 251, 264 Cytokine, 24, 41, 68, 70, 138, 179, 264 Cytoplasm, 251, 253, 256, 258, 264, 269, 275, 289, 291, 292, 306 Cytoskeletal Proteins, 256, 264 Cytoskeleton, 22, 264 Cytotoxic, 264, 308 D Dairy Products, 264, 306 Data Collection, 50, 264 Databases, Bibliographic, 223, 264 De novo, 31, 264 Deamination, 264, 316 Decarboxylation, 254, 264, 277 Decompensation, 202, 264 Degenerative, 264, 277, 305 Dehydroepiandrosterone, 181, 264 Deletion, 27, 42, 47, 69, 71, 74, 251, 265, 273 Denaturation, 158, 265 Dendritic, 265, 287 Deoxyglucose, 57, 265 Depolarization, 265, 308 Depressive Disorder, 108, 265 Desensitization, 29, 157, 265 Desogestrel, 100, 265 Deuterium, 265, 278 Developed Countries, 159, 161, 265 Developing Countries, 159, 265 DEXA, 28, 35, 39, 265 Diabetes Mellitus, 5, 8, 12, 23, 28, 30, 33, 35, 39, 41, 52, 55, 59, 61, 65, 70, 71, 72, 74, 79, 81, 83, 88, 93, 97, 100, 101, 105, 109, 110, 112, 114, 119, 120, 121, 123, 139, 141, 142, 144, 145, 146, 147, 150, 154, 155, 156, 161, 162, 163, 166, 167, 170, 171, 173, 174, 176, 177, 182, 186, 188, 189, 190, 192, 193, 194, 195, 198, 199, 203, 210, 265, 274, 277, 293

Index 323

Diabetic Retinopathy, 165, 169, 171, 192, 193, 265 Diagnostic procedure, 153, 214, 265, 296 Dialysate, 216, 265 Dialyzer, 216, 265, 276 Diarrhea, 265, 282 Diastolic, 265, 279 Diencephalon, 266, 279, 313 Dietary Fats, 266, 284 Dietary Fiber, 83, 130, 232, 266 Dietitian, 10, 148, 208, 216, 266 Diffusion, 266, 282 Digestion, 210, 247, 253, 255, 266, 273, 282, 284, 285, 311, 317 Digestive system, 151, 266 Dihydrotestosterone, 264, 266, 304, 308 Dilatation, 249, 266, 317 Dilatation, Pathologic, 266, 317 Dilated cardiomyopathy, 18, 266 Dilation, 35, 255, 266, 317 Dilution, 59, 70, 266, 298 Direct, iii, 13, 17, 20, 33, 37, 43, 53, 57, 159, 167, 259, 266, 304 Disinfectant, 266, 270 Disposition, 7, 266 Dissection, 266, 315 Dissociation, 119, 246, 266 Dissociative Disorders, 266 Diuretic, 266, 287, 309 Dominance, 164, 266 Dormancy, 174, 267 Dosage Forms, 155, 176, 267 Drive, ii, vi, 6, 13, 20, 25, 44, 129, 202, 209, 267, 282, 284 Drug Tolerance, 267, 314 Duodenum, 253, 267, 272, 311 Dyspareunia, 267, 270 Dysphoric, 265, 267 Dysplasia, 227, 267 Dyspnea, 264, 267 Dystrophy, 226, 267 E Eclampsia, 54, 267, 300 Ectopic, 17, 164, 267 Edema, 264, 265, 267, 283, 291, 300, 316 Effector, 22, 36, 41, 245, 261, 267, 292, 297 Efficacy, 59, 61, 62, 93, 139, 141, 143, 149, 154, 155, 210, 216, 267 Eicosanoids, 188, 267 Elasticity, 251, 263, 267 Elastin, 260, 267 Elective, 64, 139, 268

Electrolyte, 247, 263, 268, 288, 300, 309, 316 Electrons, 250, 253, 268, 282, 286, 294, 303 Electrophoresis, 63, 268 Elementary Particles, 268, 286, 302 Embolism, 169, 268 Embolus, 268, 281 Embryo, 248, 258, 268, 280, 300, 316 Emollient, 268, 275, 293 Endocrine System, 268 Endocytosis, 72, 257, 268 Endometrial, 46, 268 Endometrium, 268, 288 Endopeptidases, 268, 302 Endothelial cell, 17, 53, 91, 268, 313 Endothelium, 26, 35, 46, 94, 268, 269, 292, 298 Endothelium, Lymphatic, 268 Endothelium, Vascular, 268, 269 Endothelium-derived, 269, 292 Endotoxemia, 191, 269 Endotoxic, 269, 284 Endotoxin, 269, 315 End-stage renal, 62, 259, 269, 299 Energy balance, 70, 109, 131, 269, 283 Energy Intake, 42, 216, 269 Environmental Exposure, 269, 293 Environmental Health, 112, 222, 224, 269 Enzymatic, 254, 256, 261, 269, 270, 271, 277, 305 Enzyme Inhibitors, 165, 269, 298 Eosinophils, 269, 275, 284 Epidemic, 30, 54, 63, 132, 156, 177, 269, 310 Epidemiological, 41, 45, 63, 89, 154, 269 Epigastric, 269, 294 Epinephrine, 246, 254, 269, 292, 316 Epithelial, 66, 137, 269, 289 Epithelial Cells, 269, 289 Epithelium, 253, 268, 269 Erythrocyte Indices, 254, 270 Erythrocytes, 249, 254, 255, 256, 270, 304, 307 Erythropoietin, 216, 270 Esophagitis, 216, 270 Esophagus, 266, 270, 311 Essential Tremor, 226, 270 Esterification, 35, 70, 270 Estradiol, 7, 27, 270, 308 Estrogen, 26, 55, 181, 251, 260, 263, 270, 303, 307 Estrogen receptor, 27, 260, 270

324

Insulin Resistance

Estrogen Replacement Therapy, 26, 270 Ethanol, 41, 270 Ethnic Groups, 16, 19, 270 Evacuation, 262, 270, 272 Exhaustion, 249, 270 Exocrine, 270, 294 Exocytosis, 186, 270 Exogenous, 7, 11, 26, 157, 170, 270, 316 Exon, 186, 270 Expiration, 270, 305 Extracellular, 48, 184, 190, 262, 268, 271, 309, 312 Extracellular Matrix, 190, 262, 271 Extracellular Space, 271 Extraction, 15, 271 F Family Planning, 223, 271 Fasting Blood Glucose Test, 232, 271 Fatigue, 174, 176, 271, 276 Fatty Liver, 111, 115, 119, 191, 271 Feces, 262, 271, 311 Ferritin, 81, 271 Fetus, 99, 270, 271, 297, 300, 316, 317 Fibrin, 254, 271, 298, 313, 314 Fibrinogen, 271, 298, 313 Fibrinolysis, 154, 271 Fibrinolytic, 162, 271 Fibroblasts, 56, 271, 282 Fibrosis, 107, 119, 197, 227, 271, 307 Fine-needle aspiration, 271, 291 Fistula, 272, 293 Fixation, 272, 307 Flatus, 272 Flutamide, 111, 272 Fold, 28, 36, 205, 272, 288 Foot Ulcer, 193, 272 Forearm, 140, 254, 272 Frontal Lobe, 249, 259, 272 Fructose, 20, 29, 98, 272, 277, 282 G Gallbladder, 245, 253, 266, 272 Gallstones, 180, 272 Ganglia, 245, 253, 272, 292, 296, 311 Gas, 140, 248, 257, 266, 272, 278, 282, 292, 317 Gasoline, 253, 272 Gastric, 127, 252, 257, 267, 272, 273, 277 Gastric Emptying, 272, 273 Gastrin, 272, 278 Gastritis, 216, 272

Gastrointestinal, 44, 154, 170, 171, 216, 252, 255, 269, 270, 272, 284, 307, 309, 310, 311, 315 Gastrointestinal tract, 252, 270, 272, 284, 307, 309, 310, 315 Gastroparesis, 216, 273 Gelatin, 273, 275, 313 Gemfibrozil, 13, 133, 212, 273 Gene Deletion, 74, 78, 273 Gene Expression, 20, 22, 24, 30, 31, 32, 38, 42, 51, 53, 92, 140, 168, 187, 227, 273 Genetic Code, 273, 293 Genetic Engineering, 254, 260, 273 Genetic testing, 141, 273 Genetics, 5, 10, 13, 39, 50, 51, 60, 74, 99, 108, 130, 134, 144, 266, 273 Genotype, 27, 32, 99, 197, 273, 296 Germ Cells, 273, 294, 312 Gestation, 273, 297, 300 Gestational, 21, 99, 105, 110, 114, 162, 213, 232, 273 Gestational Age, 105, 273 Gland, 246, 273, 279, 286, 294, 295, 297, 302, 303, 307, 311, 313 Glomerular, 63, 273, 282, 287, 305 Glomerular Filtration Rate, 273, 287 Glomeruli, 63, 274 Glomerulus, 273, 274 Glucocorticoid, 91, 100, 274, 278, 289 Glucokinase, 77, 186, 187, 199, 274, 277 Gluconeogenesis, 32, 274 Glucose Clamp Technique, 26, 274 Glucose Intolerance, 4, 5, 13, 24, 34, 36, 40, 60, 68, 81, 101, 121, 122, 170, 171, 173, 174, 204, 265, 274 Glucose Tolerance Test, 4, 7, 9, 14, 15, 21, 24, 43, 45, 47, 50, 60, 73, 148, 232, 274 Glucuronic Acid, 274, 277 Glutamic Acid, 274, 301 Glutamine, 29, 274 Glutathione Peroxidase, 81, 274 Glyburide, 154, 155, 274 Glycerol, 33, 59, 275, 297 Glycerophospholipids, 275, 297 Glycine, 275, 307 Glycogen, 39, 57, 71, 78, 86, 171, 275, 297 Glycogen Synthase, 39, 86, 275 Glycoprotein, 25, 72, 270, 271, 275, 308, 313, 315 Glycosidic, 275, 297 Glycosylation, 29, 77, 275 Gonad, 275

Index 325

Gonadal, 27, 48, 143, 275, 310 Gonadorelin, 275, 284 Gonadotropin, 48, 119, 275, 284 Gout, 101, 194, 195, 275, 279 Governing Board, 275, 300 Grade, 62, 65, 275 Graft, 275, 278, 280, 289, 290 Gram-negative, 252, 269, 275 Granulocytes, 275, 284, 308, 318 Growth factors, 43, 93, 95, 118, 275 Guanylate Cyclase, 276, 292 H Habitual, 11, 216, 276 Half-Life, 183, 276 Headache, 276, 308 Health Behavior, 62, 276 Health Education, 43, 276 Health Promotion, 188, 276 Health Status, 276 Heart attack, 7, 257, 276 Heart failure, 18, 276 Heartbeat, 19, 276 Hematocrit, 254, 270, 276 Hemochromatosis, 24, 276 Hemodialysis, 216, 265, 276, 283 Hemodynamics, 48, 54, 85, 276 Hemoglobin, 12, 155, 209, 249, 254, 270, 276, 277 Hemoglobinuria, 226, 277 Hemorrhage, 276, 277, 291, 311, 318 Hemostasis, 277, 307 Heparin, 26, 32, 190, 277 Hepatitis, 37, 107, 123, 212, 277 Hepatocyte, 30, 72, 277 Hepatoma, 47, 277 Hereditary, 167, 194, 275, 277, 305 Heredity, 102, 273, 277 Heritability, 39, 87, 102, 277 Heterozygotes, 266, 277 Hexokinase, 48, 277 Hirsutism, 27, 33, 45, 61, 263, 277, 278, 279 Histamine, 254, 277 Histocompatibility, 199, 277, 289 Histocompatibility Antigens, 199, 277 Homogeneous, 64, 251, 262, 278, 296 Homologous, 92, 247, 277, 278, 307, 312, 315 Homozygotes, 24, 267, 278 Hormonal, 27, 29, 31, 39, 69, 160, 216, 252, 263, 270, 278 Hormone Replacement Therapy, 101, 278 Hormone therapy, 101, 278

Host, 190, 252, 253, 278, 280, 284, 318 Hybrid, 30, 278 Hybridomas, 278, 282 Hydrocortisone, 22, 278 Hydrogen, 143, 188, 193, 245, 253, 257, 265, 274, 278, 284, 289, 294, 302 Hydrogen Peroxide, 274, 278, 284 Hydrolysis, 64, 278, 282, 285, 297, 299, 302 Hydrophobic, 184, 275, 278, 285 Hydroxylysine, 260, 278 Hydroxyproline, 260, 278 Hyperandrogenism, 23, 40, 87, 111, 143, 149, 278 Hypercholesterolemia, 166, 171, 267, 279 Hyperglycaemia, 200, 279 Hyperlipoproteinemia, 279, 285 Hyperphagia, 196, 279 Hyperplasia, 27, 279 Hypersensitivity, 247, 265, 279, 284, 306, 307 Hypertrichosis, 277, 279 Hypertriglyceridemia, 15, 33, 68, 104, 105, 149, 167, 173, 174, 194, 267, 279 Hypertrophy, 66, 168, 214, 262, 279, 315 Hyperuricaemia, 195, 279 Hyperuricemia, 162, 194, 197, 275, 279 Hypoglycemia, 16, 140, 154, 157, 171, 279 Hypoglycemic, 157, 171, 178, 179, 188, 189, 193, 279 Hypoglycemic Agents, 171, 193, 279 Hypogonadism, 27, 48, 279 Hypolipidemic, 188, 189, 279 Hypotension, 183, 262, 279 Hypothalamic, 20, 22, 48, 143, 174, 214, 279 Hypothalamus, 22, 252, 263, 266, 275, 279, 297, 309, 313 Hypoxia, 73, 279, 312 I Iatrogenic, 37, 280 Id, 135, 226, 230, 231, 233, 240, 242, 280 Ileum, 258, 280, 318 Imaging procedures, 280, 314 Imidazole, 180, 254, 277, 280 Immune response, 173, 250, 252, 263, 280, 286, 307, 311, 318 Immune system, 173, 174, 252, 254, 280, 284, 286, 290, 291, 317, 318 Immunization, 280, 301, 307 Immunodeficiency, 105, 109, 113, 122, 226, 280 Immunofluorescence, 42, 72, 280

326

Insulin Resistance

Immunogenic, 280, 284 Immunoglobulin, 250, 280, 289 Immunologic, 210, 273, 280 Immunosuppressive, 263, 274, 280 Immunotherapy, 254, 265, 280 Impairment, 20, 52, 70, 174, 176, 251, 280, 288 In vitro, 13, 17, 27, 31, 35, 40, 57, 64, 68, 74, 190, 280 Incision, 280, 282 Incontinence, 280, 294 Indicative, 202, 280, 295, 317 Indinavir, 26, 280 Induction, 20, 48, 71, 249, 280 Infantile, 281, 285 Infarction, 140, 146, 259, 281, 305 Infection, 25, 36, 49, 104, 107, 109, 191, 254, 280, 281, 283, 286, 292, 295, 306, 311, 318 Infertility, 23, 40, 56, 69, 281 Infusion, 26, 28, 32, 53, 59, 66, 148, 255, 274, 281, 291 Ingestion, 141, 274, 279, 281, 299, 312 Initiation, 5, 49, 78, 281, 314 Inorganic, 246, 281, 297 Inositol, 23, 40, 76, 133, 156, 281 Inpatients, 109, 281 Insight, 4, 17, 21, 22, 38, 64, 281 Insomnia, 174, 281, 308 Insulator, 281, 290 Insulin-dependent diabetes mellitus, 13, 166, 167, 170, 173, 186, 193, 194, 199, 281 Insulin-like, 43, 81, 93, 95, 118, 143, 281 Interleukin-1, 70, 281 Interleukin-2, 282 Interleukin-6, 70, 138, 282 Intermittent, 180, 282, 296 Interstitial, 271, 282, 305 Intestinal, 78, 252, 274, 282, 286 Intestine, 255, 261, 282, 283 Intracellular, 24, 33, 35, 40, 48, 72, 76, 101, 185, 256, 281, 282, 287, 292, 300, 301, 304, 308 Intrahepatic, 32, 282 Intramuscular, 33, 282, 295 Intravenous, 4, 7, 8, 15, 21, 24, 43, 45, 50, 73, 148, 183, 190, 255, 281, 282, 295 Intrinsic, 246, 253, 282, 304 Inulin, 10, 273, 282 Invasive, 32, 70, 282, 286 Invertebrates, 274, 282 Involuntary, 253, 270, 282, 291, 308, 309 Ion Transport, 282, 289

Ions, 253, 256, 266, 268, 278, 282, 289, 309 Irritable Bowel Syndrome, 173, 174, 282, 294 Ischemia, 171, 193, 252, 282, 290, 305 Islet, 53, 157, 158, 199, 282 Isoenzyme, 27, 277, 283 Isoflavones, 182, 283 J Joint, 283, 311, 312 K Kb, 222, 283 Ketone Bodies, 283 Ketosis, 199, 283 Kidney Disease, 131, 132, 139, 141, 142, 147, 149, 151, 215, 222, 227, 231, 233, 283 Kidney Failure, 269, 283, 287 Kinetic, 59, 283 L Lactation, 258, 283 Large Intestine, 258, 260, 266, 282, 283, 304, 309 Latent, 283, 300 Least-Squares Analysis, 283, 304 Lens, 257, 283 Leprosy, 272, 283 Leptin, 20, 51, 52, 60, 64, 67, 71, 78, 85, 86, 96, 109, 117, 119, 131, 132, 137, 147, 187, 200, 283 Lesion, 25, 159, 272, 284, 285, 308 Lethal, 164, 186, 253, 284 Leucocyte, 247, 284 Leukemia, 226, 284 Leukocytes, 159, 253, 254, 255, 269, 275, 284, 289, 292, 315 Leukotrienes, 188, 251, 267, 284 Leuprolide, 149, 284 Libido, 249, 284 Library Services, 240, 284 Ligament, 284, 302 Ligands, 74, 158, 159, 284 Likelihood Functions, 284, 304 Linear Models, 284, 304 Linkage, 33, 43, 50, 60, 284 Linkage Disequilibrium, 50, 284 Lipase, 22, 29, 110, 284, 294 Lipid A, 20, 24, 31, 33, 36, 45, 49, 52, 53, 70, 96, 156, 258, 284, 294 Lipid Peroxidation, 284, 294 Lipodystrophy, 33, 49, 77, 78, 80, 86, 105, 109, 112, 149, 212, 213, 285 Lipolysis, 49, 53, 55, 64, 285 Lipopolysaccharide, 190, 275, 285

Index 327

Lipoprotein Lipase, 22, 64, 79, 285 Lipoprotein(a), 59, 82, 285 Liposarcoma, 173, 174, 285 Lipoxygenase, 284, 285 Liver scan, 285, 307 Lobe, 249, 259, 285 Localization, 33, 285 Localized, 33, 272, 277, 279, 281, 285, 297, 298 Logistic Models, 285, 304 Longitudinal Studies, 6, 19, 167, 263, 285 Longitudinal study, 6, 146, 285 Loop, 20, 22, 186, 286 Low-density lipoprotein, 87, 111, 126, 267, 285, 286 Lupus, 162, 286, 312 Lymph, 252, 268, 286 Lymph node, 252, 286 Lymphatic, 268, 281, 286, 310 Lymphocyte, 250, 286, 287 Lymphoid, 250, 284, 286 Lymphoma, 226, 286 M Macrophage, 25, 68, 281, 286 Magnetic Resonance Imaging, 28, 33, 65, 70, 142, 286, 307 Magnetic Resonance Spectroscopy, 49, 286 Major Histocompatibility Complex, 277, 286 Malabsorption, 216, 226, 286 Malignancy, 44, 245, 286 Malignant, 44, 226, 250, 251, 286 Malnutrition, 132, 162, 216, 247, 252, 256, 287, 290 Mammary, 285, 287, 303 Mammogram, 42, 256, 287, 288 Manifest, 70, 157, 160, 287 Mannitol, 48, 287 Meat, 266, 287, 306 Medial, 4, 108, 251, 287, 293, 306 Mediate, 14, 32, 34, 42, 71, 123, 287 Mediator, 23, 25, 40, 47, 121, 282, 287, 308 Medicament, 158, 190, 195, 200, 287 MEDLINE, 223, 225, 227, 287 Melanin, 287, 296, 316 Melanocytes, 164, 287 Melanoma, 44, 226, 287 Melanosis, 245, 287 Melanosomes, 287 Membrane Proteins, 257, 287 Memory, 249, 287

Meninges, 258, 287 Menopause, 55, 288, 296, 299, 300 Menstrual Cycle, 69, 288, 301 Menstruation, 247, 288, 293 Mental Disorders, 151, 288, 300 Mental Health, iv, 16, 151, 222, 224, 288, 300, 302 Mental Processes, 266, 288, 302 Mentors, 44, 46, 74, 288 Mesenteric, 64, 252, 288 Mesentery, 288 Metabolic disorder, 6, 35, 48, 64, 69, 131, 158, 168, 170, 177, 186, 196, 275, 288 Metabolite, 288, 300, 301, 303 Metastasis, 190, 288 Methionine, 288, 311 MI, 6, 12, 45, 62, 197, 213, 217, 243, 288 Microbe, 288, 314 Microbiology, 245, 252, 288 Microcalcifications, 256, 288 Microorganism, 260, 288, 318 Midaxillary line, 288, 318 Millimeter, 288, 318 Mineralocorticoid, 66, 288 Minor Histocompatibility Antigens, 277, 289 Minority Groups, 12, 289 Miscarriage, 213, 289 Mitochondria, 181, 289, 291, 293 Mitochondrial Swelling, 289, 291 Mitosis, 251, 289 Mobilization, 133, 164, 256, 258, 289 Modeling, 7, 15, 289 Modification, 6, 11, 35, 61, 63, 92, 183, 207, 273, 289, 303 Modulator, 189, 289 Molecular Structure, 210, 289 Monitor, 140, 289, 293 Monoclonal, 67, 160, 278, 289, 303 Monocytes, 281, 282, 284, 289 Monogenic, 195, 290 Mononuclear, 289, 290, 315 Monotherapy, 59, 155, 210, 290 Morphological, 48, 268, 287, 290 Motility, 290, 307 Motion Sickness, 290, 291 Mucosa, 252, 286, 290, 311 Multicenter study, 139, 145, 290 Multiple sclerosis, 185, 290 Muscle Fibers, 290 Muscular Atrophy, 226, 290 Muscular Dystrophies, 267, 290

328

Insulin Resistance

Mutagenesis, 58, 290 Mutagens, 290 Mydriatic, 266, 290 Myelin, 290 Myocardial infarction, 140, 154, 166, 167, 194, 263, 288, 290 Myocardial Ischemia, 171, 249, 290 Myocardial Reperfusion, 290, 291, 305 Myocardial Reperfusion Injury, 290, 291, 305 Myocardium, 18, 154, 249, 288, 290, 291 Myofibrils, 256, 291 Myotonic Dystrophy, 226, 291 Myristate, 120, 291 N Naive, 154, 155, 291 Natural selection, 254, 291 Nausea, 216, 267, 273, 283, 291, 316 NCI, 1, 44, 150, 221, 291 Necrosis, 123, 158, 251, 259, 281, 288, 290, 291, 305 Needle biopsy, 64, 271, 291 Neonatal, 54, 164, 212, 291 Neoplasia, 43, 226, 291 Neoplastic, 278, 286, 291 Nephrology, 20, 92, 291 Nephropathy, 62, 66, 162, 164, 165, 169, 171, 178, 192, 198, 200, 205, 283, 291 Nerve, 167, 194, 246, 252, 273, 287, 290, 291, 292, 293, 299, 305, 307, 311, 315, 317 Nervous System, 19, 226, 246, 248, 252, 258, 287, 291, 292, 296, 311, 312, 316 Neural, 246, 292, 309 Neuromuscular, 245, 292, 316 Neuromuscular Junction, 245, 292 Neuronal, 256, 292 Neurons, 272, 292, 311, 312 Neuropathy, 164, 169, 171, 178, 192, 193, 198, 292 Neuropeptide, 263, 292 Neurotransmitters, 292, 308, 309 Neutrophils, 275, 284, 292 Niacin, 59, 292, 315 Nicotine, 126, 202, 216, 292 Nitric Oxide, 17, 26, 57, 81, 82, 94, 292 Nitrogen, 247, 249, 263, 272, 274, 292, 315 Norepinephrine, 246, 292, 308 Normotensive, 21, 75, 292 Nuclear, 13, 18, 32, 38, 66, 74, 158, 176, 202, 253, 268, 291, 293 Nuclear Proteins, 38, 293 Nuclei, 249, 268, 273, 286, 289, 293, 302

Nucleic acid, 166, 177, 184, 190, 197, 273, 290, 292, 293, 303 Nucleoproteins, 293 Nucleus, 249, 251, 253, 259, 263, 264, 265, 268, 269, 289, 290, 292, 293, 302, 309, 311, 312 Nutritional Status, 216, 293 O Octreotide, 69, 293 Ointments, 267, 293 Oligo, 45, 56, 293 Oligomenorrhea, 293, 299 Oliguria, 283, 287, 293 Oncogene, 226, 293 Opacity, 257, 265, 293 Optic Chiasm, 279, 293 Optic Disk, 265, 293 Organelles, 264, 287, 289, 293 Orlistat, 93, 122, 294 Orthostatic, 293, 294 Osmolarity, 287, 294 Osmotic, 247, 289, 294 Osteoporosis, 173, 174, 215, 270, 294, 303 Outpatient, 8, 140, 294 Ovarian Cysts, 148, 230, 294 Ovaries, 106, 134, 251, 278, 294, 299, 308 Ovary, 23, 27, 40, 45, 46, 56, 69, 87, 89, 100, 101, 106, 118, 119, 149, 162, 176, 180, 185, 192, 196, 202, 232, 263, 270, 275, 279, 294, 299, 311 Overexpress, 30, 31, 294 Overweight, 14, 55, 61, 75, 88, 102, 103, 116, 117, 123, 135, 140, 142, 168, 191, 196, 215, 294 Ovulation, 23, 61, 69, 202, 249, 260, 294 Ovum, 263, 273, 294, 301 Oxidation, 18, 28, 30, 33, 35, 52, 70, 115, 180, 188, 245, 250, 264, 274, 284, 294, 313 Oxidative metabolism, 32, 77, 87, 246, 284, 294 Oxidative Stress, 95, 121, 215, 294 Oxygen Consumption, 294, 305 P Palliative, 195, 263, 294, 313 Pancreas, 157, 160, 177, 200, 245, 254, 266, 276, 281, 282, 284, 294, 295, 309, 315 Pancreatic, 23, 31, 38, 141, 142, 156, 157, 158, 166, 173, 186, 193, 199, 213, 226, 257, 295 Pancreatic cancer, 213, 226, 295 Pancreatitis, 173, 174, 295 Paralysis, 179, 295, 310

Index 329

Parathyroid, 216, 295, 312 Parathyroid Glands, 295 Parathyroid hormone, 216, 295 Parenteral, 269, 295 Paroxysmal, 226, 249, 295 Particle, 30, 114, 295, 314 Pathologic, 251, 254, 262, 279, 295 Pathologic Processes, 251, 295 Pathologies, 183, 295 Pathophysiology, 14, 31, 33, 52, 54, 58, 61, 73, 108, 202, 210, 295 Patient Compliance, 207, 208, 295 Patient Education, 9, 209, 232, 238, 240, 243, 295 Pelvic, 148, 295, 302 Penicillin, 249, 295 Peptide, 15, 44, 63, 84, 172, 183, 268, 283, 295, 299, 302, 313 Percutaneous, 70, 295 Perfusion, 67, 274, 279, 295 Pericardium, 296, 312 Perimenopausal, 82, 296 Peripheral Nervous System, 296, 309, 311 Peripheral Vascular Disease, 185, 296 Peritoneal, 265, 296 Peritoneal Dialysis, 265, 296 Pharmaceutical Preparations, 154, 270, 273, 296 Pharmaceutical Solutions, 267, 296 Pharmacists, 124, 296 Pharmacologic, 4, 48, 52, 207, 209, 276, 296, 314 Pharmacotherapy, 14, 59, 216, 296 Phenotype, 27, 36, 40, 42, 59, 60, 74, 99, 273, 296 Phenyl, 157, 158, 189, 296 Phenylalanine, 296, 316 Phlebotomy, 24, 296 Phorbol, 120, 297 Phosphates, 18, 297 Phosphodiesterase, 192, 297 Phospholipases, 297, 308 Phospholipids, 130, 133, 271, 281, 285, 297 Phosphorus, 256, 295, 297 Phosphorylase, 171, 256, 297 Phosphorylate, 181, 297 Phosphorylated, 39, 71, 72, 297 Phosphotyrosine, 21, 173, 174, 297 Physical Examination, 73, 140, 142, 148, 273, 297 Physiologic, 4, 14, 23, 26, 48, 74, 157, 247, 251, 254, 276, 282, 288, 297, 301, 304, 308

Physiology, 30, 36, 44, 66, 68, 70, 79, 86, 97, 98, 104, 121, 196, 245, 268, 291, 297 Pigment, 164, 253, 287, 297 Pigmentation, 164, 287, 297 Pilot study, 77, 142, 147, 297 Pituitary Gland, 263, 275, 297 Placenta, 251, 270, 297, 301, 316 Plants, 247, 257, 274, 282, 292, 297, 299, 306, 314 Plaque, 252, 298 Plasma cells, 250, 298 Plasma protein, 111, 247, 268, 298 Plasma Volume, 289, 298 Plasmapheresis, 132, 298 Plasmin, 298, 314, 316 Plasminogen, 59, 84, 117, 202, 204, 298, 314, 316 Plasminogen Activators, 298 Plasticity, 127, 298 Platelet Activation, 298, 308 Platelet Aggregation, 292, 298, 313 Platelets, 256, 292, 298, 313 Platinum, 286, 298 Point Mutation, 71, 298 Poisoning, 291, 299 Polymerase, 299, 306 Polymorphic, 166, 299 Polymorphism, 33, 77, 78, 97, 99, 108, 114, 131, 134, 166, 299 Polypeptide, 190, 191, 197, 200, 247, 260, 271, 298, 299, 302, 309, 318 Polyposis, 261, 299 Polysaccharide, 250, 299 Polyunsaturated fat, 133, 188, 299, 313 Porphyria, 296, 299 Porphyria Cutanea Tarda, 296, 299 Posterior, 248, 252, 288, 294, 299 Postmenopausal, 55, 64, 93, 270, 294, 299, 303 Postnatal, 92, 299, 310 Postprandial, 11, 28, 34, 38, 79, 90, 91, 108, 155, 210, 299 Postprandial Blood Glucose, 34, 299 Postsynaptic, 299, 308, 312 Post-translational, 29, 57, 249, 299, 308 Potassium, 140, 247, 289, 300 Potentiates, 69, 281, 300 Potentiation, 300, 308 Practice Guidelines, 224, 300 Pravastatin, 166, 300 Precancerous, 259, 300

330

Insulin Resistance

Precursor, 31, 181, 249, 251, 263, 267, 269, 292, 296, 298, 300, 301, 315, 316 Predisposition, 45, 166, 300 Preeclampsia, 21, 97, 300 Pre-Eclampsia, 54, 300 Pre-eclamptic, 267, 300 Pregnancy Tests, 273, 300 Premenopausal, 80, 131, 300 Prenatal, 27, 145, 268, 300 Prenatal Diagnosis, 27, 300 Prevalence, 12, 23, 24, 28, 30, 34, 37, 54, 60, 62, 65, 102, 111, 142, 156, 177, 204, 217, 231, 300 Primary endpoint, 35, 300 Primary Prevention, 9, 300 Prodrug, 173, 183, 301, 303 Progesterone, 69, 301, 310 Progressive, 155, 251, 258, 259, 267, 270, 275, 290, 291, 298, 301, 304 Proline, 260, 278, 301 Promoter, 38, 69, 77, 164, 187, 301 Prone, 199, 301 Prophylaxis, 165, 196, 208, 301 Proportional, 9, 301 Prospective Studies, 8, 43, 60, 301 Prospective study, 8, 17, 97, 116, 285, 301 Prostaglandin, 188, 301, 313 Prostaglandins A, 301 Prostate, 174, 226, 254, 302, 315 Protease, 25, 36, 37, 63, 83, 104, 261, 280, 302, 314 Protease Inhibitors, 37, 63, 104, 302 Protein C, 36, 67, 182, 247, 248, 251, 253, 260, 271, 285, 302, 316 Protein Conformation, 248, 302 Protein S, 100, 187, 227, 254, 273, 302, 306 Proteinuria, 205, 300, 302 Proteolytic, 247, 261, 271, 298, 302, 314, 316 Protocol, 7, 302 Protons, 278, 286, 302, 303 Psychology, 266, 302 Psychomotor, 256, 302 Puberty, 6, 61, 81, 302 Public Health, 12, 17, 28, 34, 44, 48, 49, 75, 130, 132, 205, 224, 302 Public Policy, 43, 223, 302 Publishing, 7, 9, 76, 167, 194, 302 Pulmonary, 254, 262, 283, 284, 303, 317 Pulmonary Artery, 254, 303, 317 Pulmonary hypertension, 262, 303 Pulse, 289, 303

Pupil, 266, 290, 303 Purifying, 39, 303 Purines, 303, 307 Q Quality of Life, 18, 45, 140, 303 R Race, 56, 60, 303 Radiation, 245, 249, 265, 268, 269, 303, 307, 318 Radiation therapy, 245, 303 Radioactive, 70, 255, 276, 278, 285, 293, 303, 307 Radiography, 273, 303 Radioisotope, 303, 314 Radiological, 150, 295, 303 Radiology, 303 Raloxifene, 55, 303, 307 Ramipril, 94, 303 Randomized, 12, 18, 26, 34, 45, 54, 59, 61, 62, 75, 92, 93, 110, 131, 267, 303, 304 Randomized clinical trial, 62, 304 Receptor, Insulin, 58, 304 Receptors, Serotonin, 304, 308 Recombinant, 69, 143, 304, 317 Reconstitution, 57, 304 Rectum, 43, 255, 260, 266, 272, 280, 283, 302, 304 Red blood cells, 140, 270, 299, 304, 306 Red Nucleus, 252, 304 Reductase, 136, 159, 166, 181, 251, 300, 304 Refer, 1, 255, 261, 272, 285, 291, 304 Refraction, 304, 310 Refractory, 102, 304 Regeneration, 304 Regimen, 11, 17, 26, 157, 209, 267, 295, 296, 304 Regression Analysis, 43, 304 Renal failure, 62, 304 Renin, 53, 66, 249, 305 Reperfusion, 193, 290, 291, 305 Reperfusion Injury, 193, 305 Respiration, 162, 250, 257, 289, 305 Resting metabolic rate, 28, 142, 148, 305 Restoration, 290, 304, 305 Retina, 265, 283, 293, 305, 306 Retinal, 265, 293, 305 Retinoblastoma, 226, 305 Retinoid, 158, 189, 305 Retinopathy, 162, 164, 178, 192, 193, 198, 265, 305 Retroperitoneal, 246, 305, 318 Reverse Transcriptase Inhibitors, 36, 305

Index 331

Rheumatism, 306 Rheumatoid, 158, 260, 306 Rheumatoid arthritis, 158, 260, 306 Ribose, 245, 306 Ribosome, 306, 315 Rod, 253, 259, 269, 306 Rosiglitazone, 54, 69, 87, 149, 155, 157, 171, 193, 196, 306 S Sagittal, 65, 306 Salicylate, 306 Salicylic, 120, 306 Salicylic Acids, 306 Salivary, 266, 295, 306 Salivary glands, 266, 306 Sampling Studies, 48, 306 Saponins, 306, 311 Sarcolemma, 48, 291, 306 Satiation, 188, 306 Saturate, 50, 306 Saturated fat, 37, 188, 306 Scans, 64, 306 Sclerosis, 159, 226, 251, 260, 290, 307 Secondary tumor, 288, 307 Secretory, 8, 9, 37, 131, 160, 166, 196, 307, 312 Sedentary, 63, 64, 73, 156, 177, 205, 305, 307 Seizures, 256, 295, 307 Selective estrogen receptor modulator, 55, 181, 303, 307 Semen, 302, 307 Senile, 294, 307 Sensitization, 139, 307 Sepsis, 162, 253, 307 Septic, 167, 194, 307 Sequencing, 33, 39, 63, 307 Serine, 22, 32, 58, 63, 120, 167, 190, 193, 268, 307, 314 Serotonin, 174, 254, 296, 304, 307, 308, 315 Serous, 268, 308 Sex Characteristics, 246, 249, 302, 308, 312 Sex Determination, 227, 308 Sex Hormone-Binding Globulin, 101, 308 Shedding, 190, 308 Shivering, 308, 313 Shock, 167, 194, 269, 278, 308, 315 Sibutramine, 122, 308 Side effect, 154, 155, 157, 158, 171, 200, 210, 246, 254, 263, 279, 308, 314 Signal Transduction, 21, 29, 58, 69, 71, 185, 186, 258, 281, 297, 308

Skeleton, 245, 283, 301, 308, 309 Skull, 309, 312 Sleep apnea, 46, 72, 309 Small intestine, 253, 258, 259, 267, 278, 280, 282, 309 Smooth muscle, 63, 256, 277, 309, 311 Sneezing, 308, 309 Social Environment, 303, 309 Sodium, 65, 147, 193, 247, 275, 289, 309, 317 Sodium Channels, 309, 317 Soft tissue, 255, 308, 309 Solitary Nucleus, 252, 309 Solvent, 253, 270, 275, 294, 296, 309 Somatic, 246, 289, 296, 309, 317 Somatostatin, 75, 95, 293, 309 Sorbitol, 277, 287, 309 Soybean Oil, 299, 309 Spastic, 282, 309 Specialist, 234, 266, 310 Species, 269, 272, 278, 289, 303, 310, 315, 318 Specificity, 58, 160, 246, 256, 268, 310 Spectrum, 4, 27, 53, 160, 162, 310 Sperm, 190, 249, 259, 310, 312 Spinal cord, 255, 258, 259, 287, 291, 292, 296, 310, 311 Spleen, 252, 286, 310 Sporadic, 299, 305, 310 Stabilization, 18, 310 Staging, 306, 310 Stagnation, 310, 314 Statistically significant, 15, 310 Steatosis, 35, 78, 102, 182, 271, 310 Steel, 259, 310 Stem Cells, 270, 310 Stent, 82, 310 Sterile, 295, 310 Sterility, 119, 263, 281, 310 Steroid, 48, 120, 181, 251, 263, 306, 310 Stimulus, 267, 311, 313 Stomach, 160, 245, 252, 266, 270, 272, 273, 274, 278, 283, 291, 309, 310, 311 Stool, 280, 282, 283, 311 Strand, 33, 299, 311 Stroke, 19, 140, 151, 154, 197, 222, 257, 258, 311 Stroke Volume, 257, 311 Stromal, 17, 46, 311 Stromal Cells, 46, 311 Subacute, 281, 311 Subclinical, 281, 307, 311

332

Insulin Resistance

Subcutaneous, 15, 31, 33, 53, 56, 64, 246, 267, 285, 295, 311, 318 Substance P, 288, 304, 307, 311 Substrate, 13, 18, 28, 56, 58, 60, 70, 99, 120, 162, 169, 181, 186, 269, 311, 316 Sulfur, 188, 288, 311 Superoxide, 57, 311 Suppression, 23, 32, 41, 53, 55, 59, 64, 69, 97, 166, 179, 248, 263, 311 Sympathetic Nervous System, 252, 311 Symphysis, 302, 311 Symptomatic, 295, 311 Synaptic, 292, 308, 311, 312 Synaptic Transmission, 292, 312 Synergistic, 19, 95, 192, 312 Systemic, 24, 65, 70, 71, 160, 253, 254, 260, 269, 276, 281, 303, 312, 315 Systemic lupus erythematosus, 160, 260, 312 Systolic, 119, 279, 312 Systolic blood pressure, 119, 312 T Telangiectasia, 227, 312 Temporal, 71, 312 Terminator, 260, 312 Testicles, 248, 312 Testicular, 251, 312 Testis, 248, 270, 312 Testosterone, 48, 61, 64, 69, 213, 304, 308, 312 Tetany, 295, 312 Thalamic, 252, 312 Thalamic Diseases, 252, 312 Therapeutics, 72, 123, 169, 178, 312 Thermal, 266, 313 Thermogenesis, 28, 313 Thigh, 64, 65, 150, 313 Third Ventricle, 279, 313 Thorax, 245, 313, 317 Threonine, 58, 71, 190, 307, 313 Threshold, 279, 313 Thrombin, 271, 298, 302, 313 Thrombolytic, 298, 313 Thrombomodulin, 302, 313 Thrombosis, 89, 94, 96, 117, 126, 302, 311, 313 Thromboxanes, 188, 251, 267, 313 Thrombus, 263, 281, 290, 298, 313 Thyroid, 160, 295, 313, 316 Thyroid Gland, 295, 313 Thyroid Hormones, 313, 316 Thyrotropin, 148, 313

Thyroxine, 247, 296, 313 Time Factors, 247, 313 Tissue Plasminogen Activator, 59, 314 Tolerance, 4, 5, 8, 9, 10, 13, 24, 37, 40, 41, 43, 46, 47, 48, 55, 61, 64, 69, 73, 75, 104, 118, 131, 143, 145, 148, 156, 160, 162, 163, 168, 169, 172, 177, 182, 188, 189, 192, 194, 195, 199, 202, 210, 213, 232, 274, 314 Tomography, 18, 70, 286, 314 Topical, 270, 278, 314 Torpor, 174, 314 Torsion, 281, 314 Toxaemia, 300, 314 Toxic, iv, 143, 180, 253, 269, 292, 314 Toxicity, 29, 69, 314 Toxicology, 101, 224, 314 Toxins, 250, 256, 274, 281, 314 Trace element, 259, 314 Tracer, 41, 314 Trachea, 313, 314 Traction, 259, 314 Transcriptase, 305, 314 Transcription Factors, 25, 38, 314 Transduction, 20, 71, 184, 186, 256, 308, 314 Transfection, 47, 254, 314 Transferases, 275, 315 Translation, 78, 186, 315 Translational, 24, 56, 57, 315 Translocating, 253, 315 Translocation, 22, 29, 36, 198, 252, 315 Transmitter, 245, 287, 292, 315, 316 Transplantation, 83, 122, 259, 277, 280, 286, 315 Trauma, 65, 131, 162, 175, 253, 270, 276, 291, 295, 312, 315 Trauma Centers, 65, 315 Triad, 108, 315 Tricuspid Atresia, 262, 315 Troglitazone, 6, 11, 16, 69, 110, 155, 166, 171, 193, 210, 315 Truncal, 84, 149, 194, 195, 315 Tryptophan, 260, 307, 315 Tuberculosis, 262, 286, 306, 315 Tuberous Sclerosis, 227, 315 Tumor marker, 254, 315 Tumor Necrosis Factor, 13, 70, 78, 120, 127, 131, 315 Tyramine, 254, 316 Tyrosine, 21, 29, 32, 41, 57, 58, 68, 70, 71, 72, 78, 173, 202, 297, 304, 316

Index 333

U Ultrasonography, 60, 273, 316 Umbilical Arteries, 316 Umbilical Cord, 133, 316 Unconscious, 280, 316 Uracil, 316 Uraemia, 295, 316 Urea, 154, 155, 316 Uremia, 283, 304, 316 Urethra, 302, 316, 317 Uric, 275, 279, 303, 316 Uridine Diphosphate, 114, 316 Urinary, 256, 280, 293, 314, 316 Urinary Plasminogen Activator, 314, 316 Urine, 76, 140, 142, 148, 171, 254, 266, 277, 280, 283, 293, 302, 316, 317 Uterus, 263, 268, 288, 294, 301, 317 V Vaccine, 302, 317 Vacuoles, 268, 293, 317 Vagus Nerve, 309, 315, 317 Valproic Acid, 134, 317 Vasculitis, 295, 317 Vasodilatation, 94, 317 Vasodilation, 26, 46, 317 Vasodilators, 292, 317 Vasomotor, 270, 317 Vector, 314, 317 Vein, 140, 142, 148, 249, 282, 293, 296, 316, 317 Venous, 70, 254, 259, 264, 302, 315, 317 Venous blood, 254, 259, 317 Ventricle, 252, 262, 303, 312, 313, 315, 317 Ventricular, 119, 262, 291, 315, 317

Venules, 254, 256, 268, 317 Very low-density lipoprotein, 35, 317 Veterinary Medicine, 223, 317 Viral, 160, 314, 317 Virilism, 278, 318 Virulence, 252, 314, 318 Virus, 37, 105, 107, 109, 113, 122, 123, 212, 253, 267, 273, 298, 314, 317, 318 Visceral Afferents, 252, 317, 318 Visceral fat, 7, 22, 55, 64, 75, 105, 126, 213, 318 Vitamin A, 136, 281, 305, 318 Vitreous Hemorrhage, 265, 318 Vitro, 17, 31, 35, 57, 74, 146, 277, 318 Vivo, 17, 21, 22, 23, 29, 31, 32, 35, 41, 42, 47, 57, 58, 64, 67, 68, 70, 71, 72, 74, 146, 158, 179, 181, 277, 280, 313, 318 W Waist circumference, 6, 65, 116, 126, 205, 258, 318 Weight Gain, 12, 20, 60, 98, 142, 212, 318 Weight Lifting, 149, 318 White blood cell, 127, 250, 284, 286, 298, 318 Windpipe, 313, 318 X Xenograft, 249, 318 X-ray, 28, 61, 142, 261, 265, 287, 293, 303, 307, 318 Y Yeasts, 296, 318 Z Zymogen, 302, 318

334

Insulin Resistance

Index 335

336

Insulin Resistance

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