UNDERSTANDINGDIABETES

This image depicts a watercolor representation (by the author) of a single pancreatic isletof Langerhans as seen through a light microscope. The nuclei are visualized throughstaining as blue; the glucagon produced by the α-cells is stained as red-orange and theinsulin produced by the β-cells as green.

UNDERSTANDINGDIABETESA Biochemical Perspective

RICHARD F. DODS

A JOHN WILEY & SONS, INC., PUBLICATION

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved.

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Library of Congress Cataloging-in-Publication Data:

Dods, Richard F., 1938-Understanding diabetes : a biochemical perspective / by Richard F. Dods.

p. ; cm.Includes bibliographical references and index.ISBN 978-1-118-35009-6 (cloth)I. Title.[DNLM: 1. Diabetes Mellitus. 2. Glucose–metabolism. WK 810]616.4’62–dc23

2012040252

Printed in the United States of America

10 9 8 7 6 5 4 3 2 1

CONTENTS

PREFACE xvii

1 DIABETES MELLITUS: A PANDEMIC IN THE MAKING 1

Diabetes Prevalence and Cost in the United States / 2A Dire Prediction Based on Alarming Data / 2The Increase of Diabetes in Youths / 4The Cost / 6

Diabetes Prevalence and Cost Worldwide / 7A Worldwide Epidemic / 7Numbers of Cases of Diabetes / 7Cost / 7

Obesity and Overweight; Another Epidemic in the UnitedStates / 9

A Parallel Pandemic / 9Definitions of Overweight and Obesity / 9Overweight and Obesity among Adults in the UnitedStates / 9Obesity and Overweight among Children and Adolescentsin the United States / 12

Overweight and Obesity Worldwide / 14Overweight and Obesity Globally in Adults / 14Overweight and Obesity in Children / 16

v

vi CONTENTS

The Relationship Between Obesity and Diabetes / 16Projects and Questions / 18Glossary / 18References / 19

2 AN EARLY HISTORY OF DIABETES MELLITUS 23

Translation / 24More simply stated / 24The Ebers Papyrus / 24Neandertals / 25Hippocrates, Aretaeus, and Demetrius / 25Galen / 26Sushruta / 27Ibn Sina (Avicenna) / 28The Yellow Emperor / 29Japanese Medicine / 29Paracelsus (Philippus Aureolus Theophrastus Bombastus vonHohenheim) / 30Thomas Willis / 31Johann Conrad Brunner / 31Matthew Dobson / 31John Rollo and William Cruickshane / 32Thomas Cawley / 33Michel Eugene Chevreul / 34Claude Bernard / 34Paul Langerhans (Edouard Laguesse and Eugene L. Opie) / 35Oscar Minkowski and Josef von Mering / 36Advances in Sugar (Glucose) Determinations / 37

Earliest Approaches—Taste and Fermentation / 37Evaporation of Urine to Yield Sugar Crystals / 38Moore’s Test / 38Trommer’s Test / 39Barreswil and Fehling’s Solutions / 39Frederick Pavy / 40Benedict’s Solution / 40Folin–Wu Determination of Blood Glucose / 41

Banting, Best, and MacLeod / 43Leonard Thompson / 44

CONTENTS vii

John Jacob Abel / 45Frederick Sanger / 45Pedro Cuatrecasas / 48

Questions and Crossword Puzzle / 50References / 52

3 A PRIMER: GLUCOSE METABOLISM 55

Prolog / 55The Carbohydrates and their Function / 56Digestion and Absorption of Carbohydrates / 57

Salivary and Pancreatic Amylase / 57Disaccharidases / 58Absorption / 59

Overview of Glucose Metabolism / 60Adenosine 5′-Triphosphate (ATP) / 61Glucose Metabolism / 63

Glucose Transport into Cells / 63Phosphorylation of Glucose / 64

Introduction to Glycogen Synthesis and Hydrolysis / 65Beautiful Concepts / 65Glycogen Synthesis / 66

Uridine Bisphosphate Glucose (UBP-Glucose) / 67Glycogen Synthase / 67Branching Enzyme / 69

Glycogenolysis / 69Debranching Enzyme / 70Glycogen Phosphorylase / 71Phosphoglucomutase / 71Glucose 6-Phosphatase / 72α(1 → 4)-Glucosidase / 72

Synchronization of Glycogenesis and Glycogenolysis (A BeautifulPathway) / 72

Dephosphorylation / 73Effectors / 73

Glycolysis (Glycolytic Pathway) / 75Phosphoglucose Isomerase / 75Phosphofructokinase / 76Aldolase / 76

viii CONTENTS

Triose Phosphate Isomerase / 76Glyceraldehyde 3-Phosphate Dehydrogenase / 77Erythrocyte Bisphosphoglyceromutase andBisphosphoglycerate Phosphatase / 773-Phosphoglycerate Kinase / 78Phosphoglyceromutase / 78Enolase / 78Pyruvate Kinase / 78Lactate Dehydrogenase / 79

Tricarboxylic Acid Cycle / 80The Coenzymes: Nicotinamide Adenine Dinucleotide(NAD+) and Flavin Adenine Dinucleotide (FADH) / 81

Steps in the Tricarboxylic Acid Cycle / 83Pyruvate Dehydrogenase; Acetyl CoA / 83Pyruvate Decarboxylase / 84Dihydrolipoyl Transacetylase / 85Dihydrolipoyl Dehydrogenase / 86Citrate Synthase / 86Aconitase / 86Isocitrate Dehydrogenase / 87α-Ketoglutarate Dehydrogenase / 87Succinate Dehydrogenase / 88Fumarase / 89l-Malate Dehydrogenase / 89Pyruvate Carboxylase / 89Glycolysis / 90Tricarboxylic Acid Cycle / 90Sum Total of Glycolysis and Tricarboxylic AcidCycle / 90Summary / 90

The Electron Transport System and OxidativePhosphorylation / 91

Steps in the Electron Transport System / 92Oxidative Phosphorylation (ATP Synthase) / 95

Shuttles / 97Glycerol 3-Phosphate Shuttle / 97Malate–Aspartate Shuttle / 97Moles ATP Produced by Oxidative Phosphorylation from1 mol of Glucose / 97

CONTENTS ix

The Phosphogluconate Oxidative Cycle / 98Steps in The Phosphogluconate Oxidative Cycle / 99

Glucose 6-Phosphate Dehydrogenase; Lactonase / 99Transaldolase / 101Transketolase / 101The Fate of Glyceraldehyde 3-phosphate / 101

Uronic Acid Pathway / 103Hexosamine Biosynthesis Pathway / 104The Steps of Gluconeogenesis / 105Conclusions / 108Questions / 108Glossary / 109

4 REGULATION OF GLUCOSE METABOLISM 113

Insulin / 114Structure / 114Transport and Secretion of Insulin / 114

Insulin Signaling Pathways / 118Akt Pathway / 119GLUT4 Translocation / 120Insulin-Stimulated Glycogenesis / 121Insulin-Stimulated Inhibition of Gluconeogenesis / 123Insulin-Stimulated Protein Synthesis / 123Insulin-Stimulated Lipogenesis (Fatty AcidSynthesis) / 124Insulin-Inhibited Lipolysis (Fatty Acid Hydrolysis) / 124Scaffold Proteins / 125

The Incretin Hormones (Incretins) / 128Amylin / 131Other Hormones / 133

Glucagon / 133Epinephrine / 135Somatotropin (Growth Hormone) / 137Somatostatin (SST) / 139Cortisol / 140Adrenocorticotropin / 142Thyroid Hormones / 143Insulin-Like Growth Factor (IGF) / 146

x CONTENTS

Fibroblast Growth Factor 19 / 146Adenosine 5′-Monophosphate-Activated Protein Kinase / 147Glossary / 149References / 150

5 GLUCOSE METABOLISM GONE WRONG 153

Pancreatic β-Cell Mass / 156Glucose Transport and Hexokinase / 158Glycogen Synthesis and Breakdown / 160Glycogen Cycling / 161Gluconeogenesis and Glycogenolysis / 164Glycolysis, Glucose Oxidation, and PyruvateDehydrogenase / 166Mitochondrial Defects / 169

Tricarboxylic Acid Pathway and OxidativePhosphorylation / 169

Hexosamine Biosynthesis Pathway / 174Techniques Used in the Investigations / 175

Hyperinsulinemic-Euglycemic Clamp / 175Vastus Lateralis Muscle Biopsy / 176

Glossary / 176References / 177

6 CLASSIFICATION SYSTEM FOR DIABETESMELLITUS 183

T1D / 184Latent Autoimmune Diabetes (LADA) or Type 1.5 / 184T2D / 187Hybrid / 187Idiopathic Diabetes (T1b) / 187Secondary / 187Genetic Defects of β-islet Function / 188

Mody / 188Other Genetic Defects of the β-cell / 189

Genetic Defects in Insulin Action / 189Diseases of the Exocrine Pancreas / 190Endocrinopathies / 190Drug or Chemically Caused Diabetes / 190Infections / 191

CONTENTS xi

Uncommon Forms of Immune-Mediated Diseases / 191Other Genetic Syndromes Sometimes Associated WithDiabetes / 192Prediabetes / 192Gestational Diabetes Mellitus (GDM) / 193Statistical Risk Classes / 194Metabolic Syndrome / 195Glossary / 197References / 198

7 DIAGNOSIS OF DIABETES MELLITUS 201

PART 1: Establishing a Normal Range / 201The Concept of Normal and Abnormal Populations / 201The Probability Factor in Diagnosing Disease / 203Probability of Disease and Prevalence / 203The Normal Range / 204Assay Sensitivity and Specificity / 205Relationships Among Sensitivity, Specificity, Prevalence,Predictability, and Normal Range / 207Exercise / 208How Does One Choose a Normal Range? / 209Truthfulness (Efficiency) / 209Non-gaussian Distribution / 210The Effect of Reproducibility on Sensitivity and Specificity / 210Severity of Disease and Assay Results / 211Parallel and Series Multiparameter Testing / 212Exercise / 213Example / 215Example / 216References / 216PART 2: Modern Techniques for the Quantitation ofGlucose / 216Methods of Historical Interest / 216Modern-day Methods of Measuring Glucose / 218

Glucose Oxidase/Peroxidase/Chromogen / 218Hexokinase/NADP / 220

Exercise / 221Glycated Hemoglobin / 221Specimen Collection / 223

xii CONTENTS

Exercise / 225The Gold Standard / 225Instrumentation / 226References / 229PART 3: Symptoms and Tools for the Diagnosis of DiabetesMellitus / 230The Symptoms of Diabetes Mellitus / 231Individuals Who Should be Tested for Diabetes / 231Tools for the Diagnosis of Diabetes / 233

Urinary Glucose / 233Fasting Blood Glucose / 233Oral Glucose Tolerance Test / 234HbA1c / 235

Cut Points for the Diagnosis of Diabetes / 237Diagnosis of Diabetes Using FBG, 2-h PG, or HbA1c / 239Diagnosis of Gestational Diabetes Mellitus / 239Autoimmune Antibodies as Predictors for T1D AndLADA / 241Glossary / 245References / 246

8 COMPLICATIONS OF DIABETES MELLITUS ANDTHEIR PATHOPHYSIOLOGY 249

The Complications of Diabetes Mellitus / 249Retinopathy and Other Eye Complications / 249Neuropathy and Related Conditions / 252Nephropathy, Diabetic Kidney Disease (DKD), andEnd-Stage Renal Disease / 254Cardiovascular Disease (CVD), Hypertension, CoronaryHeart Disease or Coronary Artery Disease (CHD),Cerebrovascular Accident (CVA), Pathophysiology ofCVD: Endothelial Dysfunction / 258The Pathophysiology of CVD: EndotheliumDysfunction / 260Diabetic Ketoacidosis (DKA) / 265Hyperglycemic Hyperosmolar Non-KetoticSyndrome / 266Hypoglycemia / 266Infections / 267

CONTENTS xiii

Alzheimer’s Disease or Alzheimer Disease (AD) / 269Diabetes and Cancer / 270

Pathophysiology of Diabetic Complications / 272Glycation / 272Sorbitol Accumulation / 275Reactive Oxygen Species (ROS) in Diabetes / 275

Glossary / 278References / 278

9 HEREDITARY TRANSMISSION OF DIABETESMELLITUS 283

Inheritance of T1D in Monozygotic and DizygoticTwins / 284

Pairwise and Probandwise Concordance in T1D / 284Pairwise and Probandwise Concordance in T2D / 286Diabetes in Offspring of One or Two Diabetic Conjugal(Biological) Parents / 288Diabetes in Siblings of Diabetics / 289Summary / 289

The Genetic Component of Diabetes Mellitus / 290The Major Histocompatibility Complex Proteins or HumanLymphocyte Antigens and Disease / 290Online Mendelian Inheritance in Man / 293HLA Nomenclature / 294

HLas and Diabetes Mellitus / 295T1D and Class II Genes / 295T1D and Class I Genes / 297

Non-HLA T1D Promoting Alleles / 298Genetics of T2D / 298T1D and Environment / 306

Enteroviruses (Coxsackie B Virus) / 308Rubella Virus (German Measles) / 309Mumps Virus / 310Cytomegalovirus / 310Retrovirus / 310Reovirus and Rotavirus / 310Epstein–Barr Virus / 311Viruses that Need More Evidence for the Assumption thatThey Promote T1D in Humans / 311

xiv CONTENTS

Viruses That Produce T1D in Animals but so Far noEvidence in Humans / 311

Other Environmental Factors / 312Early Exposure to Cow’s Milk as Opposed to BreastMilk / 312Vitamin D / 313

Summary / 314Genes and Obesity / 314

The FTO Gene / 315The KLF14 Gene / 316

Projects / 317Glossary / 317References / 318

10 TREATMENT 323

PART 1: Medicinal Treatment / 323Insulin (Early Treatment) / 323It is Not Your Father’s Insulin Any MoreModern-Day Human Insulin / 326

Genetically Engineered Insulin Derivatives / 327Other Modes of Delivering Insulin: Tablets or Capsules,Inhalable Insulin and Nasal Spray Insulin / 330Closed-Loop Insulin Delivery (Artificial Pancreas) / 330Islet Transplantation and Stem Cell Therapy / 331

Antidiabetic Oral Drugs / 332Sulfonylureas / 332Biguanides / 333Thiazolidinediones / 335

Incretin-Based Inhibitors / 335Exenatide / 337Liraglutide / 337Albiglutide and Taspoglutide (Long-Acting Release) / 337Sitagliptin, Vildagliptin, and Saxagliptin / 337

Amylin Derivatives (Pramlintide) / 339Glucokinase Activators (GKA): Potential Anti DiabeticCompounds / 340α-Glucosidase Inhibitors / 341Other New Strategies that are in the Clinical Trials Phase / 342

SGLT2 Inhibitors / 342

CONTENTS xv

11β-Hydroxysteroid Dehydrogenase Type 1Inhibitors / 342

References / 343PART 2: Prevention, Delay and Management / 345Prevention and Delay / 345

Exercise / 346Evidence / 347Diet / 349Biochemistry of the Beneficial Effects of Exercise / 349

Gastric Bypass Surgery (A Cure for T2D?) / 350Project / 352Glossary / 352References / 352

POSTSCRIPT 355The Future / 355

APPENDIX A 357General Assembly / 358The White House / 359

APPENDIX B 361Problems / 361

INDEX 377

PREFACE

In this book we commence a fascinating journey that will describe attempts toconquer a disease, really a scourge, which began as far back in history as earliestman, and continues today. Unfortunately we do not presently have a cure, but Ifeel we are on the brink of one.

This book is written for the individual who wants to learn about the under-lying biochemistry/physiology of diabetes mellitus, its history, its detection, itscomplications, and its treatment.

Alan Alda in an editorial published in Science,1 states “Scientists urgentlyneed to speak with clarity to funders, policy-makers, students, the general public,and even other scientists. . . . clarity in communicating science is at the very heartof science itself”. This book was written with this statement in mind.

Although not absolutely required, a basic knowledge of biochem-istry/physiology will help the reader understand certain concepts presentedin this book. However, in order to make technical language, objectives, andconcepts more easily understood this book includes for each chapter a Glossary,Summary, and Problems. The Glossary defines key terms used in the chapter.The Summary highlights the essential ideas presented in each section ofthe chapter. Problems for each chapter located in Appendix B present theprincipal goals of the chapter in the form of questions for the reader. Technicalterminology is presented in simple, easily understandable terms with the aid ofFootnotes.

1Alan Alda, actor, writer, and founding board member of the Center for Communicating Sci-ence, State University of New York at Stony Brook from The flame challenge. Editorial. Science2012;335:1019.

xvii

xviii PREFACE

MY GOALS IN WRITING THIS BOOK

My goals in writing this book were

• To give the reader a view of diabetes mellitus, a disease that is in epidemicproportions worldwide, by identifying its biochemical basis, classificationtypes, causes, diagnosis and monitoring, complications, and present andfuture treatment modalities.

• To provide students enrolled in a university-level biochemistry course thematerials to understand glucose metabolism and what occurs when themetabolism goes astray.

• To provide incentive for further research on this disease by presenting whatwe presently know about diabetes.

• To provide a fundamental understanding of the tests used for the diagnosisand monitoring of diabetes—assays that Medical Technologists and ClinicalChemists perform every day.

• To give diabetes counselors and educators a text and reference book thatthey can use with confidence.

• To provide to medical students and physicians an understanding of the under-lying basis for the disease that they treat.

• To provide policy-makers with an understanding and appreciation of thedisease that promotes the support of public funds for the research, treatment,and eventual cure of the disease.

• For persons afflicted with diabetes an appreciation of how science isresearching this disease and the many breakthroughs that have recentlyoccurred in comprehending the causes, complications, diagnosis, andtreatment of this disease.

After reading this book I hope you will agree that these goals have beenachieved.

CONTENT

This book is intended to acquaint the reader with diabetes mellitus, a disease thatis becoming pandemic.

In Chapter 1, “Diabetes Mellitus: A Pandemic in the Making”, diabetes melli-tus is introduced as a disease that is attaining epidemic proportions in the UnitedStates and across the world. Parallel to the outbreak of diabetes there is anotherdeveloping pandemic: overweight and obesity. The connection between these twodeveloping pandemics is discussed in this chapter and will be further elaboratedon in Chapter 6.

PREFACE xix

In Chapter 2, “A Historical View of Diabetes Mellitus”, the history of the dis-ease is presented from the caveman to its recognition in ancient Greek medicineand the early days of the Roman Empire to Banting and Best’s Nobel Prizewinning discovery of insulin to Sanger’s determination of the structure of insulinto Cuatrecasas’s purification of the receptor site for insulin.

Chapter 3, “A Primer: Glucose Metabolism”, contains the pathways for themetabolism of glucose. It includes the principal pathways by which glucose ismetabolized: glycogenesis and glycogenolysis, glycolysis, the tricarboxylic acidpathway, electron transport system and oxidative phosphorylation, phosphoglu-conate oxidative cycle, uronic acid cycle, hexosamine biosynthesis pathway, andgluconeogenesis are described. Included in this chapter are “beautiful concepts”as seen through the elegance of many of these metabolic pathways. The notionof “beautiful pathways” is elaborated on in the Prolog to Chapter 3.

Chapter 4, “Regulation of Glucose Metabolism” relates the mechanisms thatpermit glucose to enter the cell from the blood. Included in this chapter aredescriptions of insulin action, its manufacture in β-cells, the insulin signalingpathway, incretins, and other hormones that regulate insulin production, and theactions of AMP-activated protein kinase.

In Chapter 5, “Glucose Metabolism Gone Wrong”, the altered metabolism ofglucose in diabetics is presented.

Chapter 6, “Classification System for Diabetes Mellitus”, deals with the classi-fication scheme for diabetes that has been developed over the years. Described inthis chapter are type 1, type 2, impaired glucose tolerance, impaired fasting glu-cose, gestational diabetes, statistical risk class, potential abnormality of glucosetolerance, and secondary causes of diabetes mellitus.

Chapter 7, “Diagnosis of Diabetes Mellitus”, is divided into three parts—Part 1deals with the approach to establishing the normal range; Part 2 the modernlaboratory tests for glucose; and Part 3 symptoms, diagnostic tests, and criteriaused to identify diabetes.

Chapter 8, “Complications of Diabetes Mellitus and Their Pathophysiology”,describes the complications of diabetes retinopathy, angiopathy, nephropathy,infection, hyperlipidemia, atherosclerosis, ketoacidosis, lactic acidosis, hyper-glycemic hyperosmolar nonketotic coma, and hypoglycemia. Their pathophys-iology and prevalence will also be discussed.

In Chapter 9, “Hereditary Transmission of Diabetes Mellitus”, the hereditaryfactors that are involved in the susceptibility and resistance to diabetes are dis-cussed. The histocompatibility antigens (HLA) and their association with diabetesare described.

Chapter 10, “Treatment”, goes into a discussion of advancements in the treat-ment of the disease. Some of what is discussed in this chapter represents ongoingresearch into the disease. Also treated in this chapter are measures to delay andprevent the occurrence of diabetes.

Postscript “The Future”.

xx PREFACE

LEARNING AIDS

• Throughout the chapters, Problems, Summary, and Key Terms are listed.These aids are to guide readers as they navigate through the chapters. Theypermit the reader a shortcut that may be used to scan chapters that are nottotally relevant to the reader’s interest.

• The goals of each chapter are contained in the Problems located inAppendix B. In addition, summaries are included throughout each chapter.

• Key terms (including medical terms) are explained at each point as they areintroduced in the chapter. A glossary of key terms is also included at theend of each chapter.

• Each chapter has a preamble as to its importance in understanding diabetesmellitus. In addition each chapter has a summary.

• Each chapter has numbers within parenthesis relating to references, whichare listed in the reference section at the end of the chapter. Included are theURLs for many of the citations. Also the Digital Object Identifier (DOI©)for many articles is included. DOI has been around since 2000. DOIs iden-tify electronic objects such as journal articles, books, and scientific datasets in a particular location on the Internet. The system is managed by theInternational DOI Foundation (IDF), a consortium of commercial and non-commercial partners. A DOI name consists of a prefix and a suffix, forexample, 10.1089/jwh.2010.2029; the prefix is 10.1089 and the suffix isjwh.2010.2029. One way to use this system is to go to the URL of the IDF,which is http://www.doi.org/ and insert the DOI you are in search of in theplace provided and viola the document pops up. The other approach is touse the URL, http://dx.doi.org/ followed by the DOI name; for example:http://dx.doi.org/10.1089/jwh.2010.2029.

TECHNICAL TERMS

Technical terms are translated into simple language in this book. When I readan article or book, I find myself spending a considerable amount of time tryingto learn the meaning of technical terms with which I am not familiar. I oftenturn to reference books and textbooks to learn the meaning of the term. In thisbook I think I have remedied this by having footnotes and a glossary definingany technical terms that you may come across in the text.

MY BACKGROUND AND INTEREST IN DIABETES MELLITUS

As you can see from the image shown below I had an interest in diabetes mellitusearly during my education. The image is from a science notebook while I wasin high school, Lafayette High School in Brooklyn, New York, to be specific.

PREFACE xxi

Although Lafayette no longer exists it still remains alive in my heart as to whereI started my career in science.

I earned a B.S. in science at Brooklyn College, an M.S. in organic chemistryat New York University and a PhD in biochemistry at the University of Connecti-cut. I was a post-doctoral fellow in cancer research at Sloan Kettering Institutefor Cancer Research before joining New York University Medical School as aresearch associate. It was at the medical center that I first became acquainted withdiabetes mellitus and published papers on the biochemistry of the beta cell. My

xxii PREFACE

paper2 was one of the early publications characterizing beta cell protein kinaseand protein phosphatase.

I studied clinical biochemistry as an NIH fellow under the esteemed Dr SamuelNatelson at Michael Reese Medical Center in Chicago. As Director of ClinicalChemistry at Louis A. Weiss Memorial Hospital in Chicago (a position whichincluded an Adjunct Assistant Professorship with the University of Illinois Med-ical School), I published papers on the use of HbAc1 as a test for monitoringdiabetes mellitus. This article3 was one of the earliest suggesting HbAc1 as a toolfor the diagnosis of diabetes. While at Weiss, I earned a Diplomate in ClinicalBiochemistry from the American Board of Clinical Chemistry.

I wrote the chapter on Diabetes Mellitus for four of the five editions (theexception being the first edition) of Clinical Chemistry: theory, analysis, and cor-relation, edited by Lawrence Kaplan and Amadeo J. Pesce. I have also authoredtwo audiocassette courses for the American Chemical Society entitled “ClinicalChemistry” and “Pathophysiology for Chemistry”. I established a company, Clin-ical Laboratory Consultants, which advised hospital and commercial laboratoriesin the implementation and interpretation of assays and the use of instrumentsfor the diagnosis and monitoring of disease. Lastly I taught organic chemistryand biochemistry for 17 years at the Illinois Mathematics and Science Academy(IMSA), a world renowned secondary school funded by the Board of HigherEducation of the State of Illinois. While at IMSA I published several papers onproblem-based learning and its utilization in content-rich courses.4,5

DEDICATIONS

This book is dedicated to

My wife who supported and encouraged me throughout the writing of this bookand helped me when I grappled with sentences that were so convoluted that theymade little or no sense.

My cousin, Stanley Menson, who helped initiate my interest in science withhis turtle tank. He was a biology teacher for the deaf and succumbed from thecomplications of type 2 diabetes too soon.

My grandchildren, Rachel and Shannon, who I hope will follow in my footstepsinto the wonderful world of science.

My son, Steven, who has already followed me into science as an electricalengineer.

2Dods RF, Burdowski A. Adenosine 3′5′-cyclic monophosphate dependent protein kinase and phos-phoprotein phosphatase activities in rat islets of Langerhans. Biochem Biophys Res Commun1973;51:421.3Dods RF, Bolmey C. Glycosylated hemoglobin assay and oral glucose tolerance test compared fordetection of diabetes mellitus. Clin Chem 1979;25:764.4Dods RF. A problem-based learning design for teaching biochemistry. J Chem Educ 1996;73:225.5Dods RF. An action research study of the effectiveness of problem-based learning in promoting theacquisition and retention of knowledge. J Educ Gifted 1997;20:423.

PREFACE xxiii

ACKNOWLEDGMENTS

I sincerely appreciate the contributions of those who initially reviewed portions ofthe text and found them worthy enough of being incorporated into a book. Theywere Edward Hobart, M.D., Lawrence Kaplan, Ph.D., and Amadeo Pesce, Ph.D. Ithank Professor Anne Cooke who contributed the remarkable cover micrograph ofT-cells attacking beta islets. I greatly appreciate the information supplied to me byThomas F. Mich, Ph.D, retired Vice-President of Chemical Development World-Wide, Warner Lambert Pharmaceutical Company regarding medicinals prescribedfor diabetics. He passed away on October 22, 2012 due to a complication ofdiabetes mellitus, type 2. He will be missed.

No acknowledgement is complete without mentioning the team of expertswho turned the text, figures, and other supplementary materials into a book.Anita Alekhwan, Senior Acquisitions Editor, who oversaw the entire operationand provided me with very wise suggestions, her assistant Cecilia Tsai, EditorialAssistant, Kellsee Chu, Senior Production Editor who coordinated the productionphase, Haseen Khan, Project Manager of Laserwords who did the editing, andDean Gonzalez, Illustration Manager who took my crude line drawings and putthem into publishable form. To all of the above my genuine thanks for withoutyou there would be no book.

CHAPTER 1

DIABETES MELLITUS: A PANDEMICIN THE MAKING

It is a capital mistake to theorize before one has data. Insensibly one begins to twistfacts to suit theories, instead of theories to suit facts.

Sir Arthur Conan Doyle, British mystery author & physician (1859–1930)

On December 20, 2006, the General Assembly of the United Nations passed res-olution 61/225, the United Nations World Diabetes Day Resolution, designatingNovember 14 as World Diabetes Day. On October 29, 2010, the President ofthe United States, Barack Obama, declared November 2010 as National DiabetesMonth in the United States.1

Diabetes mellitus2 is an array of diseases that have a common symptom—abnormally high blood glucose levels. Diabetes mellitus is a noncommunicabledisease. It is not transmitted from person to person by viruses or bacteria asis HIV or cholera. Diabetes mellitus is a chronic, costly, and often debilitatingdisease. This will be our working definition of diabetes mellitus until later in thebook where we shall learn more specifics about the disease. The President, in hisProclamation, uses the terms type 1 and type 2 diabetes. By the end of Chapter 6,

1See Appendix A for texts of the UN Resolution and President Obama’s Proclamation, respectively.2Diabetes mellitus should not be confused with diabetes insipidus, which is caused by vasopressindeficiency. When the term diabetes alone is used in this book it will always refer to diabetes mellitus.

Understanding Diabetes: A Biochemical Perspective, First Edition. Richard F. Dods.© 2013 John Wiley & Sons, Inc. Published 2013 by John Wiley & Sons, Inc.

1

2 DIABETES MELLITUS: A PANDEMIC IN THE MAKING

you will fully understand both these terms.3 In this chapter we will learn aboutthe extent of the diabetes problem both in the United States and globally. Laterin this chapter we will learn of a related pandemic in the making—obesity andoverweight. Finally, we will describe the connections between the diabetes andobesity/overweight pandemics.

DIABETES PREVALENCE4 AND COST IN THE UNITED STATES

A Dire Prediction Based on Alarming Data

The Centers for Disease Control and Prevention (CDC) estimated that as of2008 there were as many as 18.1 million Americans who had been diagnosedwith diabetes (8 in 100 Americans). This number is presumed low because itis estimated that 6.0 million cases remain undetected. Thus, 10 in 100 adultAmericans actually had the disease in 2008 (1). Between 1980 and 2008, thenumber of diagnosed diabetic Americans has nearly tripled.

An analysis of this data according to age, gender, and race is revealing. Allof the following data derived from the CDC is for civilian, noninstitutionalizedindividuals with diagnosed diabetes.

Figure 1.1 shows the age-adjusted percentage of diagnosed cases of diabetesby sex. You may notice that percentages were similar for males and females until1999, at which time the percentage for males with diabetes began to increase ata greater rate than for females.

0 2 4 6 8

1980

1998

1999

2005

2008

Yea

r

Percentage

Female

Male

Figure 1.1 Age-adjusted percentage of civilian, noninstitutionalized persons with diag-nosed diabetes by sex for selected years. (See insert for color representation of the figure.)

3Type 1 diabetes refers to hyperglycemia (high blood glucose levels) due to insufficient insulinsecretion caused by destruction of pancreatic β-islet cells by an autoimmune response and type 2refers to hyperglycemia due to insulin resistance (relative insulin deficiency). Type 1 diabetics exhibitblood insulin levels that are low or nonexistent and type 2 diabetics have levels that are high.4Prevalence relates to the number of individuals who have diabetes at the time of the study. Incidencerefers to the frequency of occurrence and is associated with a defined period of time.