Understanding Diabetes

RICHARD F. DODS, PhD, D.ABCC, has studied, taught, and written about diabetes mellitus for many years, beginning as a research associate at New York University Medical School. As Director of Clinical Chemistry at the Louis A. Weiss Memorial Hospital, Dr. Dods published pioneering papers on the use of HbA1c as a test for monitoring diabetes mellitus. Later, he established his own company, Clinical Laboratory Consultants, which advised hospital and commercial laboratories on the implementation and interpretation of assays and the use of instruments for the diagnosis and monitoring of disease, including diabetes.

PREFACE xvii

1 DIABETES MELLITUS: A PANDEMIC IN THE MAKING 1

Diabetes Prevalence and Cost in the United States 2

A Dire Prediction Based on Alarming Data 2

The Increase of Diabetes in Youths 4

The Cost 6

Diabetes Prevalence and Cost Worldwide 7

A Worldwide Epidemic 7

Numbers of Cases of Diabetes 7

Cost 7

Obesity and Overweight; Another Epidemic in the United States 9

A Parallel Pandemic 9

Definitions of Overweight and Obesity 9

Overweight and Obesity among Adults in the United States 9

Obesity and Overweight among Children and Adolescents in the United States 12

Overweight and Obesity Worldwide 14

Overweight and Obesity Globally in Adults 14

Overweight and Obesity in Children 16

The Relationship Between Obesity and Diabetes 16

Projects and Questions 18

Glossary 18

References 19

2 AN EARLY HISTORY OF DIABETES MELLITUS 23

Translation 24

More simply stated 24

The Ebers Papyrus 24

Neandertals 25

Hippocrates, Aretaeus, and Demetrius 25

Galen 26

Sushruta 27

Ibn Sina (Avicenna) 28

The Yellow Emperor 29

Japanese Medicine 29

Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim) 30

Thomas Willis 31

Johann Conrad Brunner 31

Matthew Dobson 31

John Rollo and William Cruickshane 32

Thomas Cawley 33

Michel Eugene Chevreul 34

Claude Bernard 34

Paul Langerhans (Edouard Laguesse and Eugene L. Opie) 35

Oscar Minkowski and Josef von Mering 36

Advances in Sugar (Glucose) Determinations 37

Earliest Approaches—Taste and Fermentation 37

Evaporation of Urine to Yield Sugar Crystals 38

Moore’s Test 38

Trommer’s Test 39

Barreswil and Fehling’s Solutions 39

Frederick Pavy 40

Benedict’s Solution 40

Folin–Wu Determination of Blood Glucose 41

Banting, Best, and MacLeod 43

Leonard Thompson 44

John Jacob Abel 45

Frederick Sanger 45

Pedro Cuatrecasas 48

Questions and Crossword Puzzle 50

References 52

3 A PRIMER: GLUCOSE METABOLISM 55

Prolog 55

The Carbohydrates and their Function 56

Digestion and Absorption of Carbohydrates 57

Salivary and Pancreatic Amylase 57

Disaccharidases 58

Absorption 59

Overview of Glucose Metabolism 60

Adenosine 5 -Triphosphate (ATP) 61

Glucose Metabolism 63

Glucose Transport into Cells 63

Phosphorylation of Glucose 64

Introduction to Glycogen Synthesis and Hydrolysis 65

Beautiful Concepts 65

Glycogen Synthesis 66

Uridine Bisphosphate Glucose (UBP-Glucose) 67

Glycogen Synthase 67

Branching Enzyme 69

Glycogenolysis 69

Debranching Enzyme 70

Glycogen Phosphorylase 71

Phosphoglucomutase 71

Glucose 6-Phosphatase 72

α(1 → 4)-Glucosidase  72

Synchronization of Glycogenesis and Glycogenolysis (A Beautiful Pathway) 72

Dephosphorylation 73

Effectors 73

Glycolysis (Glycolytic Pathway) 75

Phosphoglucose Isomerase 75

Phosphofructokinase 76

Aldolase 76

Triose Phosphate Isomerase 76

Glyceraldehyde 3-Phosphate Dehydrogenase 77

Erythrocyte Bisphosphoglyceromutase and Bisphosphoglycerate Phosphatase 77

3-Phosphoglycerate Kinase 78

Phosphoglyceromutase 78

Enolase 78

Pyruvate Kinase 78

Lactate Dehydrogenase 79

Tricarboxylic Acid Cycle 80

The Coenzymes: Nicotinamide Adenine Dinucleotide (NAD+) and Flavin Adenine Dinucleotide (FADH) 81

Steps in the Tricarboxylic Acid Cycle 83

Pyruvate Dehydrogenase; Acetyl CoA 83

Pyruvate Decarboxylase 84

Dihydrolipoyl Transacetylase 85

Dihydrolipoyl Dehydrogenase 86

Citrate Synthase 86

Aconitase 86

Isocitrate Dehydrogenase 87

α-Ketoglutarate Dehydrogenase  87

Succinate Dehydrogenase 88

Fumarase 89

l-Malate Dehydrogenase  89

Pyruvate Carboxylase 89

Glycolysis 90

Tricarboxylic Acid Cycle 90

Sum Total of Glycolysis and Tricarboxylic Acid Cycle 90

Summary 90

The Electron Transport System and Oxidative Phosphorylation 91

Steps in the Electron Transport System 92

Oxidative Phosphorylation (ATP Synthase) 95

Shuttles 97

Glycerol 3-Phosphate Shuttle 97

Malate–Aspartate Shuttle 97

Moles ATP Produced by Oxidative Phosphorylation from 1 mol of Glucose 97

The Phosphogluconate Oxidative Cycle 98

Steps in The Phosphogluconate Oxidative Cycle 99

Glucose 6-Phosphate Dehydrogenase; Lactonase 99

Transaldolase 101

Transketolase 101

The Fate of Glyceraldehyde 3-phosphate 101

Uronic Acid Pathway 103

Hexosamine Biosynthesis Pathway 104

The Steps of Gluconeogenesis 105

Conclusions 108

Questions 108

Glossary 109

4 REGULATION OF GLUCOSE METABOLISM 113

Insulin 114

Structure 114

Transport and Secretion of Insulin 114

Insulin Signaling Pathways 118

Akt Pathway 119

GLUT4 Translocation 120

Insulin-Stimulated Glycogenesis 121

Insulin-Stimulated Inhibition of Gluconeogenesis 123

Insulin-Stimulated Protein Synthesis 123

Insulin-Stimulated Lipogenesis (Fatty Acid Synthesis) 124

Insulin-Inhibited Lipolysis (Fatty Acid Hydrolysis) 124

Scaffold Proteins 125

The Incretin Hormones (Incretins) 128

Amylin 131

Other Hormones 133

Glucagon 133

Epinephrine 135

Somatotropin (Growth Hormone) 137

Somatostatin (SST) 139

Cortisol 140

Adrenocorticotropin 142

Thyroid Hormones 143

Insulin-Like Growth Factor (IGF) 146

Fibroblast Growth Factor 19 146

Adenosine 5 -Monophosphate-Activated Protein Kinase 147

Glossary 149

References 150

5 GLUCOSE METABOLISM GONE WRONG 153

Pancreatic β-Cell Mass 156

Glucose Transport and Hexokinase 158

Glycogen Synthesis and Breakdown 160

Glycogen Cycling 161

Gluconeogenesis and Glycogenolysis 164

Glycolysis, Glucose Oxidation, and Pyruvate Dehydrogenase 166

Mitochondrial Defects 169

Tricarboxylic Acid Pathway and Oxidative Phosphorylation 169

Hexosamine Biosynthesis Pathway 174

Techniques Used in the Investigations 175

Hyperinsulinemic-Euglycemic Clamp 175

Vastus Lateralis Muscle Biopsy 176

Glossary 176

References 177

6 CLASSIFICATION SYSTEM FOR DIABETES MELLITUS 183

T1D 184

Latent Autoimmune Diabetes (LADA) or Type 1.5 184

T2D 187

Hybrid 187

Idiopathic Diabetes (T1b) 187

Secondary 187

Genetic Defects of β-islet Function 188

Mody 188

Other Genetic Defects of the β-cell 189

Genetic Defects in Insulin Action 189

Diseases of the Exocrine Pancreas 190

Endocrinopathies 190

Drug or Chemically Caused Diabetes 190

Infections 191

Uncommon Forms of Immune-Mediated Diseases 191

Other Genetic Syndromes Sometimes Associated With Diabetes 192

Prediabetes 192

Gestational Diabetes Mellitus (GDM) 193

Statistical Risk Classes 194

Metabolic Syndrome 195

Glossary 197

References 198

7 DIAGNOSIS OF DIABETES MELLITUS 201

PART 1: Establishing a Normal Range 201

The Concept of Normal and Abnormal Populations 201

The Probability Factor in Diagnosing Disease 203

Probability of Disease and Prevalence 203

The Normal Range 204

Assay Sensitivity and Specificity 205

Relationships Among Sensitivity, Specificity, Prevalence, Predictability, and Normal Range 207

Exercise 208

How Does One Choose a Normal Range?  209

Truthfulness (Efficiency) 209

Non-gaussian Distribution 210

The Effect of Reproducibility on Sensitivity and Specificity 210

Severity of Disease and Assay Results 211

Parallel and Series Multiparameter Testing 212

Exercise 213

Example 215

Example 216

References 216

PART 2: Modern Techniques for the Quantitation of Glucose 216

Methods of Historical Interest 216

Modern-day Methods of Measuring Glucose 218

Glucose OxidasePeroxidaseChromogen 218

HexokinaseNADP 220

Exercise 221

Glycated Hemoglobin 221

Specimen Collection 223

Exercise 225

The Gold Standard 225

Instrumentation 226

References 229

PART 3: Symptoms and Tools for the Diagnosis of Diabetes Mellitus 230

The Symptoms of Diabetes Mellitus 231

Individuals Who Should be Tested for Diabetes 231

Tools for the Diagnosis of Diabetes 233

Urinary Glucose 233

Fasting Blood Glucose 233

Oral Glucose Tolerance Test 234

HbA1c 235

Cut Points for the Diagnosis of Diabetes 237

Diagnosis of Diabetes Using FBG, 2-h PG, or HbA1c 239

Diagnosis of Gestational Diabetes Mellitus 239

Autoimmune Antibodies as Predictors for T1D And LADA 241

Glossary 245

References 246

8 COMPLICATIONS OF DIABETES MELLITUS AND THEIR PATHOPHYSIOLOGY 249

The Complications of Diabetes Mellitus 249

Retinopathy and Other Eye Complications 249

Neuropathy and Related Conditions 252

Nephropathy, Diabetic Kidney Disease (DKD), and End-Stage Renal Disease 254

Cardiovascular Disease (CVD), Hypertension, Coronary Heart Disease or Coronary Artery Disease (CHD), Cerebrovascular Accident (CVA), Pathophysiology of CVD: Endothelial Dysfunction 258

The Pathophysiology of CVD: Endothelium Dysfunction 260

Diabetic Ketoacidosis (DKA) 265

Hyperglycemic Hyperosmolar Non-Ketotic Syndrome 266

Hypoglycemia 266

Infections 267

Alzheimer’s Disease or Alzheimer Disease (AD) 269

Diabetes and Cancer 270

Pathophysiology of Diabetic Complications 272

Glycation 272

Sorbitol Accumulation 275

Reactive Oxygen Species (ROS) in Diabetes 275

Glossary 278

References 278

9 HEREDITARY TRANSMISSION OF DIABETES MELLITUS 283

Inheritance of T1D in Monozygotic and Dizygotic Twins 284

Pairwise and Probandwise Concordance in T1D 284

Pairwise and Probandwise Concordance in T2D 286

Diabetes in Offspring of One or Two Diabetic Conjugal (Biological) Parents 288

Diabetes in Siblings of Diabetics 289

Summary 289

The Genetic Component of Diabetes Mellitus 290

The Major Histocompatibility Complex Proteins or Human Lymphocyte Antigens and Disease 290

Online Mendelian Inheritance in Man 293

HLA Nomenclature 294

HLas and Diabetes Mellitus 295

T1D and Class II Genes 295

T1D and Class I Genes 297

Non-HLA T1D Promoting Alleles 298

Genetics of T2D 298

T1D and Environment 306

Enteroviruses (Coxsackie B Virus) 308

Rubella Virus (German Measles) 309

Mumps Virus 310

Cytomegalovirus 310

Retrovirus 310

Reovirus and Rotavirus 310

Epstein–Barr Virus 311

Viruses that Need More Evidence for the Assumption that They Promote T1D in Humans 311

Viruses That Produce T1D in Animals but so Far no Evidence in Humans 311

Other Environmental Factors 312

Early Exposure to Cow’s Milk as Opposed to Breast Milk 312

Vitamin D 313

Summary 314

Genes and Obesity 314

The FTO Gene 315

The KLF14 Gene 316

Projects 317

Glossary 317

References 318

10 TREATMENT 323

PART 1: Medicinal Treatment 323

Insulin (Early Treatment) 323

It is Not Your Father’s Insulin Any More Modern-Day Human Insulin 326

Genetically Engineered Insulin Derivatives 327

Other Modes of Delivering Insulin: Tablets or Capsules, Inhalable Insulin and Nasal Spray Insulin 330

Closed-Loop Insulin Delivery (Artificial Pancreas) 330

Islet Transplantation and Stem Cell Therapy 331

Antidiabetic Oral Drugs 332

Sulfonylureas 332

Biguanides 333

Thiazolidinediones 335

Incretin-Based Inhibitors 335

Exenatide 337

Liraglutide 337

Albiglutide and Taspoglutide (Long-Acting Release) 337

Sitagliptin, Vildagliptin, and Saxagliptin 337

Amylin Derivatives (Pramlintide) 339

Glucokinase Activators (GKA): Potential Anti Diabetic Compounds 340

α-Glucosidase Inhibitors  341

Other New Strategies that are in the Clinical Trials Phase 342

SGLT2 Inhibitors 342

11β-Hydroxysteroid Dehydrogenase Type 1 Inhibitors 342

References 343

PART 2: Prevention, Delay and Management 345

Prevention and Delay 345

Exercise 346

Evidence 347

Diet 349

Biochemistry of the Beneficial Effects of Exercise 349

Gastric Bypass Surgery (A Cure for T2D?) 350

Project 352

Glossary 352

References 352

POSTSCRIPT 355

The Future 355

APPENDIX A 357

General Assembly 358

The White House 359

APPENDIX B 361

Problems 361

INDEX 377