Understanding Diabetes: A Biochemical Perspective Book

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 Oxidase/Peroxidase/Chromogen / 218

Hexokinase/NADP / 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