A clear explanation of the cause, diagnosis, and treatment of diabetes Written for a broad range of readers, including students, researchers, policymakers, health care providers, and diabetes patients and caregivers, this book explains the underlying biochemistry and physiology of diabetes mellitus. Each chapter contains a glossary that defines key terms, a summary that highlights essential concepts discussed in each section of the chapter, as well as a set of simple problems to help readers gain a richer and deeper understanding of diabetes, from its history to treatment options. Understanding Diabetes begins with an overview of the disease, its worldwide prevalence and cost, and its connection to the global obesity epidemic. The author then explores the history of diabetes, including the first documented description of the disease dating back to 3400 BCE in Ancient Egypt. The next chapter, A Glucose Metabolism Primer, sets forth the pathways for the metabolism of glucose. Next, the book covers: Regulation of glucose metabolism and glucose metabolism gone wrong Diabetes classification system Diagnosis, including current laboratory tests Complications, such as retinopathy, neuropathy, and cardiovascular disease Hereditary transmission Prevention and treatment, including emerging research Although a cure has still not been found, this book demonstrates that researchers are continuing to make major breakthroughs on all fronts in the fight against diabetes, including a better understanding of its causes and an improved ability to diagnose and treat the disease.

Table of Contents:
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