Understanding Diabetes – A Biochemical Perspective

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 1 A Pandemic in the Making Diabetes Prevalence and Cost in the United States A dire prediction based on alarming data The increase of diabetes in youths The cost Diabetes Prevalence and Cost Worldwide A worldwide epidemic Numbers of cases of diabetes Cost Obesity and Overweight: Another Epidemic in the United States A parallel epidemic Definitions of overweight and obesity Overweight and obesity among adults in the U.S. Obesity and overweight among children and adolescents in the U.S. Overweight and Obesity Worldwide Overweight and obesity globally for adults The Relationship between Obesity and Diabetes Bibliography Projects and Questions 2 Early History of Diabetes Mellitus The Ebers Papyrus Neandertals Hippocrates, Aretaeus and Demetrius Galen Sushruta Ibn Sina (Avicenna) The Yellow Emperor Japanese Medicine Paracelsus (Philippus Aureolus Theophrastus Bombastus von Hohenheim) Thomas Willis John Conrad Brunner Matthew Dobson John Rollo and William Cruickshane Thomas Cawley Michel Eugene Chevreul Claude Bernard Paul Langerhans (Edouard Laguesse and Eugene L. Opie) Oscar Minkowski and Joseph von Mering Advances in Sugar (Glucose) Determinations Earliest Approaches- Taste and Fermentation Evaporation of urine to yield sugar crystals Moore's test Trommer's test Barreswil and Fehling's Solutions Frederick Pavy Benedict's Solution Folin-Wu Determination of Blood Glucose Banting, Best and MacLeod Leonard Thompson John Jacob Abel Frederick Sanger Pedro Cuatrecasas Bibliography Questions and Crossword Puzzle 3 A Glucose Metabolism Primer Prologue to Chapter 3 The Carbohydrates and Their function Digestion and Absorption of Carbohydrates Salivary and Pancreatic Amylase Disaccharidases Absorption Overview of Glucose Metabolism Adenosine 5'-Triphosphate (ATP) Glucose Metabolism Glucose transport into cells Phosphorylation of Glucose Introduction to Glycogen synthesis and Hydrolysis Beautiful Concepts Glycogen Synthesis Uridine Bisphosphate Glucose (UBP-Glucose) Glycogen Synthase Branching Enzyme Glycogenolysis Glycogen Phosphorylase Phosphoglucomutase Glucose 6-phosphatase (1 4) - Glucosidase Synchronization of Glycogenesis and Glycogenolysis (A Beautiful Pathway) Dephosphorylation Effectors Glycolysis (Glycolytic Pathway) Phosphoglucose Isomerase Phosphofructokinase Aldolase Triose Phosphate Isomerase Glyceraldehyde 3-Phosphate Dehydrogenase Erythrocyte Bisphosphoglyceromutase and Bisphosphoglycerate Phosphatase 3-Phosphoglycerate Kinase Phosphoglyceromutase Pyruvate Kinase Lactate Dehydrogenase Tricarboxylic acid cycle The Coenzymes: Nicotinamide Adenine Dinucleotide (NAD) and Flavin Adenine Dinucleotide(FADH) Steps in the Tricarboxylic Acid Cycle Pyruvate Dehydrogenase: Acetyl CoA Pyruvate decarboxylase Dihydrolipoyl transacetylase Dihydrolipoyl dehydrogenase Citrate Synthase Aconitase Isocitrate Dehydrogenase -Ketoglutarate Dehydrogenase Succinate Dehydrogenase L-Malate Dehydrogenase Pyruvate Carboxylase Summary The Electron Transport System and Oxidative Phosphorylation Steps in the electron transport system Oxidative Phosphorylation (ATP Synthase) Shuttles Glycerol 3-phosphate shuttle Malate-aspartate shuttle Moles ATP produced by oxidative phosphorylation from one mole of glucose The Phosphogluconate Oxidative Cycle Steps in the Phosphogluconate Oxidative Cycle Glucose 6-Phosphate Dehydrogenase: Lactonase 6-Phosphogluconate Dehydrogenase; Ribose and Xylulose Transaldolase Transketolase The Fate of Glyceraldehyde 3-phosphate Uronic Pathway Hexosamine biosynthesis pathway The Steps of Gluconeogenesis Conclusions Questions 4 Regulation of Glucose Metabolism Insulin Structure Transport and Secretion of Insulin Insulin Signaling Pathways Akt pathway GLUT4 Translocation Pathway 1 Pathway 2 Insulin Stimulated Glycogenesis Insulin stimulated inhibition of gluconeogenesis Insulin stimulated protein synthesis Insulin stimulated lipogenesis (fatty acid synthesis) Insulin inhibited lipolysis (fatty acid hydrolysis) Scaffold Proteins The Incretin Hormones (Incretins) Amylin Glucagon, Epinephrine, Somatotropin (Growth Hormone), Somatostatin, Cortisol, ACTH, Thyroid Hormone, and Insulin-like Growth Factors Glucagon Epinephrine Somatotropin (Growth Hormone) Somatostatin Cortisol Adrenocorticotropin (ACTH) Thyroid Hormones Insulin-like growth factor (IGF) Fibroblast growth factor 19 (FGF19) Adenosine 5'-monophosphate-activated protein kinase (AMPK) Bibliography 5 Glucose Metabolism Gone Wrong Pancreatic beta-cell mass Glucose Transport and Hexokinase Glycogen synthesis and breakdown Glycogen cycling Gluconeogenesis and Glycogenolysis Glycolysis, glucose oxidation (tricarboxylic acid pathway) and pyruvate dehydrogenase Mitochondrial defects Tricarboxylic acid pathway and oxidative phosphorylation UCPsSirt3 Lipids (Free Fatty Acids) Hexosamine biosynthesis pathway Techniques Used in the Above Investigations Hyperinsulinemic-euglycemic clamp In animals In humans Vastus lateralis muscle biopsy Bibliography 6 Classification System for Diabetes Mellitus T1D Latent autoimmune diabetes (LADA) or Type 1.5 T2D Hybrid Idiopathic diabetes (T1b) Secondary Genetic defects of beta-islet function MODY Other genetic defects of the beta-cell Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug or chemically caused diabetes Infections Uncommon forms of immune-mediated diseases Other genetic syndromes sometimes associated with diabetes Prediabetes Gestational diabetes (GDM) Statistical Risk Classes Metabolic syndrome Bibliography 7 Diagnosis of Diabetes Mellitus Part 1: Establishing a Normal Range The Concept of Normal and Abnormal Populations The Probability Factor in Diagnosing Disease Probability of Disease and Prevalence The Normal Range Assay Sensitivity and Specificity Relationships among Sensitivity, Specificity, Prevalence, Predictability and NormalRange How does one choose a normal range? Truthfulness (Efficiency) The Effect of Reproducibility on Sensitivity and Specificity Severity of Disease and Assay Results Parallel and Series Multiparameter Testing Bibliography Part 2: Modern Techniques for the Quantification of Glucose Methods of Historical Interest Modern-Day Methods of Measuring Glucose Glucose oxidase/Peroxidase/Chromogen Hexokinase/NADP Glycated Hemoglobin Specimen Collection The Gold Standard Instrumentation Bibliography Part 3: Symptoms and Tools for the Diagnosis of Diabetes Mellitus The Symptoms of Diabetes Mellitus Individuals who should be tested for diabetes Tools for the Diagnosis of Diabetes Urinary glucose Fasting blood glucose (FBG) Oral glucose tolerance test (OGTT) HbA1c Cut points for the diagnosis of diabetes Diagnosis of Diabetes using FBG, 2-h PG or HbA1c Diagnosis of Gestational Diabetes Mellitus (GDM) Autoimmune antibodies as predictors for T1D and LADA Bibliography 8 Complications of Diabetes Mellitus and Their Pathophysiology The Complications of Diabetes Mellitus Retinopathy and other eye conditions Neuropathy and related conditions Gastric Emptying (Gastroparesis) Sexual Complications Urologic Complications Nephropathy, Diabetic Kidney Disease (DKD) and End-Stage Renal Disease Cardiovascular Disease, Hypertension, Coronary Heart Disease or Coronary Artery Disease (CHD), Cerebrovascular Accident (CVA), Pathophysiology of CVD: Endothelial Dysfunction Cardiovascular Disease (DVD) Hypertension (Athersclerosis) CHD CVA The Pathophysiology of CVD: Endothelium Dysfunction Shear Stress Diabetic Ketoacidosis (DKA) Hyperglycemic Hyperosmolar non-Ketotic Syndrome Hypoglycemia Infections Alzheimer's Disease or Alzheimer Disease (AD) Diabetes and Cancer Pathophysiology of Diabetic Complications Glycation Sorbitol Accumulation Reactive Oxygen Species (ROS) in Diabetes Bibliography 9 Hereditary Transmission of Diabetes Mellitus Inheritance of T1D in Monozygotic (MZ) and Dizygotic (DZ) Twins Pairwise and Probandwise Concordance in T1D Pairwise and Probandwise Concordance in T2D Diabetes in offspring of one or two diabetic conjugal (biological) parents Diabetes in siblings of diabetics Summary The Genetic Component of Diabetes Mellitus The Major Histocompatibility Complex Proteins (MHC) or Human Lymphocyte Antigens (HLA) and Disease Online Mendelian Inheritance in Man (OMIM) HLA Nomenclature HLAs and Diabetes Mellitus T1D and Class II Genes T1D and Class I Genes Non-HLA T1D Promoting Alleles Genetics of T2D T1D and Environment Enteroviruses (Coxsackie B Virus) Rubella Virus (German measles) Mumps Virus Cytomegalovirus (CMV) Retrovirus Reovirus and Rotavirus Epstein - Barr virus Viruses that produce T1D in animals but so far no evidence in humans Other Environmental Factors Early Exposure to cow's milk as opposed to breast milk Vitamin D Summary Genes and Obesity The FTO Gene The KLF14 Gene Bibliography Projects 10 Treatment Part 1: Medicinal Treatment Insulin (Early Treatment) It is not your father's insulin any more Modern-Day Human Insulin Genetically Engineered Insulin Derivatives Other modes of delivering insulin: Tablets or capsules, inhalable insulin and nasal spray insulin Closed-Loop Insulin Delivery (Artificial Pancreas) Islet Transplantation and stem cell therapy Antidiabetic Oral Drugs Sulfonylureas Biguanides Thiazolidinediones Incretin-based inhibitors Exenatide Liraglutide Albiglutide and Taspoglutide (Long-Acting Release) Sitagliptin, Vildagliptin and Saxagliptin Amylin derivatives (Pramlintide) Glucokinase Activators (GKA): Potential Anti Diabetic Compounds -Glucosidase Inhibitors Other new strategies that are in the clinical trials phase SGLT2 Inhibitors 11beta-Hydroxysteroid Dehydrogenase Type 1 inhibitors Bibliography Part 2: Prevention, Delay and Management Prevention and Delay Exercise Evidence Diet Biochemistry of the beneficial effects of exercise Gastric Bypass Surgery (A Cure for T2D) Bibliography Epilogue