Understanding Diabetes. a Biochemical Perspective

Description

Written in an easily understandable manner, this book explains the biochemistry behind diabetes, one of the most widely increasing illnesses today. It also discusses the most up-to-date detection, treatment, and management techniques for this debilitating disease. Taking a biochemical perspective, this book is written for clinical chemists, pharmaceutical chemists, medical technologists, medical students, residents, and physicians. The coverage explores technical concepts in easily understandable terms using a glossary, footnotes, and thorough explanations of what otherwise would be complex terminology and concepts.

Table of contents

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
• ? (1à4) - 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 ß-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 ß-islet function
• MODY
• Other genetic defects of the ß-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 Normal Range
• 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
• 11ß-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