Understanding Diabetes A Biochemical Perspective

by Dods, R. F.

• ISBN13: 9781118350096
• ISBN10: 111835009X
• Edition: 1st
• Format: Paperback
• Copyright: 2013-03-25
• Publisher: Wiley

Summary

Understanding Diabetes explains diabetes in an easily understandable manner. Written from a biochemical perspective, this book is written for clinical chemists, pharmaceutical chemists, medical technologists, medical students, residents and physicians. Understanding Diabetes explores technical concepts in easily understandable terms using a glossary, footnotes and thorough explanations of what otherwise would be complex terminology and concepts. It presents diabetes as a disease that is global and is becoming considerably more prevalent. The chapter on the history of diabetes shows the advances in the understanding of diabetes from its characterization in ancient Egypt of 3400 BCE in the Ebers Papyrus to the early 1900's. A primer chapter on glucose metabolism is presented. This chapter is referred to in later chapters in the text. It is instrumental in understanding the disease. The defects that have been found in glucose and lipid metabolism underlie the mechanisms by which diabetes causes its symptoms. In later chapters the complications of diabetes are presented as well as classification, genetic factors, detection and monitoring, treatment and how persons afflicted with this disease can cope with the disease.

Author Biography

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.

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

ɑ (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

ɑ-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 β-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 β-islet function

MODY

Other genetic defects of the β-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

ɑ-Glucosidase Inhibitors

Other new strategies that are in the clinical trials phase

SGLT2 Inhibitors

11β-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