Endocrinology Adult and Pediatric: Diabetes Mellitus and Obesity E-Book

Meet the growing challenges of diabetes and obesity management with Endocrinology: Adult and Pediatric: Diabetes Mellitus and Obesity - a new diabetes and obesity eBook from the same expert endocrinologists responsible for the highly acclaimed two-volume Endocrinology clinical reference. With all of the latest advances loaded on your favorite eReader, you’ll be able to put today’s best practices to work for your patients . Stay abreast of the newest knowledge and advances in diabetes mellitus and obesity, including today’s increased focus on controlling autoimmunity and preserving or replenishing beta-cell mass in the management of type 1 diabetes; complications of diabetes and their pathogenesis, morbidity, and treatment; new findings and treatments for obesity; and much more. Count on all the authority that has made Endocrinology, 6th Edition , edited by Drs. Jameson and DeGroot, the go-to clinical reference for endocrinologists worldwide. Consult this title on your favorite e-reader , conduct rapid searches, and adjust font sizes for optimal readability. Compatible with Kindle®, nook®, and other popular devices. Front cover Endocrinology Adult and Pediatric Online_Copyright page Senior Editors Contributors Preface Online_Table of contents 1 APPETITE REGULATION AND THERMOGENESIS Components of Feeding Components of Energy Expenditure Integration of Energy Balance Specific Hormones and Neuropeptides ADIPOSE TISSUE DERIVED THE HYPOTHALAMUS Neuropeptide Y The Melanocortin System: α-MSH, Agouti-Related Peptide, and Central Melanocortin Receptors Melanin-Concentrating Hormone THE GUT Ghrelin Peptide YY Glucagon-Like Peptide-1 and Oxyntomodulin The Role of Energy Expenditure in Body Weight Regulation MEASURING ENERGY EXPENDITURE Comparing Energy Expenditure Between Individual Subjects HOW DOES ENERGY EXPENDITURE CONTRIBUTE TO OBESITY? REGULATION OF ENERGY EXPENDITURE Physical Activity REGULATION OF THERMOGENESIS Brown Adipose Tissue and Mitochondria REGULATORY INPUTS ACTING ON ENERGY EXPENDITURE Effects of the Sympathetic Nervous System on EE and Obesity Thyroid Hormone Summary Acknowledgment REFERENCES 2 OBESITY: The Problem and Its Management Epidemiology of Overweight and Obesity Diseases Associated With Obesity CARDIOVASCULAR AND CEREBROVASCULAR DISEASE Hypertension Dyslipidemia Coronary Artery Disease Congestive Heart Failure Stroke DIABETES MELLITUS NONALCOHOLIC FATTY LIVER DISEASE CANCER GYENECOLOGIC ABNORMALITIES OBSTRUCTIVE SLEEP APNEA GALLSTONES OSTEOARTHRITIS Regulation of Energy Balance ENERGY EXPENDITURE ENERGY INTAKE Adiposity Signals Gastrointestinal Signals CENTRAL INTEGRATION OF ENERGY HOMEOSTASIS Therapy for Obesity LIFESTYLE MODIFICATION DIET EXERCISE BEHAVIORAL MODIFICATION PHARMACOTHERAPY Orlistat Sibutramine BARIATRIC SURGERY Roux-en-Y Gastric Bypass Biliopancreatic Diversion Vertical Banded Gastroplasty Laparoscopic Adjustable Gastric Banding FUTURE THERAPY REFERENCES 3 GENETIC SYNDROMES ASSOCIATED WITH OBESITY Obesity Associated With Developmental Delay PRADER-WILLI SYNDROME Definition, Prevalence, Etiology, and Pathogenesis Clinical Features Diagnosis Treatment FRAGILE X SYNDROME Definition, Prevalence, Etiology, and Pathogenesis Clinical Features Diagnosis and Treatment BARDET-BIEDL SYNDROME Definition, Prevalence, Etiology, and Pathogenesis Genotype-Phenotype Correlations Diagnosis and Treatment BORJESON-FORSSMAN-LEHMANN SYNDROME WILSON-TURNER SYNDROME COHEN SYNDROME ALBRIGHT’S HEREDITARY OSTEODYSTROPHY (AHO) BDNF AND TRKB DEFICIENCY ADDITIONAL SYNDROMES Obesity Without Developmental Delay ALSTROM SYNDROME ULNAR-MAMMARY SYNDROME SIMPSON-GOLABI-BEHMEL, TYPE 2 CONGENITAL LEPTIN DEFICIENCY Diagnosis and Treatment LEPTIN RECEPTOR DEFICIENCY POMC DEFICIENCY PROHORMONE CONVERTASE 1 DEFICIENCY MELANOCORTIN 4 RECEPTOR DEFICIENCY Diagnosis and Treatment OTHER SYNDROMES Summary REFERENCES 4 ANOREXIA NERVOSA, BULIMIA NERVOSA, AND OTHER EATING DISORDERS History and Epidemiology Diagnosis Genetics General Physical and Laboratory Findings Neuroimaging Neuroendocrinology Central Nervous System–Related Neuropeptides NEUROPEPTIDE Y AND PEPTIDE YY LEPTIN ADIPONECTIN GHRELIN CHOLECYSTOKININ MELANOCORTIN AND CORTICOTROPIN-RELEASING HORMONE VASOPRESSIN AND OXYTOCIN OPIOID PEPTIDES LONG-TERM EFFECTS OF MULTIPLE NEUROPEPTIDE DISTURBANCES Treatment REFERENCES 5 DEVELOPMENT OF THE ENDOCRINE PANCREAS Pancreas Morphogenesis Early Organ Specification and Bud Formation TISSUE INTERACTION AND SIGNALING PATHWAYS INDUCTION OF THE PANCREATIC GENE EXPRESSION PROGRAM Cell Type Differentiation SIGNALING PATHWAYS TRANSCRIPTION FACTORS ISLET FORMATION The Role of Pancreatic Development in Human Diabetes REFERENCES 6 BIOSYNTHESIS, PROCESSING, AND SECRETION OF THE ISLET HORMONES: The Biosynthesis of Insulin GENERAL ASPECTS MORPHOLOGIC ORGANIZATION OF THE INSULIN BIOSYNTHETIC MACHINERY STRUCTURE AND PROPERTIES OF PROINSULIN ENZYMATIC BASIS OF THE CONVERSION OF PROINSULIN TO INSULIN Role of PC2 and PC1/3 in Proinsulin Processing Significance of Circulating Proinsulin and Des-31,32 Intermediate in Man SECRETORY GRANULE FORMATION AND MATURATION BIOSYNTHETIC ROLE AND BIOLOGICAL ACTIONS OF THE C PEPTIDE Regulation of Insulin Production Insulin Secretion and Its Regulation Insulin Gene Mutations as a Cause of Permanent Neonatal Diabetes Biosynthesis and Processing of Other Islet Hormones ISLET AMYLOID POLYPEPTIDE BIOSYNTHESIS AND LEVELS OF IAPP IN ISLETS Biological Actions of IAPP Mechanism of Amyloid Formation BIOSYNTHESIS AND PROCESSING OF GLUCAGON, GLP1, GLP2, SOMATOSTATIN, PANCREATIC POLYPEPTIDE, AND GHRELIN Conclusions Acknowledgments REFERENCES 7 INSULIN SECRETION Islet Structure in Health Islet Function in Health Insulin Clearance Islet Structure and Function in Type 1 Diabetes Islet Structure and Function in Type 2 Diabetes Islet Turnover and Regeneration Summary REFERENCES 8 THE MECHANISMS OF INSULIN ACTION Insulin, Insulin-Like Growth Factors, and Their Receptors RECEPTOR/LIGAND BINDING INSULIN RECEPTOR TYROSINE KINASE The Insulin Signaling Cascade INTRODUCTION INSULIN RECEPTOR SUBSTRATE RECRUITMENT AND PHOSPHORYLATION SITE SELECTION THE IRS→PI3K→AKT CASCADE Genetic Validation of the IRS-Based Insulin Signaling Cascade SYSTEMIC INACTIVATION OF INSULIN OR IGF-1 RECEPTORS INSULIN RECEPTOR SUBSTRATE–PROTEIN SIGNALING DOWNSTREAM INSULIN SIGNALING COMPONENTS Modulation of Insulin Signaling by Protein and Lipid Phosphatases Regulation of Protein Synthesis by Insulin Insulin-Regulated Glucose Transport Heterologous Regulation of the IRS Proteins INTRODUCTION TRANSCRIPTIONAL CONTROL MULTISITE SER/THR PHOSPHORYLATION OF IRS PROTEINS DEGRADATION OF IRS1 OTHER POSTTRANSLATIONAL MODIFICATIONS Physiology of Insulin Resistance INTRODUCTION NUTRIENT EXCESS AND INSULIN RESISTANCE INFLAMMATION AND INSULIN RESISTANCE IRS-Based Regulation of Nutrient Homeostasis and Lifespan THE IR→IRS SIGNALING CASCADE IN LIVER IRS-PROTEIN SIGNALING IN PANCREATIC β CELLS CENTRAL CONTROL OF NUTRIENT HOMEOSTASIS AND LIFESPAN Summary and Perspectives REFERENCES 9 GLUCAGON AND THE GLUCAGON-LIKE PEPTIDES Biosynthesis of Pancreatic Glucagon ISLET TRANSCRIPTION FACTORS AND THE α CELL PROGLUCAGON GENE TRANSCRIPTION FACTORS ISLET PROGLUCAGON BIOSYNTHESIS Glucagon Secretion HYPOGLYCEMIA GLUCAGON SECRETION AND DIABETES Glucagon Action PHARMACEUTICAL USE OF GLUCAGON IN HUMAN PATIENTS GLUCAGON EXCESS AND DEFICIENCY The Glucagon-like Peptides: GLP-1 and GLP-2 GLUCAGON-LIKE PEPTIDE 1: PRECLINICAL STUDIES THERAPEUTIC USE OF GLP-1R AGONISTS FOR THE TREATMENT OF PATIENTS WITH TYPE 2 DIABETES DIPEPTIDYL PEPTIDASE-4 INHIBITORS GLUCAGON-LIKE PEPTIDE-2 REFERENCES 10 REGULATION OF INTERMEDIATORY METABOLISM DURING FASTING AND FEEDING Energy Metabolism Glucose Distribution Glucose Metabolism: Methodological Considerations Glucose Metabolism: Basal (Postabsorptive) State GLUCOSE PRODUCTION GLUCOSE DISPOSAL GLUCOSE CYCLES Glucose Metabolism: Fed (Postprandial) State QUANTITATION OF INSULIN SENSITIVITY AND INSULIN SECRETION DYNAMIC INTERACTION BETWEEN INSULIN SENSITIVITY AND INSULIN SECRETION EFFECT OF INSULIN ON HEPATIC AND PERIPHERAL GLUCOSE METABOLISM INTRACELLULAR PATHWAYS OF GLUCOSE DISPOSAL Overview Insulin Receptor/Insulin Receptor Tyrosine Kinase Insulin Receptor Signal Transduction Glucose Transport Glucose Phosphorylation Glycogen Synthesis Glycolysis/Glucose Oxidation FREE FATTY ACID–AMINO ACID–GLUCOSE INTERACTIONS LIPID SYNTHESIS KETONE METABOLISM ORAL GLUCOSE COUNTERREGULATORY HORMONES REFERENCES 11 ROLE OF THE ADIPOCYTE IN METABOLISM AND ENDOCRINE FUNCTION Obesity, Insulin Resistance, Inflammation, ER Stress, and Type 2 Diabetes Mellitus LINK BETWEEN OBESITY AND INSULIN RESISTANCE (Figs. 11-1 and 11-2) LINKS BETWEEN OBESITY, INFLAMMATION, AND ER STRESS (see Figs. 11-1 and 11-2) LINK BETWEEN TOO LITTLE FAT AND INSULIN RESISTANCE Obesity Is Another Ectopic Fat Storage Syndrome Adipose Tissue: Hypertrophy vs. Hyperplasia Regulation of Adipogenesis BROWN ADIPOSE TISSUE IN HUMANS INTEGRATIVE BIOLOGY OF THE ADIPOSE TISSUE Endocrine Signals Glucocorticoids Growth Hormone/IGF-1 Estrogen in Adipose Tissue Neural Signals to the Adipose Tissue Regulation of Lipolysis (Fig. 11-9) Adipocyte as an Endocrine Organ Leptin Adiponectin Resistin TNF-α Apelin Adipose (Adp) The Adipocyte as a Target for the Treatment of Obesity and Type 2 Diabetes REFERENCES 12 LIPODYSTROPHY SYNDROMES Lipodystrophies: Definition and Diagnosis Pathophysiology of Lipodystrophy Classifications of Lipodystrophies and Their Clinical Manifestations GENERALIZED LIPODYSTROPHY Congenital Generalized Lipodystrophy Acquired Generalized Lipodystrophy (Lawrence Syndrome) PARTIAL LIPODYSTROPHY Inherited Partial Lipodystrophies Dunnigan-Variety (Face-Sparing) Lipodystrophy Köbberling-Type Lipodystrophy Familial Partial Lipodystrophy Due to PPARG Mutations Familial Partial Lipodystrophy Due to AKT2 Mutation Partial Lipodystrophy Due to CAV1 Mutation Other Syndromes With a Component of Lipodystrophy Acquired Partial Lipodystrophy (Barraquer-Simons Syndrome) HIV-Associated Lipodystrophy Syndrome LOCALIZED LIPODYSTROPHIES Mechanisms Responsible for Severe Insulin Resistance FAT REDISTRIBUTION AND FAT METABOLISM ADIPOCYTOKINES INFLAMMATION ENDOPLASMIC RETICULUM AND MITOCHONDRIAL STRESS OTHER MECHANISMS Treatment of Syndromes of Lipodystrophies LIFESTYLE MODIFICATION MANAGEMENT OF INSULIN RESISTANCE Metformin Thiazolidinediones MANAGEMENT OF DYSLIPIDEMIA Statins Fibrates Nicotinic Acid Other Lipid-Lowering Agents Leptin MANAGEMENT OF HIV-INFECTED PATIENTS WITH HAART-INDUCED METABOLIC SYNDROME Growth Hormone and Growth Hormone–Releasing Hormone Analogs HALS-Specific Treatment Modification of HAART Uridine MANAGEMENT OF COSMETIC APPEARANCE Future Perspective REFERENCES 13 CLASSIFICATION AND DIAGNOSIS OF DIABETES MELLITUS Definition Classification TYPE 1 DIABETES Autoimmune Type 1 Diabetes Idiopathic Type 1 Diabetes TYPE 2 DIABETES OTHER SPECIFIC TYPES OF DIABETES GENETIC DEFECTS IN β CELL FUNCTION GENETIC DEFECTS IN INSULIN ACTION DISEASES OF THE EXOCRINE PANCREAS ENDOCRINOPATHIES DRUG- OR CHEMICAL-INDUCED DIABETES INFECTIONS UNCOMMON FORMS OF IMMUNE-MEDIATED DIABETES OTHER GENETIC SYNDROMES SOMETIMES ASSOCIATED WITH DIABETES GESTATIONAL DIABETES Diagnosis DIAGNOSTIC CRITERIA WHAT LEVEL OF FASTING PLASMA GLUCOSE CONSTITUTES DIABETES? WHAT LEVEL OF FASTING PLASMA GLUCOSE CONSTITUTES NORMALITY? WHERE NEXT? REFERENCES 14 TYPE 1 (INSULIN-DEPENDENT) DIABETES MELLITUS: Etiology, Pathogenesis, Prediction, and Prevention History Definition Symptoms and Signs Diagnostic Criteria Classification Epidemiology PREVALENCE INCIDENCE GEOGRAPHICAL DISTRIBUTION VARIATION WITH AGE VARIATION WITH GENDER SEASONAL VARIATIONS Etiology INHERITANCE GENETIC FACTORS ENVIRONMENTAL FACTORS Viral Infection Hygiene Hypothesis Dietary Factors Maternal Factors Birth Weight and Growth Rate Psychological Stress Toxic Substances Pathology Pathogenesis Immunologic Abnormalities CELLULAR IMMUNOPATHOPHYSIOLOGY HUMORAL IMMUNOPATHOPHYSIOLOGY Islet Cell Antibodies Glutamic Acid Decarboxylase Antibodies Insulin Autoantibodies Islet Antigen-2 Antibodies (Insulinoma-Associated Antigen-2 Antibodies) ZnT8 Transporter (SLC30A8) Candidate (Minor) Autoantigens Prediction Prevention Intervention Summary Acknowledgements REFERENCES 15 TYPE 2 DIABETES MELLITUS: Genetic versus Acquired Factors GENETIC FACTORS ACQUIRED FACTORS Lifestyle: Diet, Exercise, and Obesity Low Birth Weight Aging Natural History of Type 2 Diabetes Pathophysiology of Type 2 Diabetes Mellitus ABNORMAL PANCREATIC β CELL FUNCTION Insulin Secretion in Subjects With Impaired Glucose Tolerance Insulin Secretion in Subjects With Type 2 Diabetes In Response to Intravenous Glucose In Response to Oral Glucose and Mixed Meals Proinsulin Secretion Mechanisms of β Cell Dysfunction PERIPHERAL INSULIN RESISTANCE Causes of Peripheral Insulin Resistance Circulating Factors That Influence Insulin Action Impaired Access of Insulin to Target Cells Cellular Defects in Insulin Action Characteristics of Insulin Resistance in Subjects With Impaired Glucose Tolerance or Type 2 Diabetes PATHOPHYSIOLOGIC ABNORMALITIES IN INSULIN TARGET TISSUES Skeletal Muscle Mechanisms of Skeletal Muscle Insulin Resistance Oxidative and Nonoxidative Glucose Metabolism in Skeletal Muscle Skeletal Muscle Lipid Metabolism Kinetic Defects in Insulin Action Liver Hepatic Glucose Output Hepatic Glucose Uptake Mechanisms of Hepatic Insulin Resistance Adipose Tissue Adipokines Impact of Regional Fat Distribution and Adipocyte Size Inflammatory Pathway Activation and Insulin Resistance Other Contributors to the Insulin-Resistant Phenotype INSULIN-MEDIATED VERSUS NON– INSULIN-MEDIATED GLUCOSE UPTAKE PATHOPHYSIOLOGY OF FASTING VERSUS POSTPRANDIAL HYPERGLYCEMIA GASTROINTESTINAL INCRETINS AND INTESTINAL BYPASS SURGERY Incretins Intestinal Bypass Surgery Syndromes of Severe Insulin Resistance LIPOATROPHIC DIABETES DEFECTS IN INSULIN RECEPTOR SIGNALING Type B Insulin Resistance Type A Insulin Resistance Other Congenital Syndromes of Insulin Receptor Signaling DEFECTS RELATED TO THE INSULIN MOLECULE Anti-insulin Antibodies Increased Insulin Degradation Mutant Insulins Molecular Genetics of Type 2 Diabetes Mellitus CANDIDATE GENE APPROACH GENOME-WIDE ASSOCIATION STUDIES MATURITY-ONSET DIABETES OF THE YOUNG (MODY) Concluding Overview REFERENCES 16 LIPOPROTEIN METABOLISM AND THE TREATMENT OF LIPID DISORDERS Lipoprotein Metabolism LIPOPROTEINS Chylomicrons Very Low-Density Lipoproteins Low-Density Lipoproteins High-Density Lipoproteins METABOLISM OF LIPIDS AND LIPOPROTEINS Low-Density Lipoprotein Metabolism High-Density Lipoprotein Metabolism Disorders of Lipid Metabolism in Patients With Diabetes TYPE 1 DIABETES TYPE 2 DIABETES Genetic Basis of Lipid Disorders MONOGENIC LOW-DENSITY LIPOPROTEIN DISORDERS Familial Hypercholesterolemia Familial Defective Apolipoprotein B Autosomal Recessive Hypercholesterolemia PCSK9 Mutations MONOGENIC HIGH-DENSITY LIPOPROTEIN DISORDERS Tangier Disease Lecithin Cholesterol Acyltransferase Deficiency Apolipoprotein AI Mutations Diagnosis of Lipid Disorders Management/Treatment ASSESSING THE NEED TO TREAT PATIENTS WITH HYPERLIPIDEMIA DIETARY AND DRUG TREATMENT OF LIPID DISORDERS Diet/Lifestyle Therapies OUTCOME STUDIES OF PHARMACOLOGIC THERAPY OF HYPERLIPIDEMIA CHD Outcomes With HMG CoA Reductase Inhibitors (Statins) Lipid-Lowering Outcomes Trials With Agents Other Than Statins Fibrates and CHD Outcomes PRESCRIPTION DRUGS USED FOR LIPID LOWERING HMG-CoA Reductase Inhibitors (Statins) Niacin Cholesterol Absorption Inhibitors (Cholestyramine, Colestipol, Colesevelam, Ezetimibe) Fibrates (Gemfibrozil and Fenofibrate) REFERENCES 17 HYPERGLYCEMIA SECONDARY TO NONDIABETIC CONDITIONS AND THERAPIES Disorders of the Pancreas PANCREATECTOMY CHRONIC PANCREATITIS PANCREATIC CANCER HEMOCHROMATOSIS HEMOSIDEROSIS CYSTIC FIBROSIS Hyperglycemia Associated With Endocrinopathies ACROMEGALY GROWTH HORMONE TREATMENT CUSHING’S SYNDROME GLUCAGONOMA SYNDROME SOMATOSTATINOMA PHEOCHROMOCYTOMA Drugs That Can Cause Hyperglycemia DRUGS THAT AFFECT β CELL FUNCTION DRUGS THAT INHIBIT INCREASES IN β CELL CYTOSOLIC CA2+ DRUGS THAT CAUSE K+ DEPLETION MECHANISMS UNKNOWN DRUGS THAT CAUSE INSULIN RESISTANCE ORAL CONTRACEPTIVES AND SEX HORMONES NICOTINIC ACID PROTEASE INHIBITORS ATYPICAL ANTIPSYCHOTIC AGENTS REFERENCES 18 THE METABOLIC SYNDROME History Pathophysiology INSULIN RESISTANCE AND COMPENSATORY HYPERINSULINEMIA THE INSULIN SIGNALING CASCADE THE LIPID THEORY Excess Free Fatty Acids Altered Fatty Acid Metabolism: Malonyl Coenzyme A, Mitochondria, and Adenosine Monophosphate–Activated Protein Kinase Malonyl CoA Mitochondrial Dysfunction AMP-Activated Protein Kinase Adipose Tissue Overview Adiponectin Leptin Vascular Endothelial Cells Liver Pancreatic β Cell Molecular Mechanisms of Insulin Resistance and Cellular Dysfunction According to the Lipid Theory The Hypothalamus, Food Intake, and Insulin Resistance OTHER THEORIES OF INSULIN RESISTANCE Diagnosis Linkage of Metabolic Syndrome to Coronary Heart Disease and Type 2 Diabetes Linkage of the Metabolic Syndrome to Other Disorders NONALCOHOLIC FATTY LIVER DISEASE/NONALCOHOLIC STEATOHEPATITIS POLYCYSTIC OVARY SYNDROME CERTAIN CANCERS ALZHEIMER’S DISEASE CUSHING’S SYNDROME AND RELATED DISORDERS LIPODYSTROPHY HYPERALIMENTATION ADDITIONAL DISORDERS Treatment of the Metabolic Syndrome LIFESTYLE MODIFICATION (WEIGHT LOSS AND PHYSICAL ACTIVITY) DRUG THERAPY SPECIAL CONSIDERATIONS Children and Adolescents Low-Birth-Weight Infants The Thrifty Genotype and the Increasing Incidence of the Metabolic Syndrome Concluding Remarks Acknowledgments REFERENCES 19 TREATMENT OF TYPE 1 DIABETES MELLITUS IN ADULTS Goals of Management GLYCEMIC GOALS ACUTE COMPLICATIONS CHRONIC COMPLICATIONS QUALITY OF LIFE Team Approach to Management Monitoring GLYCEMIC CONTROL Acute Measurement of Glycemic Control Measurement of Chronic Glycemic Control KETONE TESTING COMPLICATION SURVEILLANCE Insulin Therapy PRINCIPLES OF INSULIN REPLACEMENT INSULIN PREPARATIONS Human Insulins Short-Acting Human Insulin: Regular Intermediate-Acting Human Insulin: NPH and Lente Long-Acting Human Insulin: Ultralente Insulin Analogues Rapid-Acting Analogues: Lispro, Aspart, and Glulisine Long-Acting Analogues: Glargine and Detemir INTENSIVE INSULIN THERAPY REGIMENS Multiple Daily Injection Regimen Continuous Subcutaneous Insulin Infusion Clinical Efficacy of CSII versus MDI Implementation of Intensive Insulin Therapy INSULIN DELIVERY Subcutaneous Insulin Delivery Alternative Routes of Insulin Delivery COMPLICATIONS OF INSULIN THERAPY ADJUSTMENT OF INSULIN THERAPY IN SPECIAL SITUATIONS Intercurrent Illness Surgery Nutrition Other Therapies for Type 1 Diabetes Future Perspectives REFERENCES 20 KETOACIDOSIS AND HYPEROSMOLAR COMA Ketoacidosis PATHOPHYSIOLOGY HORMONAL INITIATION OF KETOACIDOSIS HYPERGLYCEMIA KETOGENESIS CLINICAL FEATURES PRECIPITATING EVENTS SYMPTOMS AND SIGNS LABORATORY ABNORMALITIES TREATMENT Fluids Insulin Potassium Phosphate Bicarbonate Monitoring Therapy COMPLICATIONS Shock Cerebral Edema Infection Vascular Thrombosis Respiratory Distress Syndrome Nonketotic Hyperosmolar Coma PATHOPHYSIOLOGY CLINICAL FEATURES PRECIPITATING EVENTS SYMPTOMS AND SIGNS LABORATORY ABNORMALITIES TREATMENT Fluids Insulin Other Therapy COMPLICATIONS REFERENCES 21 HYPOGLYCEMIA AND HYPOGLYCEMIC SYNDROMES Hypoglycemia PHYSIOLOGY OF HYPOGLYCEMIA Physiologic Responses to Hypoglycemia NEUROHUMORAL REGULATION DURING HYPOGLYCEMIA Insulin Glucagon Epinephrine and Norepinephrine Cortisol and Growth Hormone SYNDROMES OF DISORDERED COUNTERREGULATORY RESPONSES DURING HYPOGLYCEMIA HYPOGLYCEMIA-ASSOCIATED NEUROENDOCRINE AND AUTONOMIC FAILURE STRATEGIES TO IMPROVE COUNTERREGULATORY RESPONSES DURING HYPOGLYCEMIA DRUG-INDUCED HYPOGLYCEMIA TREATMENT AND STRATEGIES TO REDUCE HYPOGLYCEMIA Clinical Strategies to Reduce Hypoglycemia Pancreas Transplantation and Hypoglycemia Hypoglycemia and Gastric Bypass Surgery NEONATAL HYPOGLYCEMIA Diagnostic Investigation of an Infant With Persistent Hypoglycemia MITOCHONDRIAL FATTY ACID OXIDATION DISORDERS GLYCOGEN STORAGE DISEASES SEPSIS, TRAUMA, AND BURNS CARDIAC FAILURE RENAL AND HEPATIC DISEASE: GENERAL CONSIDERATIONS Liver Disease Renal Disease GLUCAGON DEFICIENCY CATECHOLAMINE DEFICIENCY CORTISOL AND GROWTH HORMONE DEFICIENCY AUTOIMMUNE HYPOGLYCEMIA Anti-Insulin Receptor Antibodies ANTI-INSULIN ANTIBODY HYPOGLYCEMIA PREGNANCY EXERCISE FACTITIOUS HYPOGLYCEMIA NON–ISLET CELL TUMORS REACTIVE HYPOGLYCEMIA Alimentary Prediabetes Idiopathic Functional (Nonhypoglycemic) Insulin-Producing Islet Cell Tumors and Nesidioblastosis HISTORICAL PERSPECTIVE INCIDENCE DEMOGRAPHICS PATHOPHYSIOLOGY SYMPTOMS AND SIGNS PATHOLOGY DIAGNOSIS THE 72-HOUR FAST LOCALIZATION TREATMENT GENERAL APPROACH TO THE PATIENT Diagnosis TREATMENT AND STRATEGIES TO REDUCE HYPOGLYCEMIA REFERENCES 22 MANAGEMENT OF TYPE 2 DIABETES MELLITUS Glucose Treatment Guidelines Lifestyle Intervention EDUCATION OF PATIENTS NUTRITION EXERCISE SELF-MONITORING OF BLOOD GLUCOSE Pharmacotherapy of Type 2 Diabetes INSULIN SENSITIZERS WITH PREDOMINANT ACTION IN THE LIVER: BIGUANIDES INSULIN SENSITIZERS WITH PREDOMINANT ACTION IN PERIPHERAL INSULIN-SENSITIVE TISSUES: THIAZOLIDINEDIONES INSULIN SECRETAGOGUES SULFONYLUREAS REPAGLINIDE NATEGLINIDE CARBOHYDRATE ABSORPTION INHIBITORS: α-GLUCOSIDASE INHIBITORS INCRETIN-BASED THERAPIES EXENATIDE DIPEPTIDYL PEPTIDASE IV INHIBITORS PRAMLINTIDE INSULINS Basal Insulin Monotherapy Premixed Insulin Basal-Bolus Insulin Practical Aspects of Initiating and Progressively Managing Type 2 Diabetes STRATEGIES Minimal Cost Strategy Minimum Weight Gain Strategy Insulin Avoidance/β-Cell Preservation Strategy Minimal Insulin Resistance Strategy Minimal Effort Strategy Hypoglycemia Avoidance Strategy Postprandial Targeting Strategy GUIDELINES Future Directions Place of Glucose Management in the Treatment of Type 2 Diabetes REFERENCES 23 MANAGEMENT OF DIABETES MELLITUS IN CHILDREN Presentation of Diabetes Mellitus TYPE 1 DIABETES MELLITUS TYPE 2 DIABETES MELLITUS Distinguishing Between Type 1 and Type 2 Diabetes in Children Management of Diabetes Mellitus INITIAL MANAGEMENT OF NEWLY DIAGNOSED TYPE 1 DIABETES MELLITUS OUTPATIENT DIABETES CARE The Diabetes Team Initial Diabetes Education Continuing Diabetes Education and Long-Term Supervision of Diabetes Care Psychosocial Issues GOALS OF THERAPY INSULIN THERAPY Insulin Therapy in Young Children: Technical Considerations Intensified Insulin Therapy in Children Basal-Bolus Regimens and Continuous Subcutaneous Insulin Infusion MEDICAL NUTRITION THERAPY Carbohydrate Sucrose Fructose Carbohydrate Counting and Exchange Lists Protein Fat MNT Education and Formulation of the Meal Plan The Meal Plan Exercise Type 2 Diabetes Mellitus in Children and Adolescents TREATMENT Nonpharmacologic Therapy Weight Control and Physical Activity Pharmacologic Therapy Oral Agents Metformin. Insulin Secretagogues (Sulfonylureas and Meglitinides). Thiazolidinediones (TZDs). Alpha-Glucosidase Inhibitors. Insulin Therapy New Therapies for Type 2 Diabetes COMORBIDITIES Hypertension Hyperlipidemia Prevention of Type 2 Diabetes Mellitus MONOGENIC DIABETES MATERNALLY INHERITED DIABETES AND DEAFNESS NEONATAL DIABETES MELLITUS CYSTIC FIBROSIS–RELATED DIABETES Monitoring Diabetes Control SELF-MONITORING OF BLOOD GLUCOSE CONTINUOUS GLUCOSE MONITORING Urine Ketone Testing Blood Ketone Testing Glycated Hemoglobin or Hemoglobin A1c Hypoglycemia in Children With Diabetes Mellitus SYMPTOMS AND SIGNS OF HYPOGLYCEMIA IMPACT OF HYPOGLYCEMIA ON THE CHILD’S BRAIN FREQUENCY OF HYPOGLYCEMIA CAUSES OF HYPOGLYCEMIA IN DIABETES MELLITUS NOCTURNAL HYPOGLYCEMIA TREATMENT Diabetic Ketoacidosis MORBIDITY AND MORTALITY OF DKA IN CHILDREN Treatment for Cerebral Edema Screening for Other Autoimmune Diseases in Type 1 Diabetes Screening for Long-Term Complications Conclusion REFERENCES 24 PANCREATIC AND ISLET TRANSPLANTATION Pancreas Transplantation INDICATIONS AND TYPES OF PANCREAS TRANSPLANTS SURGICAL TECHNIQUES Exocrine Drainage Venous Drainage ANTIREJECTION THERAPY TRANSPLANT OUTCOMES AND IMPACT Survival Retinopathy Nephropathy Neuropathy Vascular Disease Quality of Life COSTS AND ORGAN AVAILABILITY Islet Transplantation ISLET ISOLATION AND TRANSPLANTATION RECENT PROGRESS RISKS AND BENEFITS Immunosuppression Islet Infusions Hepatic Steatosis Glycemic Control and Hypoglycemia COSTS AND ORGAN AVAILABILITY Frontiers in Transplantation IMMUNE MODULATION AND TOLERANCE IMMUNOBARRIER TECHNOLOGIES SOURCES OF INSULIN-PRODUCING TISSUE β-Cell Replication and Neogenesis Embryonic and iPS Cells Genetic Engineering Transdifferentiation Xenotransplantation ENHANCING ISLET ENGRAFTMENT, SURVIVAL, AND FUNCTION β-Cell Mass and Islet Cell Function Vascularization of Islet Grafts β-Cell Turnover in Islet Grafts Inhibiting Inflammation Role of HLA-Matching Making Stronger β Cells for Transplantation Conclusions REFERENCES 25 DIABETES CONTROL, LONG-TERM COMPLICATIONS, AND LARGE VESSEL DISEASE Animal Studies Human Studies OBSERVATIONAL STUDIES Retinopathy Nephropathy Neuropathy Cardiovascular Disease INTERVENTIONAL-CLINICAL TRIALS Type 1 Diabetes Diabetes Control and Complications Trial Design. Intensive Treatment and Metabolic Goals. Results. Adherence and Metabolic Results. Retinopathy Nephropathy Neuropathy Association of Glycemia and Microvascular Complications. Macrovascular. Other Outcomes and Adverse Events. Type 2 Diabetes United Kingdom Prospective Diabetes Study and Kumamoto Study United Kingdom Prospective Diabetes Study Results. Cardiovascular Disease. Pathogenetic Mechanisms. REFERENCES 26 DIABETIC EYE DISEASE Pathogenesis Natural History of Diabetic Retinopathy NONPROLIFERATIVE DIABETIC RETINOPATHY PROLIFERATIVE DIABETIC RETINOPATHY DIABETIC MACULAR EDEMA, ISCHEMIA, AND TRACTION Clinical Classification of Diabetic Retinopathy Severity NONPROLIFERATIVE DIABETIC RETINOPATHY LEVELS PROLIFERATIVE DIABETIC RETINOPATHY LEVELS Epidemiology PREVALENCE AND INCIDENCE OF RETINOPATHY RISK FACTORS FOR DIABETIC RETINOPATHY Gender, Race, Genetics, and Age DIABETES-RELATED RISK FACTORS Duration of Diabetes Glycemic Status OTHER RISK FACTORS Blood Pressure Serum Lipids Proteinuria and Renal Disease Cigarette Smoking and Alcohol Consumption Pregnancy Comorbidity Other Ocular Disease Associated With Diabetes CATARACT GLAUCOMA VISUAL IMPAIRMENT Detection Management MEDICAL OPHTHALMOLOGIC SURGICAL REHABILITATION Novel Therapies REFERENCES 27 DIABETES MELLITUS: Neuropathy History Definitions and Classification Epidemiology Clinical Features FOCAL AND MULTIFOCAL NEUROPATHIES CRANIAL MONONEUROPATHIES ISOLATED AND MULTIPLE MONONEUROPATHIES TRUNCAL NEUROPATHIES PROXIMAL MOTOR NEUROPATHY CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY SYMMETRICAL NEUROPATHIES Autonomic Neuropathy Cardiovascular Gastrointestinal Erectile Dysfunction Bladder Dysfunction Sweating Abnormalities Distal Sensory Neuropathy Small-Fiber Neuropathy Natural History of Chronic Distal Sensory Neuropathy Measures of Neuropathy CLINICAL SYMPTOMS CLINICAL SIGNS QUANTITATIVE SENSORY TESTING Semmes-Weinstein Monofilaments Vibration Perception Thermal and Cooling Thresholds Computer-Assisted Sensory Examination AUTONOMIC FUNCTION TESTING ELECTROPHYSIOLOGY Pathogenesis HYPERGLYCEMIA POLYOL PATHWAY GLYCATION OXIDATIVE STRESS Poly(ADP-Ribose) Polymerase-1 (PARP) C-PEPTIDE VASCULAR ENDOTHELIAL GROWTH FACTOR NEUROTROPHINS MITOGEN-ACTIVATED PROTEIN KINASE Pathology MYELINATED FIBERS UNMYELINATED FIBERS STRUCTURE-FUNCTION RELATIONSHIP AUTONOMIC TISSUE NERVE VASCULATURE Skin Biopsy Corneal Confocal Microscopy Treatment SENSORY NEUROPATHY Current Treatments Glycemic Control Tricyclic Antidepressants Serotonin and Noradrenaline Reuptake Inhibitors Anticonvulsants Other Agents Potential Future Therapies Alpha-Lipoic Acid Other Agents AUTONOMIC NEUROPATHY Erectile Dysfunction Sweating Disorders Others The Neuropathic Foot NEUROPATHIC FOOT ULCERATION CHARCOT’S NEUROARTHROPATHY REFERENCES 28 DIABETIC NEPHROPATHY Natural History of Diabetic Nephropathy TYPE 1 DIABETES TYPE 2 DIABETES Kidney Structure in Diabetes STRUCTURAL-FUNCTIONAL RELATIONSHIPS IN DIABETIC NEPHROPATHY MICROALBUMINURIA AND RENAL STRUCTURE CONTRASTS IN NEPHROPATHY LESIONS BETWEEN TYPE 1 AND TYPE 2 DIABETES STRUCTURAL-FUNCTIONAL RELATIONSHIPS IN TYPE 2 DIABETES OTHER RENAL DISORDERS IN DIABETIC PATIENTS DIABETIC NEPHROPATHY LESIONS ARE REVERSIBLE Genetic Predisposition to Diabetic Nephropathy FAMILIAL STUDIES OF BLOOD PRESSURE, CARDIOVASCULAR DISEASE, AND DIABETIC NEPHROPATHY SODIUM/LITHIUM AND SODIUM/HYDROGEN COUNTERTRANSPORT DIABETIC NEPHROPATHY GENES Pathogenesis of Diabetic Nephropathy GLYCEMIC CONTROL HEMODYNAMIC MECHANISMS Pathophysiology of Diabetic Nephropathy GROWTH FACTORS Transforming Growth Factor-β Growth Hormone and Insulin-Like Growth Factor Vascular Endothelial Growth Factor Epidermal Growth Factor PROTEIN KINASE C CYTOKINES Plasma Prorenin Levels and Diabetic Complications Angiotensin II Bradykinin Endothelin OXIDATIVE STRESS GLYCOSYLATION PRODUCTS INCREASED ACTIVITY OF ALDOSE REDUCTASE THE STENO HYPOTHESIS Treatment BLOOD GLUCOSE CONTROL Primary Prevention Secondary Prevention Tertiary Prevention BLOOD PRESSURE CONTROL Primary Prevention Secondary Prevention Tertiary Prevention LIPID LOWERING DIETARY PROTEIN RESTRICTION REFERENCES 29 DIABETIC FOOT AND VASCULAR COMPLICATIONS Pathophysiology NEUROPATHY INFECTION ISCHEMIA Presentation and Diagnosis ULCERS INFECTION/OSTEOMYELITIS PERIPHERAL VASCULAR DISEASE Medical Management PREVENTION ANTIBIOTICS Wound Care/Debridement Surgical Management DRAINAGE PROCEDURES LOWER EXTREMITY ARTERIAL RECONSTRUCTION ENDOVASCULAR PROCEDURES AMPUTATIONS Future Trends REFERENCES 30 DIABETES MELLITUS AND PREGNANCY History Epidemiology Pathogenesis METABOLIC EFFECTS OF PREGNANCY Utilization of Maternal Fuels by the Conceptus Circulating Concentrations of Nutrient Fuels In Normal Pregnancy In Gestational Diabetes Mellitus In Women With Preexisting Diabetes Mellitus MATERNAL METABOLISM AND PREGNANCY OUTCOME Congenital Malformations and Early Fetal Loss Disturbances of Fetal Growth Anthropometric and Metabolic Development in Childhood Diagnosis and Classification CLASSIFICATION Gestational Diabetes Mellitus Preexisting Diabetes Retinopathy Nephropathy Neuropathy Cardiovascular Disease DIAGNOSIS OF GESTATIONAL DIABETES MELLITUS Detection Diagnosis HETEROGENEITY OF GESTATIONAL DIABETES MELLITUS Phenotypic Heterogeneity Genotypic Heterogeneity Treatment of Diabetes Mellitus Diagnosed Before Pregnancy PRECONCEPTION PLANNING Diet Insulin Short-Acting Insulins Long-Acting Insulins Exercise MONITORING CONTROL OF DIABETES Blood Glucose Ketones Hemoglobin A1c OBSTETRIC SURVEILLANCE DELIVERY AND PUERPERIUM Treatment of Gestational Diabetes Mellitus RATIONALE Morbidities Congenital Malformations Fetal Hyperinsulinism METABOLIC SURVEILLANCE METABOLIC MANAGEMENT Goals Lifestyle Modification Nutritional T