Diabetes Syndrome X

L Schmeltz and B Metzger, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

© 2007 Elsevier Ltd. All Rights Reserved.

6.19.1 Introduction 418

6.19.1.1 Epidemics of Obesity, Diabetes, and the Metabolic Syndrome 419

6.19.1.2 Impact of High Prevalence of Diabetes, Obesity, and the Metabolic

Syndrome 420

6.19.1.2.1 Cardiovascular disease 420

6.19.1.2.2 Diabetic complications - retinopathy nephropathy and neuropathy 420

6.19.1.3 Financial Impact on the Health Care System 420

6.19.1.4 Reasons for the High Prevalence of Diabetes and Obesity 421

6.19.1.5 Diabetes Prevention Trials 421

6.19.2 Classification of Diabetes Mellitus and the Metabolic Syndrome 421

6.19.2.1 Type 1 Diabetes Mellitus 421

6.19.2.1.1 Immune-mediated diabetes mellitus (Type 1A) 421

6.19.2.1.2 Idiopathic diabetes mellitus (Type 1B) 422

6.19.2.2 Type 2 Diabetes Mellitus 423

6.19.2.3 Other Specific Types of Diabetes 423

6.19.2.3.1 Genetic b-cell defects 423

6.19.2.3.2 Genetic defects in insulin action 423

6.19.2.3.3 Diseases of the exocrine pancreas 423

6.19.2.3.4 Endocrinopathies 423

6.19.2.3.5 Drug or chemical-induced diabetes 423

6.19.2.3.6 Infections 424

6.19.2.3.7 Uncommon forms of immune-mediated diabetes 424

6.19.2.3.8 Genetic syndromes sometimes associated with diabetes 424

6.19.2.4 Gestational Diabetes Mellitus 424

6.19.2.5 Diagnostic Criteria for Diabetes 424

6.19.2.6 Diagnostic Criteria for the Metabolic Syndrome 424

6.19.3 Disease Basis 426

6.19.3.1 Normal Glucose Homeostasis 426

6.19.3.1.1 Insulin biosynthesis 426

6.19.3.1.2 Insulin secretion 427

6.19.3.1.3 Insulin action 429

6.19.3.2 Pathogenesis of Type 1 Diabetes Mellitus 430

6.19.3.2.1 Genetic predisposition 430

6.19.3.2.2 Presence of autoimmunity 430

6.19.3.2.3 Environmental factors 430

6.19.3.3 Pathogenesis of Type 2 Diabetes Mellitus 431

6.19.3.3.1 Abnormalities in glucose homeostasis 431

6.19.3.3.2 Genetic predisposition 431

6.19.3.3.3 Metabolic abnormalities in type 2 diabetes 432

6.19.4 Animal Models of Diabetes 433

6.19.4.1 Animal Models of Type 1 Diabetes 433

6.19.4.1.1 Animals with b-cell destroyed by chemical cytotoxins 433

6.19.4.1.2 Animals with autoimmune diabetes 434

6.19.4.2 Animal Models of Type 2 Diabetes 435 6.19.4.2.1 Genetically altered animals 435

6.19.4.2.2 Insulin-resistant mutant rodents with diabetes and obesity 435

6.19.4.2.3 Rodents with spontaneous diabetes 435

6.19.4.2.4 Rodents with overnutrition-evoked diabetes and obesity 435

6.19.5 Clinical Trial Issues 436

6.19.6 Current Treatment 436

6.19.6.1 Benefits of Glycemic Control 436

6.19.6.2 Goals of Diabetic Management 437

6.19.6.3 Lifestyle Modifications 437

6.19.6.4 Overview and Summary of Oral Hypoglycemic Agents 438

6.19.6.4.1 Sulfonylureas 438

6.19.6.4.2 Glitinides (non-sulfonylurea secretagogues) 443

6.19.6.4.3 Biguanides 444

6.19.6.4.4 a-glucosidase inhibitors 445

6.19.6.4.5 Thiazolidinediones 446

6.19.6.5 Insulin 448

6.19.6.5.1 Sources of insulin 449

6.19.6.5.2 Pharmacodynamics and pharmacokinetics of insulin 450

6.19.6.5.3 Types of insulin 450

6.19.6.5.4 General principles of insulin therapy 451

6.19.6.5.5 Side effects of insulin 452

6.19.6.6 Amylin Analogs (Pramlintide) 452

6.19.6.7 Glucagon-Like Peptide-1 (GLP-1) Agonists (Exenatide) 452

6.19.7 Unmet Medical Needs 453

6.19.7.1 Limitations of Existing Therapies 453

6.19.7.1.1 Obesity 453

6.19.7.1.2 Type 2 diabetes mellitus 453

6.19.7.1.3 Diabetic complications 453

6.19.7.2 Arresting Loss of p-Cells 453

6.19.8 New Areas of Research 453

6.19.8.1 Incretin Augmentation of Insulin Secretion 453

6.19.8.2 Other Potential Therapeutic Targets 454

6.19.8.3 Alternative Methods of Insulin Delivery 454

6.19.8.4 The Artificial Pancreas 455

6.19.8.5 p-Cell Replacement Therapy 455 References 455

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