International Textbook of Diabetes Mellitus (eBook)
John Wiley & Sons (Verlag)
9781118387689 (ISBN)
The International Textbook of Diabetes Mellitus has been a successful, well-respected medical textbook for almost 20 years, over 3 editions. Encyclopaedic and international in scope, the textbook covers all aspects of diabetes ensuring a truly multidisciplinary and global approach. Sections covered include epidemiology, diagnosis, pathogenesis, management and complications of diabetes and public health issues worldwide. It incorporates a vast amount of new data regarding the scientific understanding and clinical management of this disease, with each new edition always reflecting the substantial advances in the field. Whereas other diabetes textbooks are primarily clinical with less focus on the basic science behind diabetes, ITDM's primary philosophy has always been to comprehensively cover the basic science of metabolism, linking this closely to the pathophysiology and clinical aspects of the disease.
Edited by four world-famous diabetes specialists, the book is divided into 13 sections, each section edited by a section editor of major international prominence. As well as covering all aspects of diabetes, from epidemiology and pathophysiology to the management of the condition and the complications that arise, this fourth edition also includes two new sections on NAFLD, NASH and non-traditional associations with diabetes, and clinical trial evidence in diabetes.
This fourth edition of an internationally recognised textbook will once again provide all those involved in diabetes research and development, as well as diabetes specialists with the most comprehensive scientific reference book on diabetes available.
Ralph DeFronzo, Professor of Medicine and Chief of the Diabetes Division,
The University of Texas Health Science Centre at San Antonio, and Deputy Director of Texas Diabetic Institute, San Antonio, Texas, USA.
Ele Ferrannini, Professor of Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy.
K. George M. M Alberti, Visiting Professor, King's College, London, UK; Senior Research Investigator, Imperial College, London, UK; Emeritus Professor of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne.
Paul Zimmet, Director Emeritus, Victor Smorgon Diabetes Centre, Baker IDI Heart and Diabetes Institute; Adjunct Professor, Monash University; Honorary President, International Diabetes Federation; Chair, Programme Committee, World Diabetes Congress 2013, Melbourne, VIC, Australia.
Ralph DeFronzo, Professor of Medicine and Chief of the Diabetes Division, The University of Texas Health Science Centre at San Antonio, and Deputy Director of Texas Diabetic Institute, San Antonio, Texas, USA. Ele Ferrannini, Professor of Internal Medicine, Department of Clinical and Experimental Medicine, University of Pisa School of Medicine, Pisa, Italy. K. George M. M Alberti, Visiting Professor, King's College, London, UK; Senior Research Investigator, Imperial College, London, UK; Emeritus Professor of Medicine, University of Newcastle upon Tyne, Newcastle upon Tyne. Paul Zimmet, Director Emeritus, Victor Smorgon Diabetes Centre, Baker IDI Heart and Diabetes Institute; Adjunct Professor, Monash University; Honorary President, International Diabetes Federation; Chair, Programme Committee, World Diabetes Congress 2013, Melbourne, VIC, Australia.
Cover???????????????????????? 1
Contents?????????????????????????????? 9
Contributors?????????????????????????????????????? 13
Preface???????????????????????????? 25
Section I Epidemiology?????????????????????????????????????????????????????????? 27
Chapter 1 Classification of diabetes mellitus and other categories of glucose intolerance???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 29
Introduction?????????????????????????????????????? 29
Historical perspective and current classifications?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 29
Previous classifications?????????????????????????????????????????????????????????????? 29
Current classification?????????????????????????????????????????????????????????? 30
Type 1 process?????????????????????????????????????????? 31
Type 2 process?????????????????????????????????????????? 32
Other specific types?????????????????????????????????????????????????????? 33
Classification of genetic disorders???????????????????????????????????????????????????????????????????????????????????? 33
Genetic defects of ?-cell function 33
Genetic defects in insulin action???????????????????????????????????????????????????????????????????????????????? 33
Diseases of the exocrine pancreas???????????????????????????????????????????????????????????????????????????????? 34
Endocrinopathies?????????????????????????????????????????????? 34
Drug-or chemical-induced diabetes???????????????????????????????????????????????????????????????????????????????? 34
Infections?????????????????????????????????? 35
Uncommon but specific forms of immune-mediated diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 35
Other genetic syndromes associated with diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 35
Diabetes in children and youth?????????????????????????????????????????????????????????????????????????? 36
Diagnosis of diabetes using HbA1c???????????????????????????????????????????????????????????????????????????????? 37
Diagnosis of gestational diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????? 39
Impaired glucose regulation (impaired glucose tolerance and impaired fasting glycemia)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 39
Normoglycemia???????????????????????????????????????? 40
Summary???????????????????????????? 40
References?????????????????????????????????? 40
Chapter 2 Epidemiology and risk factors for type 1 diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 43
Introduction?????????????????????????????????????? 43
Prevalence and incidence?????????????????????????????????????????????????????????????? 43
Geographic location???????????????????????????????????????????????????? 44
Race and ethnicity?????????????????????????????????????????????????? 44
Age and gender?????????????????????????????????????????? 44
Increasing incidence and seasonality?????????????????????????????????????????????????????????????????????????????????????? 44
?-Cell autoimmunity and risk factors 44
Family history of T1DM?????????????????????????????????????????????????????????? 45
HLA class II susceptibility genotypes???????????????????????????????????????????????????????????????????????????????????????? 45
Other genetic factors associated with type 1 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 46
Islet autoantibodies?????????????????????????????????????????????????????? 46
Autoantibody screening among relatives?????????????????????????????????????????????????????????????????????????????????????????? 46
Autoantibody screening in the general population?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 47
Measurement of autoantibodies in adult-onset diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 47
Measurement of ?-cell function 47
Environmental factors???????????????????????????????????????????????????????? 48
Gene-environment interaction in clinical type 1 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 49
Established type 1 diabetes???????????????????????????????????????????????????????????????????? 50
Clinical onset?????????????????????????????????????????? 50
Remission (honeymoon period)?????????????????????????????????????????????????????????????????????? 50
Acute complications???????????????????????????????????????????????????? 50
Morbidity and mortality???????????????????????????????????????????????????????????? 50
References?????????????????????????????????? 50
Chapter 3 Epidemiology and geography of type 2 diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 55
Age- and sex-specific prevalence of type 2 diabetes in different ethnic groups?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 55
Diagnostic criteria for diabetes?????????????????????????????????????????????????????????????????????????????? 55
Conversion factors for glucose concentrations???????????????????????????????????????????????????????????????????????????????????????????????????????? 55
Age- and sex-specific plasma glucose concentration?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 56
Age- and sex-specific prevalence of diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????? 56
Previously undiagnosed diabetes???????????????????????????????????????????????????????????????????????????? 61
Prevalence of impaired glucose tolerance and impaired fasting glycemia in different ethnic groups???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 61
Europe?????????????????????????? 61
Asia?????????????????????? 61
Sex differences in prevalence of diabetes, IGT, and IFG???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 62
The ratio of IGT to diabetes?????????????????????????????????????????????????????????????????????? 62
Secular trends in prevalence of type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????? 62
Type 2 diabetes in children???????????????????????????????????????????????????????????????????? 65
Prevalence and incidence?????????????????????????????????????????????????????????????? 65
Characteristics and diagnosis???????????????????????????????????????????????????????????????????????? 67
Risk factors?????????????????????????????????????? 67
Complications and comorbid conditions???????????????????????????????????????????????????????????????????????????????????????? 68
Modifiable risk factors for type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????? 68
Obesity???????????????????????????? 68
Physical activity???????????????????????????????????????????????? 68
Dietary factors???????????????????????????????????????????? 69
Nontraditional modifiable risk factors for type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 70
Inflammation?????????????????????????????????????? 70
Smoking???????????????????????????? 70
References?????????????????????????????????? 71
Section II Physiology of pancreatic function?????????????????????????????????????????????????????????????????????????????????????????????????????? 79
Chapter 4 Development and maintenance of the islet ? cell 81
Introduction?????????????????????????????????????? 81
Pancreas development?????????????????????????????????????????????????????? 81
Induction of the definitive endoderm?????????????????????????????????????????????????????????????????????????????????????? 82
Patterning of the gut tube into organ domains???????????????????????????????????????????????????????????????????????????????????????????????????????? 83
Induction of the dorsal and ventral pancreatic buds???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 84
Pancreatic growth and epithelial branching morphogenesis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 84
Cytodifferentiation in the developing pancreas?????????????????????????????????????????????????????????????????????????????????????????????????????????? 85
Tip versus trunk domains?????????????????????????????????????????????????????????????? 85
Endocrine versus exocrine cell fate decision?????????????????????????????????????????????????????????????????????????????????????????????????????? 86
The endocrine progenitor cell???????????????????????????????????????????????????????????????????????? 86
What makes a ? cell? 87
Translating pancreas development into cell-based therapies for diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 88
Postnatal ?-cell growth and maintenance 88
Neonatal ?-cell turnover 88
?-Cell growth with aging 89
Compensatory ?-cell growth: adaptation to demand 89
Origins of new ? cells in the adult: neogenesis, transdifferentiation, and replication 90
Regulators of ?-cell growth: growth factors and cell cycle regulators 90
Conclusions and areas of future study???????????????????????????????????????????????????????????????????????????????????????? 91
References?????????????????????????????????? 92
Chapter 5 Pancreatic morphology in normal and diabetic states???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 95
Pancreatic anatomy and morphology???????????????????????????????????????????????????????????????????????????????? 95
Islet composition and morphology?????????????????????????????????????????????????????????????????????????????? 96
Islet ? cell regenerative potential 99
Disturbances in pancreas/islet morphology in diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 99
Type 1 diabetes???????????????????????????????????????????? 99
Type 2 diabetes???????????????????????????????????????????? 100
Influence of exocrine pancreas abnormalities on islet morphology and function???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 100
Mechanisms of ?-cell loss in type 2 diabetes 100
Chronically elevated glucose and/or free fatty acids?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 101
Islet amyloid???????????????????????????????????????? 101
Islet inflammation?????????????????????????????????????????????????? 102
Summary and future directions???????????????????????????????????????????????????????????????????????? 102
Acknowledgments???????????????????????????????????????????? 102
References?????????????????????????????????? 102
Chapter 6 Insulin gene expression and biosynthesis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 108
Introduction?????????????????????????????????????? 108
Insulin gene expression???????????????????????????????????????????????????????????? 108
Structure of the insulin gene???????????????????????????????????????????????????????????????????????? 108
Physiologic regulation of insulin gene expression???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 110
Dysregulation of the insulin gene???????????????????????????????????????????????????????????????????????????????? 111
Insulin biosynthesis?????????????????????????????????????????????????????? 113
Introduction?????????????????????????????????????? 113
Structure of the insulin molecule???????????????????????????????????????????????????????????????????????????????? 113
Proinsulin biosynthesis: translation and translocation?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 113
Proinsulin biosynthesis: effectors and stimulus-response coupling mechanisms?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 113
Proinsulin biosynthesis: translational control mechanism?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 114
Transport of proinsulin from the ER to Golgi apparatus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 115
Proteolytic enzymes of proinsulin conversion?????????????????????????????????????????????????????????????????????????????????????????????????????? 115
Regulation of proinsulin conversion???????????????????????????????????????????????????????????????????????????????????? 117
The mature ?-granule storage pool 118
Dysfunctional proinsulin processing in diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????? 118
Acknowledgments???????????????????????????????????????????? 118
References?????????????????????????????????? 118
Chapter 7 ?-Cell biology of insulin secretion 122
Introduction?????????????????????????????????????? 122
?-Cell metabolism 122
Glucose sensing glycolysis?????????????????????????????????????????????????????????????????? 122
Mitochondrial metabolism?????????????????????????????????????????????????????????????? 123
ATP generation in the respiratory chain???????????????????????????????????????????????????????????????????????????????????????????? 123
NADH shuttles???????????????????????????????????????? 123
Lipid metabolism?????????????????????????????????????????????? 124
Metabolism-secretion coupling???????????????????????????????????????????????????????????????????????? 125
Triggering pathway?????????????????????????????????????????????????? 125
Metabolic amplifying pathway?????????????????????????????????????????????????????????????????????? 125
Dynamics of insulin secretion???????????????????????????????????????????????????????????????????????? 125
Biphasic insulin secretion?????????????????????????????????????????????????????????????????? 125
Exocytotic machinery?????????????????????????????????????????????????????? 126
Modulation of insulin secretion by various intracellular signals?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 127
Gs-protein-coupled receptor???????????????????????????????????????????????????????????????????? 127
Gq-protein-coupled receptor???????????????????????????????????????????????????????????????????? 128
Gi/o-protein-coupled receptors?????????????????????????????????????????????????????????????????????????? 128
Autocrine effect of insulin on insulin secretion?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 128
Pathophysiology of pancreatic ? cells 129
?-Cell mass and function in type 2 diabetes 129
Abnormalities in the dynamics of insulin secretion?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 129
Conclusions???????????????????????????????????? 129
References?????????????????????????????????? 129
Chapter 8 Normal ?-cell function 134
Introduction?????????????????????????????????????? 134
Methods for the assessment of insulin secretion???????????????????????????????????????????????????????????????????????????????????????????????????????????? 135
Relationship between plasma insulin concentration and insulin secretion???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 135
Insulin secretion indices???????????????????????????????????????????????????????????????? 136
Mathematical models???????????????????????????????????????????????????? 136
?-Cell response to intravenous glucose 136
The hyperglycemic clamp???????????????????????????????????????????????????????????? 136
The intravenous glucose tolerance test?????????????????????????????????????????????????????????????????????????????????????????? 137
?-Cell response to oral glucose 137
The incretin effect???????????????????????????????????????????????????? 138
Insulin secretion mechanisms during an oral glucose load?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 139
Insulin secretion in normal living conditions???????????????????????????????????????????????????????????????????????????????????????????????????????? 139
?-Cell response to nonglucose secretagogues 139
Proteins and amino acids?????????????????????????????????????????????????????????????? 139
Lipids and free fatty acids???????????????????????????????????????????????????????????????????? 140
Slow ?-cell response modes and adaptation mechanisms 140
Glucose-induced potentiation of insulin secretion???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 140
Adaptation to insulin sensitivity???????????????????????????????????????????????????????????????????????????????? 141
?-Cell response to hormones and the nervous system 141
Pulsatile secretion of insulin?????????????????????????????????????????????????????????????????????????? 142
?-Cell mass and function 142
Insulin clearance???????????????????????????????????????????????? 143
Insulin clearance in fasting conditions???????????????????????????????????????????????????????????????????????????????????????????? 143
Insulin clearance in the fed state?????????????????????????????????????????????????????????????????????????????????? 144
?-Cell function and glucose homeostasis 145
Conclusions???????????????????????????????????? 145
References?????????????????????????????????? 145
Chapter 9 Neuropeptides and islet hormone secretion???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 151
Introduction?????????????????????????????????????? 151
Islet parasympathetic nerves?????????????????????????????????????????????????????????????????????? 151
Gastrin-releasing polypeptide (GRP)???????????????????????????????????????????????????????????????????????????????????? 152
Vasoactive intestinal polypeptide (VIP)???????????????????????????????????????????????????????????????????????????????????????????? 153
Pituitary adenylate cyclase-activating polypeptide (PACAP)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 153
Parasympathetic effects and mediation???????????????????????????????????????????????????????????????????????????????????????? 154
Islet sympathetic nerves?????????????????????????????????????????????????????????????? 154
Galanin???????????????????????????? 155
Neuropeptide Y (NPY)?????????????????????????????????????????????????????? 156
Sympathetic effects and mediation???????????????????????????????????????????????????????????????????????????????? 156
Islet sensory neuropeptides???????????????????????????????????????????????????????????????????? 156
Calcitonin gene-related polypeptide (CGRP)?????????????????????????????????????????????????????????????????????????????????????????????????? 157
Substance P???????????????????????????????????? 157
Summary of present-day knowledge?????????????????????????????????????????????????????????????????????????????? 157
Questions for future research???????????????????????????????????????????????????????????????????????? 158
What are the physiologic roles of the islet autonomic nerves????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 158
What is the contribution of neuropeptides??????????????????????????????????????????????????????????????????????????????????????????????????? 158
Do the autonomic nerves contribute to development of type 2 diabetes????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 158
Is islet neurotransmission a therapeutic target for type 2 diabetes??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 158
Acknowledgments???????????????????????????????????????????? 159
References?????????????????????????????????? 159
Chapter 10 Biosynthesis, secretion, and action of glucagon?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 162
Introduction?????????????????????????????????????? 162
Amino acid composition, extraction, synthesis, and biosynthesis???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 162
Physiologic effects of glucagon???????????????????????????????????????????????????????????????????????????? 164
Other effects of glucagon???????????????????????????????????????????????????????????????? 165
Control of glucagon release???????????????????????????????????????????????????????????????????? 165
Some aspects of glucagon physiology and pathophysiology???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 166
Glucagon as a counterregulatory hormone???????????????????????????????????????????????????????????????????????????????????????????? 166
Glucagon in exercise?????????????????????????????????????????????????????? 167
Glucagon in stress?????????????????????????????????????????????????? 167
Glucagon in starvation?????????????????????????????????????????????????????????? 167
Glucagon and adaptation to extrauterine life?????????????????????????????????????????????????????????????????????????????????????????????????????? 167
Glucagon and diabetes???????????????????????????????????????????????????????? 167
The glucagonoma syndrome?????????????????????????????????????????????????????????????? 168
References?????????????????????????????????? 168
Chapter 11 Incretin physiology in health and disease?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 171
The incretin effect in health???????????????????????????????????????????????????????????????????????? 171
Secretion of incretin hormones?????????????????????????????????????????????????????????????????????????? 174
Degradation and elimination of incretin hormones?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 175
Physiologic effects of incretin hormones?????????????????????????????????????????????????????????????????????????????????????????????? 175
GLP-1???????????????????????? 175
GIP???????????????????? 178
Other gastrointestinal hormones with potential incretin function?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 179
Cholecystokinin (CCK)???????????????????????????????????????????????????????? 179
Secretin?????????????????????????????? 179
Gastrin???????????????????????????? 179
The incretin effect in patients with diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????? 179
Potential mechanisms of incretin dysfunction in type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 180
Summary and conclusions???????????????????????????????????????????????????????????? 182
References?????????????????????????????????? 182
Section III Normal physiology of insulin action???????????????????????????????????????????????????????????????????????????????????????????????????????????? 187
Chapter 12 Mechanisms of insulin signal transduction?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 189
Introduction?????????????????????????????????????? 189
Fuel homeostasis?????????????????????????????????????????????? 189
Changing perspectives of insulin action???????????????????????????????????????????????????????????????????????????????????????????? 189
Insulin resistance?????????????????????????????????????????????????? 190
Insulin receptors???????????????????????????????????????????????? 190
Ligand binding?????????????????????????????????????????? 190
Tyrosine kinase activity?????????????????????????????????????????????????????????????? 190
Insulin-like growth factors???????????????????????????????????????????????????????????????????? 191
Hybrid receptors?????????????????????????????????????????????? 192
Insulin receptor mutations?????????????????????????????????????????????????????????????????? 192
Insulin receptor substrate molecules?????????????????????????????????????????????????????????????????????????????????????? 192
Receptor substrate/docking proteins???????????????????????????????????????????????????????????????????????????????????? 192
Insulin receptor substrate (IRS) family of docking proteins???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 193
Other receptor substrates???????????????????????????????????????????????????????????????? 193
Proteins that dock with receptor substrate molecules?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 194
Ras/MAP kinase pathway: mitogenic signaling???????????????????????????????????????????????????????????????????????????????????????????????????? 194
PI-3 kinase pathways: regulation of metabolism and gene expression?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 195
Phosphatidylinositide-3 kinase?????????????????????????????????????????????????????????????????????????? 195
Degradation of the PI-3 kinase signal???????????????????????????????????????????????????????????????????????????????????????? 198
PI-3 kinase-independent pathways for stimulation of glucose transport???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 198
The CAP/Cbl/TC10 pathway?????????????????????????????????????????????????????????????? 198
Muscle contraction?????????????????????????????????????????????????? 200
AS160???????????????????????? 200
The glucose transport effector system???????????????????????????????????????????????????????????????????????????????????????? 201
GLUT4 vesicle translocation and trafficking???????????????????????????????????????????????????????????????????????????????????????????????????? 201
The cellular cytoskeleton???????????????????????????????????????????????????????????????? 204
Insulin resistance in humans: abnormalities in insulin signaling and in the glucose transport effector system???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 205
Abnormalities in insulin signaling?????????????????????????????????????????????????????????????????????????????????? 205
The glucose transport system?????????????????????????????????????????????????????????????????????? 206
Modulation of insulin action?????????????????????????????????????????????????????????????????????? 206
Serine-threonine phosphorylation of the insulin receptor and IRS proteins???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 206
Protein phosphotyrosine phosphatases?????????????????????????????????????????????????????????????????????????????????????? 208
Other mechanisms?????????????????????????????????????????????? 208
Regulation of gene transcription?????????????????????????????????????????????????????????????????????????????? 208
Insulin response elements???????????????????????????????????????????????????????????????? 208
TPA and serum response elements???????????????????????????????????????????????????????????????????????????? 209
Forkhead transcription factors?????????????????????????????????????????????????????????????????????????? 209
Sterol response element binding protein-1c (SREBP-1c)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 210
Signal transducer and activator of transcription 5B (STAT5B)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 210
Acknowledgments???????????????????????????????????????????? 210
References?????????????????????????????????? 210
Chapter 13 Regulation of glucose metabolism in liver?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 219
Introduction?????????????????????????????????????? 219
Hepatic glucose production?????????????????????????????????????????????????????????????????? 220
Overview?????????????????????????????? 220
Glycogenolysis?????????????????????????????????????????? 221
Gluconeogenesis???????????????????????????????????????????? 222
Hepatic glucose disposal?????????????????????????????????????????????????????????????? 230
Overview?????????????????????????????? 230
Glucose uptake?????????????????????????????????????????? 230
Glucokinase???????????????????????????????????? 230
Glycogen synthesis?????????????????????????????????????????????????? 231
Glycolysis?????????????????????????????????? 232
Pyruvate dehydrogenase and lipogenesis?????????????????????????????????????????????????????????????????????????????????????????? 233
Summary???????????????????????????? 234
References?????????????????????????????????? 234
Chapter 14 Insulin actions in vivo: glucose metabolism?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 237
Introduction?????????????????????????????????????? 237
Glucose???????????????????????????? 237
Glucose metabolism?????????????????????????????????????????????????? 239
Introduction?????????????????????????????????????? 239
Methods???????????????????????????? 240
The basal state???????????????????????????????????????????? 241
Glucose production?????????????????????????????????????????????????? 241
Glucose disposal?????????????????????????????????????????????? 244
Glucose cycles?????????????????????????????????????????? 245
The fed state???????????????????????????????????????? 246
Introduction?????????????????????????????????????? 246
Methods???????????????????????????? 246
Intravenous glucose???????????????????????????????????????????????????? 247
Cellular, biochemical, and molecular mechanisms of insulin action (see also Chapter 12)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 251
Glucose transport???????????????????????????????????????????????? 252
Glucose phosphorylation (Table )?????????????????????????????????????????????????????????????????????????????? 252
Glycogen synthesis (Figure )?????????????????????????????????????????????????????????????????????? 253
Glycolysis/glucose oxidation?????????????????????????????????????????????????????????????????????? 253
Oral glucose?????????????????????????????????????? 253
References?????????????????????????????????? 255
Chapter 15 Measuring insulin action in vivo???????????????????????????????????????????????????????????????????????????????????????????????????? 260
Historical perspective?????????????????????????????????????????????????????????? 260
Opening the loop: the pancreatic suppression test???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 260
Qualitative versus quantitative???????????????????????????????????????????????????????????????????????????? 261
The glucose clamp???????????????????????????????????????????????? 261
Performing the clamp?????????????????????????????????????????????????????? 261
Components of insulin action calculated from the euglycemic clamp???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 262
A quantitative index from the glucose clamp???????????????????????????????????????????????????????????????????????????????????????????????????? 262
Insulin action dynamics???????????????????????????????????????????????????????????? 263
Dynamic insulin action: the minimal model???????????????????????????????????????????????????????????????????????????????????????????????? 264
Hyperbolic relationship between insulin sensitivity and insulin secretion: the disposition index?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 266
Surrogate measures of insulin sensitivity???????????????????????????????????????????????????????????????????????????????????????????????? 266
Fasting insulin???????????????????????????????????????????? 267
Other surrogate measures?????????????????????????????????????????????????????????????? 267
Insulin sensitivity based upon the OGTT???????????????????????????????????????????????????????????????????????????????????????????? 268
Conclusions???????????????????????????????????? 270
Acknowledgments???????????????????????????????????????????? 270
References?????????????????????????????????? 270
Chapter 16 Protein metabolism in health and diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 276
Introduction?????????????????????????????????????? 276
Integrative physiology of insulin action on protein metabolism?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 277
Insulin transport from the circulation to the target tissues?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 277
Insulin-induced vasodilation?????????????????????????????????????????????????????????????????????? 277
Molecular mechanisms of insulin action on protein metabolism?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 278
Effect of insulin on tissue amino acid availability???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 279
Effects of insulin on protein metabolism in specific tissues?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 280
Skeletal muscle???????????????????????????????????????????? 280
Splanchnic tissues?????????????????????????????????????????????????? 281
Skin?????????????????????? 282
Effects of insulin on whole body protein turnover???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 282
Pathophysiology of insulin action on protein metabolism???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 282
Aging???????????????????????? 282
Physical activity???????????????????????????????????????????????? 283
Protein metabolism in diabetes?????????????????????????????????????????????????????????????????????????? 283
Type 1 diabetes mellitus?????????????????????????????????????????????????????????????? 283
Type 2 diabetes mellitus?????????????????????????????????????????????????????????????? 283
Critical illness?????????????????????????????????????????????? 284
Conclusions???????????????????????????????????? 284
Acknowledgments???????????????????????????????????????????? 284
References?????????????????????????????????? 284
Chapter 17 Lipid and lipoprotein metabolism, hypolipidemic agents, and therapeutic goals?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 288
Introduction?????????????????????????????????????? 288
Lipoprotein metabolism in normal individuals and in type 2 diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 289
Therapeutic approaches to the dyslipidemia of insulin resistance and type 2 diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 291
Rationale for treating LDL?????????????????????????????????????????????????????????????????? 291
Rationale for treating HDL and TG???????????????????????????????????????????????????????????????????????????????? 291
Treatment options???????????????????????????????????????????????? 293
References?????????????????????????????????? 296
Chapter 18 Metabolomics: applications in type 2 diabetes mellitus and insulin resistance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 301
Introduction?????????????????????????????????????? 301
What is "metabolomics?"???????????????????????????????????????????????????????????? 302
Altered metabolites and their potential origins in type 2 diabetes and insulin resistance???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 304
Future directions and potential application of metabolite profiling in type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 304
References?????????????????????????????????? 305
Section IV NAFLD, NASH and non-traditional associations with diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 307
Chapter 19 Pathogenesis of nonalcoholic fatty liver disease (NAFLD)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 309
Introduction?????????????????????????????????????? 309
Pathogenesis of NAFLD???????????????????????????????????????????????????????? 310
Sources of intrahepatocellular triglycerides?????????????????????????????????????????????????????????????????????????????????????????????????????? 310
Cause of NAFLD: obesity and abnormalities in adipose tissue???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 312
Cause of NAFLD: high simple sugar intake and de novo lipogenesis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 312
Cause of NAFLD: physical inactivity???????????????????????????????????????????????????????????????????????????????????? 313
Causes of NAFLD: familial and genetic factors???????????????????????????????????????????????????????????????????????????????????????????????????????? 313
Consequences of NAFLD???????????????????????????????????????????????????????? 314
Hyperglycemia and hyperinsulinemia?????????????????????????????????????????????????????????????????????????????????? 314
Hypertriglyceridemia and low HDL cholesterol, increased risk of type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 315
Markers of cardiovascular risk, increased risk of cardiovascular disease and thromboembolic complications???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 315
Other metabolic disease???????????????????????????????????????????????????????????? 315
Conclusions???????????????????????????????????? 315
References?????????????????????????????????? 315
Chapter 20 Treatment of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 318
Introduction?????????????????????????????????????? 318
Role of lifestyle intervention in NAFLD???????????????????????????????????????????????????????????????????????????????????????????? 319
Dietary alone interventions???????????????????????????????????????????????????????????????????? 319
Physical activity only?????????????????????????????????????????????????????????? 320
Combined dietary intervention and exercise?????????????????????????????????????????????????????????????????????????????????????????????????? 320
Dietary intervention and weight-loss medications?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 322
Surgically induced dietary intervention???????????????????????????????????????????????????????????????????????????????????????????? 322
Pharmacologic agents?????????????????????????????????????????????????????? 323
Statins???????????????????????????? 323
Fibrates?????????????????????????????? 323
Ezetimibe???????????????????????????????? 323
Pentoxifylline?????????????????????????????????????????? 324
Omega-3 polyunsaturated fatty acids???????????????????????????????????????????????????????????????????????????????????? 324
Vitamin E???????????????????????????????? 324
Glucose-lowering agents???????????????????????????????????????????????????????????? 324
Obeticholic acid (OCA)?????????????????????????????????????????????????????????? 326
Future directions???????????????????????????????????????????????? 327
References?????????????????????????????????? 327
Chapter 21 Type 2 diabetes and cancer???????????????????????????????????????????????????????????????????????????????????????? 332
Introduction?????????????????????????????????????? 332
Epidemiology?????????????????????????????????????? 332
Links between diabetes and cancer???????????????????????????????????????????????????????????????????????????????? 334
Common risk factors???????????????????????????????????????????????????? 334
Biologic links?????????????????????????????????????????? 334
Hyperglycemia???????????????????????????????????????? 335
Insulin and IGF-I???????????????????????????????????????????????? 335
Dyslipidemia?????????????????????????????????????? 335
Inflammatory cytokines and adipokines???????????????????????????????????????????????????????????????????????????????????????? 336
Altered estrogen levels in T2DM and cancer?????????????????????????????????????????????????????????????????????????????????????????????????? 336
Animal studies?????????????????????????????????????????? 336
In experimental studies, type 1 and type 2 diabetes have a different impact on tumor growth???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 336
Genetically induced obesity and cancer?????????????????????????????????????????????????????????????????????????????????????????? 337
Diet-induced obesity (DIO) and cancer???????????????????????????????????????????????????????????????????????????????????????? 338
Non-obese models of type 2 diabetes and cancer?????????????????????????????????????????????????????????????????????????????????????????????????????????? 339
Conclusions and future directions???????????????????????????????????????????????????????????????????????????????? 340
References?????????????????????????????????? 340
Chapter 22 Diabetes and sleep apnea???????????????????????????????????????????????????????????????????????????????????? 342
Introduction?????????????????????????????????????? 342
Definitions???????????????????????????????????? 342
OSA epidemiology and risk factors???????????????????????????????????????????????????????????????????????????????? 343
OSA pathophysiology???????????????????????????????????????????????????? 344
OSA clinical features and diagnosis???????????????????????????????????????????????????????????????????????????????????? 344
OSA and glucose metabolism?????????????????????????????????????????????????????????????????? 345
OSA and prediabetes???????????????????????????????????????????????????? 345
OSA and insulin resistance?????????????????????????????????????????????????????????????????? 345
OSA and ?-cell function 349
Mechanisms underpinning the relationship between OSA and dysglycemia?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 349
OSA and T2DM?????????????????????????????????????? 350
Other OSA comorbidities???????????????????????????????????????????????????????????? 355
Road traffic accidents?????????????????????????????????????????????????????????? 355
Cardiovascular mortality and morbidity?????????????????????????????????????????????????????????????????????????????????????????? 355
OSA management?????????????????????????????????????????? 356
Impact of T2DM on OSA???????????????????????????????????????????????????????? 357
Summary and future directions???????????????????????????????????????????????????????????????????????? 357
Declaration???????????????????????????????????? 357
References?????????????????????????????????? 357
Section V Pathogenesis?????????????????????????????????????????????????????????? 363
Chapter 23 The insulin resistance syndrome?????????????????????????????????????????????????????????????????????????????????????????????????? 365
What is insulin resistance????????????????????????????????????????????????????????????????????? 365
Multiple roles of insulin???????????????????????????????????????????????????????????????? 365
How do we measure insulin resistance????????????????????????????????????????????????????????????????????????????????????????? 366
Simple characteristics associated with insulin resistance???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 366
Concept of ectopic fat as a cause of tissue insulin resistance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 368
Pathways linked to insulin resistance???????????????????????????????????????????????????????????????????????????????????????? 368
Lipid alterations in insulin resistance syndrome?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 368
Liver markers and insulin resistance?????????????????????????????????????????????????????????????????????????????????????? 368
Adipose-derived markers and insulin resistance?????????????????????????????????????????????????????????????????????????????????????????????????????????? 369
Endothelial-derived markers and insulin resistance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 372
Cardiac biomarkers and insulin resistance???????????????????????????????????????????????????????????????????????????????????????????????? 372
Insulin resistance as cardiovascular risk factor????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 372
Other markers and future research???????????????????????????????????????????????????????????????????????????????? 372
Introducing insulin resistance to the clinic: the metabolic syndrome?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 373
What are the metabolic syndrome criteria????????????????????????????????????????????????????????????????????????????????????????????????? 373
The purpose of the metabolic syndrome concept???????????????????????????????????????????????????????????????????????????????????????????????????????? 374
Statistical considerations and other issues???????????????????????????????????????????????????????????????????????????????????????????????????? 376
Treatment of patients with features of the metabolic syndrome???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 376
Current thinking regarding metabolic syndrome???????????????????????????????????????????????????????????????????????????????????????????????????????? 376
Conclusion?????????????????????????????????? 377
References?????????????????????????????????? 377
Chapter 24 ?-Cell mass and function in human type 2 diabetes 380
Introduction?????????????????????????????????????? 380
?-Cell mass in type 2 diabetes 380
The role of ?-cell death and regeneration 382
The dominance of ?-cell functional impairment 384
Disruption of ?-cell dialogue in the islet 387
Incretin defect???????????????????????????????????????????? 387
Additional aspects of ?-cell dysfunction 389
Loss of ?-cell functional identity 390
Conclusions???????????????????????????????????? 391
References?????????????????????????????????? 391
Chapter 25 Pathogenesis of type 2 diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 397
Normal glucose homeostasis?????????????????????????????????????????????????????????????????? 397
Natural history of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????? 398
?-Cell function 399
Type 2 diabetes with hypoinsulinemia?????????????????????????????????????????????????????????????????????????????????????? 400
First-phase insulin secretion???????????????????????????????????????????????????????????????????????? 401
Pathogenesis of ?-cell failure (Figure ) 401
In utero fetal malnutrition???????????????????????????????????????????????????????????????????? 403
Insulin resistance and type 2 diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????? 403
Site of insulin resistance in type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????? 404
Cellular mechanisms of insulin resistance???????????????????????????????????????????????????????????????????????????????????????????????? 407
Insulin receptor/insulin receptor tyrosine kinase???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 407
Insulin receptor signal transduction?????????????????????????????????????????????????????????????????????????????????????? 407
Insulin receptor signal transduction defects in type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 407
The adipocyte, FFA metabolism, and lipotoxicity???????????????????????????????????????????????????????????????????????????????????????????????????????????? 411
Alpha cell and glucagon???????????????????????????????????????????????????????????? 413
The kidney: increased glucose reabsorption?????????????????????????????????????????????????????????????????????????????????????????????????? 413
The brain???????????????????????????????? 414
Implications for therapy?????????????????????????????????????????????????????????????? 414
References?????????????????????????????????? 414
Chapter 26 The genetics of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????? 427
The diabetic spectrum???????????????????????????????????????????????????????? 427
The diabetes epidemic???????????????????????????????????????????????????????? 427
Heritability of T2DM?????????????????????????????????????????????????????? 428
Identification of T2DM affecting genetic variants???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 428
Linkage studies???????????????????????????????????????????? 428
Association studies on candidate genes?????????????????????????????????????????????????????????????????????????????????????????? 429
Genome-wide association studies (GWAS)?????????????????????????????????????????????????????????????????????????????????????????? 430
High density mapping?????????????????????????????????????????????????????? 430
Functions of associated genes???????????????????????????????????????????????????????????????????????? 430
The missing heritability?????????????????????????????????????????????????????????????? 433
The genetic architecture of T2DM?????????????????????????????????????????????????????????????????????????????? 433
Gene-gene and gene-environment interactions???????????????????????????????????????????????????????????????????????????????????????????????????? 434
Epigenetics???????????????????????????????????? 435
Systems biology???????????????????????????????????????????? 435
Conclusions???????????????????????????????????? 435
References?????????????????????????????????? 435
Chapter 27 Glucose toxicity???????????????????????????????????????????????????????????????????? 439
Introduction?????????????????????????????????????? 439
Hyperglycemia and glucose utilization???????????????????????????????????????????????????????????????????????????????????????? 440
The mass-action effect of glucose???????????????????????????????????????????????????????????????????????????????? 440
Consequences of the acute stimulatory effect of hyperglycemia on postprandial glucose disposal in patients with type 1 and 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 440
Chronic hyperglycemia as a cause of insulin resistance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 440
Insulin resistance in patients with type 1 diabetes-a consequence of glucose toxicity??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 440
Induction of in vivo insulin resistance by hyperglycemia?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 440
Hyperglycemia as a mediator of insulin resistance in type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 441
Physiologic basis of glucose-induced insulin resistance in vivo???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 442
Chronic hyperglycemia as a cause of impaired insulin secretion?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 442
Insulin secretion during experimental hyperglycemia???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 442
Molecular mechanisms of glucose toxicity?????????????????????????????????????????????????????????????????????????????????????????????? 443
The hexosamine/O-linked N-acetyl glucosamine pathway?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 443
Oxidative stress from excess glucose metabolism???????????????????????????????????????????????????????????????????????????????????????????????????????????? 446
Clinical significance of glucose toxicity???????????????????????????????????????????????????????????????????????????????????????????????? 447
Type 1 diabetes???????????????????????????????????????????? 447
Type 2 diabetes???????????????????????????????????????????? 447
Acknowledgments???????????????????????????????????????????? 448
References?????????????????????????????????? 448
Chapter 28 Monogenic disorders of the ? cell 452
Introduction?????????????????????????????????????? 452
Monogenic ?-cell disorders in key aspects of ?-cell function 452
Clinical categories of monogenic ?-cell disorders 453
Maturity-onset diabetes of the young?????????????????????????????????????????????????????????????????????????????????????? 453
Diagnosis of MODY???????????????????????????????????????????????? 454
Prevalence of MODY subtypes???????????????????????????????????????????????????????????????????? 454
The MODY phenotypes???????????????????????????????????????????????????? 454
Glucokinase MODY?????????????????????????????????????????????? 454
Transcription factor MODY???????????????????????????????????????????????????????????????? 457
Neonatal diabetes: diabetes diagnosed within 6 months of life???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 459
Clinical features???????????????????????????????????????????????? 460
Diabetes with extra-pancreatic features???????????????????????????????????????????????????????????????????????????????????????????? 462
Renal cysts and diabetes (RCAD) syndrome: HNF1B-MODY?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 462
Mitochondrial diabetes?????????????????????????????????????????????????????????? 462
Maternally inherited diabetes and deafness (MIDD)???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 462
Wolfram syndrome?????????????????????????????????????????????? 463
Using molecular genetics in diabetes care???????????????????????????????????????????????????????????????????????????????????????????????? 463
References?????????????????????????????????? 464
Chapter 29 Immunopathogenesis of type 1 diabetes in Western society???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 468
Introduction?????????????????????????????????????? 468
Genetic studies provide clues about key disease mechanisms?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 469
Genes and environment: a moving target????????????????????????????????????????????????????????????????????????????????????????????? 472
Multiple T-cell types and autoreactive T-cell specificities mediate T1DM?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 473
Autoimmunity persists in many patients even many years after diagnosis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 473
Nonautoimmune factors???????????????????????????????????????????????????????? 473
The relationship between pathogenic factors and ?-cell destruction remains poorly understood 475
Conclusions???????????????????????????????????? 475
References?????????????????????????????????? 475
Chapter 30 Molecular genetics of type 1 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 480
Introduction?????????????????????????????????????? 480
The HLA complex???????????????????????????????????????????? 481
HLA-DR and -DQ?????????????????????????????????????????? 483
Other HLA-encoded susceptibility determinants???????????????????????????????????????????????????????????????????????????????????????????????????????? 485
Other candidate genes for T1DM?????????????????????????????????????????????????????????????????????????? 485
The insulin gene (INS)?????????????????????????????????????????????????????????? 485
The CTLA4 gene?????????????????????????????????????????? 486
The PTPN22 gene???????????????????????????????????????????? 486
The IL2RA gene?????????????????????????????????????????? 486
Genome-wide analyses?????????????????????????????????????????????????????? 486
Linkage studies???????????????????????????????????????????? 486
Genome-wide association studies (GWAS)?????????????????????????????????????????????????????????????????????????????????????????? 487
Other genetic markers-the "missing heritability"?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 488
Clinical utility of T1DM susceptibility genes???????????????????????????????????????????????????????????????????????????????????????????????????????? 489
Conclusion?????????????????????????????????? 490
References?????????????????????????????????? 490
Section VI Obesity?????????????????????????????????????????????????? 493
Chapter 31 The relationship between obesity and type 2 diabetes-the role of gut factors???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 495
Introduction?????????????????????????????????????? 495
The relationship of obesity to insulin resistance and diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 496
Gut hormone regulation of appetite, food intake, and insulin secretion?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 497
Pancreatic polypeptide (PP)-fold peptides???????????????????????????????????????????????????????????????????????????????????????????????? 497
Incretins???????????????????????????????? 497
Role of gut hormones in obesity and type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 498
The role of microbiota in obesity and diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????? 499
Gut microbiota in health and disease?????????????????????????????????????????????????????????????????????????????????????? 499
The relationship of gut microbiota to energy balance, obesity, and obesity-related disorders?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 499
Potential mechanisms of disease related to gut microbiota???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 500
Dietary interventions that alter the gut microbiota and host metabolism???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 501
Summary???????????????????????????? 503
References?????????????????????????????????? 503
Chapter 32 The role of energy metabolism in the regulation of energy balance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 505
Introduction?????????????????????????????????????? 505
Methods of measuring energy expenditure???????????????????????????????????????????????????????????????????????????????????????????? 505
Direct calorimetry?????????????????????????????????????????????????? 505
Indirect calorimetry?????????????????????????????????????????????????????? 506
Doubly labeled water?????????????????????????????????????????????????????? 506
Portable devices?????????????????????????????????????????????? 506
Questionnaires and activity logs?????????????????????????????????????????????????????????????????????????????? 506
Components of energy expenditure and their relevance for human obesity?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 507
Resting metabolic rate?????????????????????????????????????????????????????????? 507
Diet-induced thermogenesis?????????????????????????????????????????????????????????????????? 507
Activity thermogenesis?????????????????????????????????????????????????????????? 508
Energy expenditure in the etiology of obesity???????????????????????????????????????????????????????????????????????????????????????????????????????? 508
Low metabolic rate?????????????????????????????????????????????????? 508
Low activity thermogenesis?????????????????????????????????????????????????????????????????? 509
Low sympathetic nervous system activity???????????????????????????????????????????????????????????????????????????????????????????? 509
Low fat oxidation???????????????????????????????????????????????? 510
Molecular mechanisms of energy expenditure variability and avenues for treatment?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 510
Leptin?????????????????????????? 510
?3-adrenergic receptors 510
Uncoupling proteins???????????????????????????????????????????????????? 510
Diacylglycerol transferase and acetyl CoA carboxylase???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 511
Acetyl CoA carboxylase?????????????????????????????????????????????????????????? 511
Analysis of energy expenditure data in humans???????????????????????????????????????????????????????????????????????????????????????????????????????? 511
Conclusions???????????????????????????????????? 511
References?????????????????????????????????? 511
Chapter 33 Treatment of obesity: lifestyle and pharmacotherapy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 515
Introduction?????????????????????????????????????? 515
Principles of diet-induced weight loss?????????????????????????????????????????????????????????????????????????????????????????? 515
Choosing the dietary energy deficit???????????????????????????????????????????????????????????????????????????????????? 516
Theoretical versus clinical outcome???????????????????????????????????????????????????????????????????????????????????? 516
Prognostic markers of weight loss success and reasons for failure???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 516
Options for weight loss diets???????????????????????????????????????????????????????????????????????? 517
Very-low-energy diets (VLED)?????????????????????????????????????????????????????????????????????? 517
Low-energy diets (LED)?????????????????????????????????????????????????????????? 517
Ad libitum lower fat diets (25-30% energy from fat)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 517
Low-carbohydrate, high-protein diets (HPLCDs)???????????????????????????????????????????????????????????????????????????????????????????????????????? 519
Dietary weight maintenance programs???????????????????????????????????????????????????????????????????????????????????? 521
Weight management programs for the prevention of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 521
Weight loss management in type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????? 522
Physical activity in type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????? 522
Pharmacotherapy???????????????????????????????????????????? 522
Phentermine???????????????????????????????????? 522
Phentermine/topiramate?????????????????????????????????????????????????????????? 523
Lipase inhibitors (orlistat)?????????????????????????????????????????????????????????????????????? 524
Lorcaserin?????????????????????????????????? 525
Pharmaceutical compounds for diabetes treatment with weight loss properties???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 526
Metformin???????????????????????????????? 526
Amylase inhibitors (acarbose)???????????????????????????????????????????????????????????????????????? 526
GLP-1 analogues???????????????????????????????????????????? 527
Other pharmacologic agents under development?????????????????????????????????????????????????????????????????????????????????????????????????????? 528
Bupropion/naltrexone?????????????????????????????????????????????????????? 528
References?????????????????????????????????? 528
Chapter 34 Treatment of obesity: bariatric surgery?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 531
Introduction?????????????????????????????????????? 531
Current surgical approaches???????????????????????????????????????????????????????????????????? 531
Weight loss after bariatric surgery???????????????????????????????????????????????????????????????????????????????????? 532
Mechanisms of weight loss???????????????????????????????????????????????????????????????? 533
Satiety: the role of gut hormones and neural signals?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 534
Energy expenditure?????????????????????????????????????????????????? 535
Treatment of diabetes and related metabolic diseases?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 535
Diabetes remission?????????????????????????????????????????????????? 535
Improving glycemic control with bariatric surgery???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 536
Bariatric surgery and microvascular complications???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 536
Bariatric surgery and other comorbidities???????????????????????????????????????????????????????????????????????????????????????????????? 537
Mechanisms of diabetes remission and improvement in glucose homeostasis???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 537
Insulin resistance?????????????????????????????????????????????????? 537
Insulin secretion and ?-cell function 538
Appetite and energy expenditure???????????????????????????????????????????????????????????????????????????? 538
Mechanisms of diabetes remission: other perspectives?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 539
Conclusion?????????????????????????????????? 539
References?????????????????????????????????? 539
Chapter 35 Animal models of obesity and type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 545
Introduction?????????????????????????????????????? 545
Environmental influences?????????????????????????????????????????????????????????????? 546
Early environment and epigenetics???????????????????????????????????????????????????????????????????????????????? 546
Viral infections?????????????????????????????????????????????? 546
The gut microbiome?????????????????????????????????????????????????? 546
Genetic models?????????????????????????????????????????? 547
Tissue-targeted knockout or knockdown of insulin receptors?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 549
Fatty acid binding proteins???????????????????????????????????????????????????????????????????? 550
References?????????????????????????????????? 551
Chapter 36 The role of the hypothalamus in the maintenance of energy balance and peripheral glucose control???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 555
Introduction?????????????????????????????????????? 555
Leptin and insulin signaling pathways in the hypothalamus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 556
Hypothalamic leptin and insulin mediate food intake, energy expenditure, and glucose homeostasis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 557
Leptin in POMC and AgRP neurons???????????????????????????????????????????????????????????????????????????? 557
Insulin in POMC and AgRP neurons?????????????????????????????????????????????????????????????????????????????? 558
Leptin's and insulin's mechanisms of action in regulating energy and glucose homeostasis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 558
Potential role of autophagy in leptin's and insulin's mechanisms of action?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 560
References?????????????????????????????????? 561
Section VII Clinical trial evidence in diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????? 565
Chapter 37 Prevention of type 1 diabetes?????????????????????????????????????????????????????????????????????????????????????????????? 567
Introduction?????????????????????????????????????? 567
Studies in established T1DM???????????????????????????????????????????????????????????????????? 567
Studies designed to prevent T1DM?????????????????????????????????????????????????????????????????????????????? 570
Conclusions???????????????????????????????????? 572
References?????????????????????????????????? 572
Chapter 38 Prevention of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????? 576
Prediabetes???????????????????????????????????? 576
Impaired glucose tolerance and impaired fasting glucose???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 576
HbA1c and prediabetes???????????????????????????????????????????????????????? 577
Lifestyle interventions???????????????????????????????????????????????????????????? 577
Obesity???????????????????????????? 578
Physical activity???????????????????????????????????????????????? 578
Diet?????????????????????? 580
Pharmaceutical intervention???????????????????????????????????????????????????????????????????? 580
Metformin???????????????????????????????? 580
Thiazolidinediones?????????????????????????????????????????????????? 582
Alpha-glucosidase inhibitors?????????????????????????????????????????????????????????????????????? 582
Meglitinides?????????????????????????????????????? 582
Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 582
Insulin analogues???????????????????????????????????????????????? 582
Weight loss therapies???????????????????????????????????????????????????????? 583
Other agents?????????????????????????????????????? 583
Lifestyle versus pharmacotherapy?????????????????????????????????????????????????????????????????????????????? 583
Cost-effectiveness?????????????????????????????????????????????????? 583
Translation of diabetes prevention into routine primary care?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 584
Identifying those at high risk?????????????????????????????????????????????????????????????????????????? 584
Risk scores???????????????????????????????????? 584
Two-stepped approach?????????????????????????????????????????????????????? 584
Implementing prevention programs?????????????????????????????????????????????????????????????????????????????? 585
High risk versus population???????????????????????????????????????????????????????????????????? 586
Conclusion?????????????????????????????????? 586
References?????????????????????????????????? 586
Chapter 39 Prevention of diabetic microvascular complications???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 590
Introduction?????????????????????????????????????? 590
Diabetic nephropathy?????????????????????????????????????????????????????? 590
Intensive glycemic control in the prevention of diabetic nephropathy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 591
Blood pressure control, renin-angiotension-aldosterone system and prevention of diabetic nephropathy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 592
Other therapies for preventing diabetic nephropathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 594
Diabetic neuropathy???????????????????????????????????????????????????? 594
Role of metabolic and blood pressure control in diabetic neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 594
Strategies in preventing diabetic neuropathy: from pathophysiology to prevention?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 595
Diabetic retinopathy?????????????????????????????????????????????????????? 596
Glycemia, blood pressure, dyslipidemia, and diabetic retinopathy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 596
Anti-vascular endothelial growth factor (VEGF) and other treatments in the prevention of diabetic retinopathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 596
Conclusion?????????????????????????????????? 597
References?????????????????????????????????? 597
Section VIII Management of diabetes: diet, exercise and drugs???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 601
Chapter 40 Dietary management of diabetes mellitus in Europe and North America?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 603
Introduction?????????????????????????????????????? 603
Total energy intake???????????????????????????????????????????????????? 604
Quantity and nature of dietary fat?????????????????????????????????????????????????????????????????????????????????? 605
Protein???????????????????????????? 606
Carbohydrate, dietary fiber, and glycemic index???????????????????????????????????????????????????????????????????????????????????????????????????????????? 606
Distribution of energy from macronutrients?????????????????????????????????????????????????????????????????????????????????????????????????? 607
Antioxidant nutrients, vitamins, and minerals???????????????????????????????????????????????????????????????????????????????????????????????????????? 609
Alcohol???????????????????????????? 609
Sweeteners, supplements and functional foods?????????????????????????????????????????????????????????????????????????????????????????????????????? 609
Implementation of diet therapy?????????????????????????????????????????????????????????????????????????? 609
References?????????????????????????????????? 613
Chapter 41 Exercise???????????????????????????????????????????????????? 615
Introduction?????????????????????????????????????? 615
Exercise physiology???????????????????????????????????????????????????? 615
Hormonal regulation???????????????????????????????????????????????????? 617
Metabolism during exercise in diabetics???????????????????????????????????????????????????????????????????????????????????????????? 618
Type 1?????????????????????????? 618
Type 2?????????????????????????? 618
Special patient groups?????????????????????????????????????????????????????????? 622
Adaptations to training???????????????????????????????????????????????????????????? 624
Insulin action and secretion in healthy subjects?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 624
Adaptations to training in diabetics?????????????????????????????????????????????????????????????????????????????????????? 625
Benefits, risks, and precautions associated with exercise in diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 627
Benefits?????????????????????????????? 627
Metabolic risks and precautions???????????????????????????????????????????????????????????????????????????? 628
Long-term complications???????????????????????????????????????????????????????????? 629
Other conditions requiring special precautions?????????????????????????????????????????????????????????????????????????????????????????????????????????? 631
Guidelines for training in diabetes???????????????????????????????????????????????????????????????????????????????????? 631
Exercise in the prevention of diabetes?????????????????????????????????????????????????????????????????????????????????????????? 632
References?????????????????????????????????? 633
Chapter 42 Sulfonylureas and meglitinides: insights into physiology and translational clinical utility?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 641
Historical perspective: the merger of clinical and basic science?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 641
Mechanism of action of sulfonylureas and meglitinides???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 642
Pancreatic ?-cell effects 642
Extrapancreatic effects of sulfonylureas?????????????????????????????????????????????????????????????????????????????????????????????? 644
Pharmacology and clinical pharmacology?????????????????????????????????????????????????????????????????????????????????????????? 644
Chemistry and structure of sulfonylureas and meglitinides???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 644
Pancreatic ?-cell KATP channel and insulin secretion 645
Acute pancreatic effects of sulfonylureas???????????????????????????????????????????????????????????????????????????????????????????????? 645
Chronic effects of sulfonylureas?????????????????????????????????????????????????????????????????????????????? 647
Effects on the secretion of insulin precursors?????????????????????????????????????????????????????????????????????????????????????????????????????????? 648
Effects on proinsulin biosynthesis?????????????????????????????????????????????????????????????????????????????????? 648
Effects on glucagon and somatostatin secretion?????????????????????????????????????????????????????????????????????????????????????????????????????????? 648
Extrapancreatic effects of sulfonylureas?????????????????????????????????????????????????????????????????????????????????????????????? 648
Clinical aspects of sulfonylurea therapy?????????????????????????????????????????????????????????????????????????????????????????????? 650
Similarities and differences among sulfonylureas?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 651
Tolbutamide???????????????????????????????????? 651
Chlorpropamide?????????????????????????????????????????? 651
Glibenclamide???????????????????????????????????????? 652
Gliclazide?????????????????????????????????? 652
Glipizide???????????????????????????????? 653
Glimepiride???????????????????????????????????? 653
Repaglinide???????????????????????????????????? 654
Adverse effects of sulfonylureas?????????????????????????????????????????????????????????????????????????????? 654
Hypoglycemia?????????????????????????????????????? 654
Weight gain???????????????????????????????????? 656
Cardiovascular safety???????????????????????????????????????????????????????? 657
Sulfonylureas as current therapeutic agents for type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 658
Interactions?????????????????????????????????????? 659
Toxicity?????????????????????????????? 660
Contraindications???????????????????????????????????????????????? 660
Conclusion?????????????????????????????????? 660
References?????????????????????????????????? 660
Chapter 43 Metformin and other biguanides: pharmacology and therapeutic usage???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 667
Introduction?????????????????????????????????????? 667
Pharmacology?????????????????????????????????????? 668
Mechanism of action???????????????????????????????????????????????????? 669
Mitochondrial respiration and AMP-activated protein kinase?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 669
Gluconeogenesis???????????????????????????????????????????? 670
Peripheral glucose uptake???????????????????????????????????????????????????????????????? 670
Lipid metabolism?????????????????????????????????????????????? 671
Treatment of type 2 diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????? 671
Glycemic control?????????????????????????????????????????????? 671
Product formulations?????????????????????????????????????????????????????? 671
Microvascular and macrovascular risk reduction?????????????????????????????????????????????????????????????????????????????????????????????????????????? 672
Additional therapeutic potential?????????????????????????????????????????????????????????????????????????????? 674
Diabetes prevention???????????????????????????????????????????????????? 674
Diabetes in pregnancy???????????????????????????????????????????????????????? 674
Weight loss???????????????????????????????????? 674
Polycystic ovary syndrome???????????????????????????????????????????????????????????????? 675
Nonalcoholic fatty liver disease (NAFLD)?????????????????????????????????????????????????????????????????????????????????????????????? 675
HIV lipodystrophy???????????????????????????????????????????????? 676
Cancer biology?????????????????????????????????????????? 676
Adverse events, contraindications, and side effects???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 676
Lactic acidosis???????????????????????????????????????????? 676
Other adverse effects???????????????????????????????????????????????????????? 677
Conclusion?????????????????????????????????? 677
References?????????????????????????????????? 678
Chapter 44 PPAR agonists in the treatment of diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 683
Introduction?????????????????????????????????????? 683
Mechanism of action???????????????????????????????????????????????????? 684
Glycemic effects?????????????????????????????????????????????? 686
Pioglitazone monotherapy?????????????????????????????????????????????????????????????? 686
Combination therapy with sulfonylureas?????????????????????????????????????????????????????????????????????????????????????????? 687
Combination with metformin?????????????????????????????????????????????????????????????????? 687
Combination with DPP-4 inhibitor?????????????????????????????????????????????????????????????????????????????? 687
Combination with GLP-1 agonist?????????????????????????????????????????????????????????????????????????? 687
Combination with insulin?????????????????????????????????????????????????????????????? 687
Metabolic effects???????????????????????????????????????????????? 688
Insulin sensitivity???????????????????????????????????????????????????? 688
Beta-cell function?????????????????????????????????????????????????? 688
Diabetes prevention???????????????????????????????????????????????????? 689
Lipids?????????????????????????? 689
Adipose tissue?????????????????????????????????????????? 690
Cardiovascular effects?????????????????????????????????????????????????????????? 690
Myocardial function and blood flow?????????????????????????????????????????????????????????????????????????????????? 690
Blood pressure?????????????????????????????????????????? 691
Glomerular function and albuminuria???????????????????????????????????????????????????????????????????????????????????? 691
Anti-atherogenic effects?????????????????????????????????????????????????????????????? 691
Other potential beneficial nonglycemic effects?????????????????????????????????????????????????????????????????????????????????????????????????????????? 692
Nonalcoholic steato-hepatitis (NASH)?????????????????????????????????????????????????????????????????????????????????????? 692
Cancer?????????????????????????? 692
Polycystic ovary syndrome (PCOS)?????????????????????????????????????????????????????????????????????????????? 693
Inflammation and immunity???????????????????????????????????????????????????????????????? 693
Dose/drug interactions?????????????????????????????????????????????????????????? 693
Dosage?????????????????????????? 693
Drug interactions???????????????????????????????????????????????? 693
Monitoring requirements/precautions/contraindications???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 693
Renal impairment?????????????????????????????????????????????? 693
Hepatic impairment?????????????????????????????????????????????????? 693
Congestive heart failure (CHF)?????????????????????????????????????????????????????????????????????????? 694
Side effects?????????????????????????????????????? 694
Edema???????????????????????? 694
Weight gain???????????????????????????????????? 695
Bone fractures?????????????????????????????????????????? 695
Anemia?????????????????????????? 695
Hypoglycemia?????????????????????????????????????? 695
Future developments???????????????????????????????????????????????????? 695
Conclusion?????????????????????????????????? 695
Acknowledgments???????????????????????????????????????????? 696
References?????????????????????????????????? 696
Chapter 45 ?-Glucosidase inhibitors 699
Introduction?????????????????????????????????????? 699
Mechanism of action???????????????????????????????????????????????????? 699
Clinical efficacy of ?-glucosidase inhibitors 700
Treatment of diabetes mellitus?????????????????????????????????????????????????????????????????????????? 700
Dose-response relationship?????????????????????????????????????????????????????????????????? 701
Efficacy of ?-glucosidase inhibitors combined with diet therapy in patients with type 2 diabetes 701
Efficacy of ?-glucosidase inhibitors in comparison to sulfonylureas or metformin 701
Efficacy of ?-glucosidase inhibitors as an adjunct treatment to sulfonylurea and/or metformin 701
Thiazolidinedione and ?-glucosidase inhibitors 702
Efficacy of ?-glucosidase inhibitors in comparison to dipeptidyl peptidase-4 inhibitors 702
Efficacy of ?-glucosidase inhibitors in insulin-treated type 2 diabetic patients 702
Comparative studies between ?-glucosidase inhibitors 702
Benefits of ?-glucosidase inhibitors in elderly patients 702
Impaired glucose tolerance and prevention of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 702
Efficacy of ?-glucosidase inhibitors in type 1 diabetic patients 703
Other effects of ?-glucosidase inhibitors 704
Gastrointestinal peptide secretion?????????????????????????????????????????????????????????????????????????????????? 704
Cardiovascular risk factors???????????????????????????????????????????????????????????????????? 704
Potential effects of ?-glucosidase inhibitors on the prevention of long-term diabetic complications 704
Treatment of reactive hypoglycemia?????????????????????????????????????????????????????????????????????????????????? 705
Tolerability of acarbose?????????????????????????????????????????????????????????????? 705
Gastrointestinal side effects???????????????????????????????????????????????????????????????????????? 705
Hypoglycemia?????????????????????????????????????? 705
Other potential and demonstrated side effects related to ?-glucosidase inhibitor therapy 706
Contraindications to ?-glucosidase inhibitors 706
Indications for ?-glucosidase inhibitors 706
Recommended doses are as follows:???????????????????????????????????????????????????????????????????????????????? 707
Conclusions???????????????????????????????????? 707
References?????????????????????????????????? 707
Chapter 46 Combination therapy in type 2 diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 712
Introduction?????????????????????????????????????? 712
Natural history of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????? 712
Beta-cell function?????????????????????????????????????????????????? 713
Insulin resistance?????????????????????????????????????????????????? 713
Implications for therapy?????????????????????????????????????????????????????????????? 714
Combination therapy???????????????????????????????????????????????????? 715
Newly diagnosed T2DM patients???????????????????????????????????????????????????????????????????????? 715
Initial combination therapy in new onset diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 715
Rationale???????????????????????????????? 715
Sulfonylurea plus metformin???????????????????????????????????????????????????????????????????? 715
Metformin plus repaglinide/nateglinide?????????????????????????????????????????????????????????????????????????????????????????? 717
Metformin plus thiazolidinediones???????????????????????????????????????????????????????????????????????????????? 717
Metformin plus DPP-4 inhibitor?????????????????????????????????????????????????????????????????????????? 718
Thiazolidinedione plus DPP-4 inhibitor?????????????????????????????????????????????????????????????????????????????????????????? 718
Combination of SGLT2 inhibitors plus metformin?????????????????????????????????????????????????????????????????????????????????????????????????????????? 719
Initial triple combination therapy?????????????????????????????????????????????????????????????????????????????????? 719
Combination therapy in T2DM patients inadequately controlled on antidiabetic therapy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 720
Introduction?????????????????????????????????????? 720
Sulfonylureas/glinides: the "treat-to-fail" approach?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 720
Pioglitazone: unique benefits, unique side effects?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 721
Glucagon-like peptide-1 analogues: robust glycemic control and weight loss?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 722
Metformin + GLP-1 analogue + pioglitazone: the pathophysiologic option?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 723
Metformin + basal insulin: reliable but old fashioned???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 723
Metformin + exenatide + basal insulin: the complementary combination?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 723
DPP-4 inhibitors: weak but easy???????????????????????????????????????????????????????????????????????????? 724
Basal insulin analogues: when the ? cells fail ... 724
Conclusion and recommendations?????????????????????????????????????????????????????????????????????????? 724
References?????????????????????????????????? 725
Chapter 47 New drugs for the treatment of diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 735
Introduction?????????????????????????????????????? 735
Approaches to new antidiabetic agents???????????????????????????????????????????????????????????????????????????????????????? 735
Inhibitors of intestinal carbohydrate digestion and absorption?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 736
Initiators of insulin secretion???????????????????????????????????????????????????????????????????????????? 736
KATP channel closers?????????????????????????????????????????????????????? 737
Glucokinase activators?????????????????????????????????????????????????????????? 739
Potentiators of insulin secretion???????????????????????????????????????????????????????????????????????????????? 739
Incretins???????????????????????????????? 739
DPP-4 inhibitors?????????????????????????????????????????????? 741
Fatty acid receptor agonists?????????????????????????????????????????????????????????????????????? 741
Other insulin secretion potentiators?????????????????????????????????????????????????????????????????????????????????????? 742
Increasing insulin action???????????????????????????????????????????????????????????????? 742
Initiating insulin receptor activity?????????????????????????????????????????????????????????????????????????????????????? 742
Potentiating insulin receptor activity?????????????????????????????????????????????????????????????????????????????????????????? 744
Adipokines?????????????????????????????????? 744
Adipocyte hormones?????????????????????????????????????????????????? 744
Fibroblast growth factor 21???????????????????????????????????????????????????????????????????? 745
Selective PPAR modulators???????????????????????????????????????????????????????????????? 745
Vitamins and minerals???????????????????????????????????????????????????????? 746
Inhibitors of counterregulatory hormones?????????????????????????????????????????????????????????????????????????????????????????????? 747
Glucagon antagonists?????????????????????????????????????????????????????? 747
Glucocorticoid antagonists?????????????????????????????????????????????????????????????????? 747
Direct modifiers of glucose metabolism?????????????????????????????????????????????????????????????????????????????????????????? 747
AMP kinase activators???????????????????????????????????????????????????????? 748
Glycogen synthase kinase inhibitors???????????????????????????????????????????????????????????????????????????????????? 748
Inhibitors of hepatic glucose production?????????????????????????????????????????????????????????????????????????????????????????????? 748
Modifiers of lipid metabolism???????????????????????????????????????????????????????????????????????? 748
Sodium-glucose co-transporter inhibitors?????????????????????????????????????????????????????????????????????????????????????????????? 749
Sirtuins?????????????????????????????? 749
Conclusions???????????????????????????????????? 750
References?????????????????????????????????? 750
Chapter 48 Incretin-based therapies???????????????????????????????????????????????????????????????????????????????????? 752
Biologic actions of incretin hormones in patients with type 2 diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 752
GLP-1 as a parent compound for incretin-based antidiabetic drugs?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 753
Development of GLP-1 receptor agonists (incretin mimetics)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 753
Exeantide???????????????????????????????? 753
Liraglutide???????????????????????????????????? 753
Exenatide once weekly???????????????????????????????????????????????????????? 754
Agents under development?????????????????????????????????????????????????????????????? 754
Efficacy of incretin mimetics as glucose-lowering agents (reduction in HbA1c)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 754
Monotherapy???????????????????????????????????? 754
Add-on to oral glucose-lowering agents?????????????????????????????????????????????????????????????????????????????????????????? 754
Comparison to insulin treatment???????????????????????????????????????????????????????????????????????????? 755
Combination with basal insulin?????????????????????????????????????????????????????????????????????????? 756
Inability to provoke hypoglycemia???????????????????????????????????????????????????????????????????????????????? 757
Deceleration of gastric emptying?????????????????????????????????????????????????????????????????????????????? 757
Inducing weight loss?????????????????????????????????????????????????????? 757
Gastrointestinal adverse events???????????????????????????????????????????????????????????????????????????? 758
Antibody formation?????????????????????????????????????????????????? 758
Development of inhibitors of dipeptidyl peptidase-4 (DPP-4)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 758
Sitagliptin???????????????????????????????????? 759
Vildagliptin?????????????????????????????????????? 759
Saxagliptin???????????????????????????????????? 759
Linagliptin???????????????????????????????????? 759
Alogliptin?????????????????????????????????? 759
Efficacy as glucose-lowering agents (reduction in HbA1c)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 759
Monotherapy???????????????????????????????????? 759
Add-on to oral antidiabetic agents?????????????????????????????????????????????????????????????????????????????????? 759
Add-on to insulin???????????????????????????????????????????????? 762
Comparison to GLP-1 receptor agonists???????????????????????????????????????????????????????????????????????????????????????? 762
Inability to provoke hypoglycemia???????????????????????????????????????????????????????????????????????????????? 762
Weight neutrality???????????????????????????????????????????????? 762
Adverse events?????????????????????????????????????????? 763
Concerns and expectations regarding incretin-based therapies?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 763
Cardiovascular risk???????????????????????????????????????????????????? 763
Acute pancreatitis?????????????????????????????????????????????????? 763
Pancreatic carcinoma?????????????????????????????????????????????????????? 764
C-cells, medullary thyroid carcinoma?????????????????????????????????????????????????????????????????????????????????????? 764
Clinical use of incretin-based medications?????????????????????????????????????????????????????????????????????????????????????????????????? 764
DPP-4 inhibitors versus sulfonylureas???????????????????????????????????????????????????????????????????????????????????????? 765
GLP-1 receptor agonists versus insulin?????????????????????????????????????????????????????????????????????????????????????????? 765
Recommendations for special populations???????????????????????????????????????????????????????????????????????????????????????????? 765
Renal functional impairment???????????????????????????????????????????????????????????????????? 765
Liver disease???????????????????????????????????????? 766
Gastrointestinal disease?????????????????????????????????????????????????????????????? 766
Recommendations by guidelines for the treatment of type 2 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 766
Future developments???????????????????????????????????????????????????? 768
References?????????????????????????????????? 768
Chapter 49 Insulin pumps?????????????????????????????????????????????????????????????? 771
History???????????????????????????? 771
Efficacy, benefits, data supporting insulin pump therapy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 773
Insulin pump use?????????????????????????????????????????????? 775
Real-time continuous glucose monitoring (RT-CGM) linked to insulin pump???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 776
Adding RT-CGM to pump therapy???????????????????????????????????????????????????????????????????????? 778
Future trends???????????????????????????????????????? 778
Conclusion?????????????????????????????????? 779
Acknowledgment?????????????????????????????????????????? 782
References?????????????????????????????????? 782
Chapter 50 Innovative therapies in diabetes: colesevelam and bromocriptine?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 784
Colesevelam???????????????????????????????????? 784
Mechanism of action???????????????????????????????????????????????????? 784
Pharmacokinetic and pharmacodynamics?????????????????????????????????????????????????????????????????????????????????????? 785
Efficacy of coleselevam???????????????????????????????????????????????????????????? 785
Safety of colesevelam???????????????????????????????????????????????????????? 786
Drug interactions???????????????????????????????????????????????? 787
Conclusion?????????????????????????????????? 787
Bromocriptine-QR?????????????????????????????????????????????? 787
Mechanism of action???????????????????????????????????????????????????? 787
Dosage and pharmacokinetics???????????????????????????????????????????????????????????????????? 787
Efficacy?????????????????????????????? 788
Safety?????????????????????????? 788
Contraindications???????????????????????????????????????????????? 788
Drug interactions???????????????????????????????????????????????? 788
Conclusion?????????????????????????????????? 789
Acknowledgment?????????????????????????????????????????? 789
References?????????????????????????????????? 789
Section IX Management of diabetes: monitoring and other interventions???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 791
Chapter 51 Implantable pumps and artificial and bio-artificial pancreas system?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 793
Introduction?????????????????????????????????????? 793
The artificial pancreas???????????????????????????????????????????????????????????? 794
Implanted closed-loop system?????????????????????????????????????????????????????????????????????? 794
External closed-loop system???????????????????????????????????????????????????????????????????? 794
Feasibility studies???????????????????????????????????????????????????? 796
Future directions: bio-artificial pancreas?????????????????????????????????????????????????????????????????????????????????????????????????? 797
References?????????????????????????????????? 797
Chapter 52 Pancreas and islet transplantation???????????????????????????????????????????????????????????????????????????????????????????????????????? 800
Role of pancreas and islet transplantation in management of diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 800
The pancreas transplantation procedure?????????????????????????????????????????????????????????????????????????????????????????? 801
The islet transplantation procedure???????????????????????????????????????????????????????????????????????????????????? 801
Success rates for pancreas and islet transplantation?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 802
Pancreas?????????????????????????????? 802
Autoislets?????????????????????????????????? 802
Alloislets?????????????????????????????????? 803
Clinical outcomes on diabetes complications after successful pancreas and alloislet transplantation???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 803
Beta-cell function?????????????????????????????????????????????????? 803
Alpha-cell function???????????????????????????????????????????????????? 803
Nephropathy???????????????????????????????????? 804
Neuropathy?????????????????????????????????? 805
Retinopathy???????????????????????????????????? 805
Macrovascular disease???????????????????????????????????????????????????????? 806
Quality of life???????????????????????????????????????????? 806
References?????????????????????????????????? 806
Chapter 53 Hypoglycemia and other complications of insulin therapy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 809
Introduction?????????????????????????????????????? 809
Definition of hypoglycemia?????????????????????????????????????????????????????????????????? 809
Physiologic responses to hypoglycemia???????????????????????????????????????????????????????????????????????????????????????? 811
Defects in counterregulation associated with diabetes treatments?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 812
Impaired awareness of hypoglycemia?????????????????????????????????????????????????????????????????????????????????? 812
The brain's responses to hypoglycemia???????????????????????????????????????????????????????????????????????????????????????? 813
Risk for severe hypoglycemia?????????????????????????????????????????????????????????????????????? 815
Consequences of hypoglycemia?????????????????????????????????????????????????????????????????????? 815
Nocturnal hypoglycemia?????????????????????????????????????????????????????????? 816
Addressing hypoglycemia in insulin therapy?????????????????????????????????????????????????????????????????????????????????????????????????? 817
Assessing a person with diabetes for hypoglycemia experience and risk???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 817
Management of hypoglycemia?????????????????????????????????????????????????????????????????? 817
Acute episodes?????????????????????????????????????????? 817
Prevention of future events and restoration of impaired hypoglycemia awareness?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 819
Transplantation as a treatment for hypoglycemia???????????????????????????????????????????????????????????????????????????????????????????????????????????? 820
Barriers to avoidance of hypoglycemia and restoration of impaired hypoglycemia awareness?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 820
Nonhypoglycemic complications of insulin therapy?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 820
Weight gain???????????????????????????????????? 820
Injection site issues???????????????????????????????????????????????????????? 821
Insulin allergy???????????????????????????????????????????? 821
Lipohypertrophy and lipoatrophy???????????????????????????????????????????????????????????????????????????? 821
Cancer?????????????????????????? 821
References?????????????????????????????????? 821
Chapter 54 Diabetic ketoacidosis and hyperosmolar state???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 825
Introduction?????????????????????????????????????? 825
Diabetic ketoacidosis???????????????????????????????????????????????????????? 825
Definition and classification???????????????????????????????????????????????????????????????????????? 825
Epidemiology?????????????????????????????????????? 826
Precipitating factors???????????????????????????????????????????????????????? 826
Pathogenesis?????????????????????????????????????? 827
Carbohydrate metabolism???????????????????????????????????????????????????????????? 827
Fat and ketone body metabolism?????????????????????????????????????????????????????????????????????????? 828
Protein and amino acid metabolism???????????????????????????????????????????????????????????????????????????????? 828
Water and electrolyte metabolism?????????????????????????????????????????????????????????????????????????????? 829
Diagnosis???????????????????????????????? 829
Laboratory evaluation???????????????????????????????????????????????????????? 830
Laboratory pitfalls???????????????????????????????????????????????????? 831
Hyperglycemic hyperosmolar state?????????????????????????????????????????????????????????????????????????????? 831
Definition?????????????????????????????????? 831
Epidemiology?????????????????????????????????????? 831
Precipitating and predisposing factors?????????????????????????????????????????????????????????????????????????????????????????? 831
Pathogenesis?????????????????????????????????????? 833
Diagnosis???????????????????????????????? 833
Treatment of hyperglycemic crises???????????????????????????????????????????????????????????????????????????????? 834
Hydration and fluid therapy???????????????????????????????????????????????????????????????????? 834
Insulin therapy???????????????????????????????????????????? 834
Transition to subcutaneous insulin?????????????????????????????????????????????????????????????????????????????????? 836
Potassium???????????????????????????????? 836
Bicarbonate???????????????????????????????????? 837
Phosphate???????????????????????????????? 837
Management of patients after resolution of hyperglycemic crisis???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 837
Complications of therapy?????????????????????????????????????????????????????????????? 838
Prevention of hyperglycemic crises?????????????????????????????????????????????????????????????????????????????????? 838
Future prospects?????????????????????????????????????????????? 839
Acknowledgments???????????????????????????????????????????? 839
References?????????????????????????????????? 839
Section X Management of diabetes: glucose and lipid monitoring, specific subgroups?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 841
Chapter 55 Type 2 diabetes in obese adolescents: pathophysiology and treatment?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 843
Type 2 diabetes in obese youth: a growing challenge???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 843
Clinical characteristic of T2DM in youth?????????????????????????????????????????????????????????????????????????????????????????????? 843
Beta-cell dysfunction: an early alteration in the development of T2DM???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 844
Natural history of IGT and the development of T2DM?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 845
Insulin resistance and T2DM: fat accumulation in all the wrong tissues?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 845
The muscle?????????????????????????????????? 845
The abdominal fat: a complex layer of metabolically different adipose tissues???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 845
The liver???????????????????????????????? 845
Treatment for T2DM: lessons from the TODAY study?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 846
References?????????????????????????????????? 847
Chapter 56 Diabetes in pregnancy?????????????????????????????????????????????????????????????????????????????? 849
Maternal adaptation to pregnancy?????????????????????????????????????????????????????????????????????????????? 849
Classification of glucose abnormalities in pregnancy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 849
Epidemiology of diabetes in pregnancy???????????????????????????????????????????????????????????????????????????????????????? 850
Diagnosis of gestational diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????? 850
Screening and its cost-effectiveness?????????????????????????????????????????????????????????????????????????????????????? 850
Diagnosis of GDM: the traditional criteria?????????????????????????????????????????????????????????????????????????????????????????????????? 852
The HAPO Study?????????????????????????????????????????? 852
IADPSG criteria: a new approach for the diagnosis of diabetes in pregnancy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 852
Adverse pregnancy outcomes in gestations complicated by diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 853
Congenital anomalies?????????????????????????????????????????????????????? 853
Spontaneous abortions???????????????????????????????????????????????????????? 854
Stillbirth?????????????????????????????????? 854
Macrosomia and large-for-gestational-age?????????????????????????????????????????????????????????????????????????????????????????????? 854
Detection and treatment of diabetes in pregnancy?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 854
Glycemic control targets?????????????????????????????????????????????????????????????? 854
Preconception care for pregestational diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????? 855
Diet and behavioral adjustments???????????????????????????????????????????????????????????????????????????? 855
Insulin treatment???????????????????????????????????????????????? 856
Long-acting insulin analogues???????????????????????????????????????????????????????????????????????? 856
Intermediate-acting insulin???????????????????????????????????????????????????????????????????? 856
Short-acting insulin?????????????????????????????????????????????????????? 856
Rapid-acting insulin analogues?????????????????????????????????????????????????????????????????????????? 856
Safety of insulin analogues???????????????????????????????????????????????????????????????????? 856
Oral antidiabetic agents?????????????????????????????????????????????????????????????? 856
New technologies?????????????????????????????????????????????? 857
Continuous subcutaneous insulin infusion (CSII) ("insulin pump")?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 857
Continuous glucose monitoring system (CGMS)???????????????????????????????????????????????????????????????????????????????????????????????????? 857
Special considerations during pregnancy, labor, and delivery?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 857
Fetal assessment?????????????????????????????????????????????? 857
Timing of delivery?????????????????????????????????????????????????? 858
Mode of delivery?????????????????????????????????????????????? 858
Glycemic control during labor???????????????????????????????????????????????????????????????????????? 859
Postpartum care of women with diabetes?????????????????????????????????????????????????????????????????????????????????????????? 859
Breastfeeding???????????????????????????????????????? 859
Postpartum contraception?????????????????????????????????????????????????????????????? 859
References?????????????????????????????????? 859
Chapter 57 Aging and diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????? 862
Diabetes epidemiology in older adults???????????????????????????????????????????????????????????????????????????????????????? 862
Pathophysiology of diabetes in the elderly?????????????????????????????????????????????????????????????????????????????????????????????????? 863
Metabolic alterations???????????????????????????????????????????????????????? 863
Environmental impact?????????????????????????????????????????????????????? 863
Genetic predisposition?????????????????????????????????????????????????????????? 864
Other factors???????????????????????????????????????? 864
Effect on clinical presentation???????????????????????????????????????????????????????????????????????????? 864
Prevention and management of diabetes and its comorbidities in older adults???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 864
Screening???????????????????????????????? 864
Prevention of type 2 diabetes???????????????????????????????????????????????????????????????????????? 864
Challenges and management principles?????????????????????????????????????????????????????????????????????????????????????? 865
Geriatric syndromes in older adults with diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 865
Cognitive impairment?????????????????????????????????????????????????????? 865
Depression?????????????????????????????????? 866
Polypharmacy?????????????????????????????????????? 866
Physical disability and falls???????????????????????????????????????????????????????????????????????? 867
Urinary incontinence?????????????????????????????????????????????????????? 867
Chronic pain?????????????????????????????????????? 867
Diabetes education, self-management, and decision support in the elderly?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 867
Diabetes self-management?????????????????????????????????????????????????????????????? 867
Internet-based self-management interventions?????????????????????????????????????????????????????????????????????????????????????????????????????? 867
Clinical decision support in elderly diabetes care?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 868
Shared decision-making aids???????????????????????????????????????????????????????????????????? 868
References?????????????????????????????????? 868
Chapter 58 Psychological problems and management of patients with diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 872
Introduction?????????????????????????????????????? 872
Depression?????????????????????????????????? 872
Prevalence?????????????????????????????????? 872
Associated factors?????????????????????????????????????????????????? 872
Treatments for depression???????????????????????????????????????????????????????????????? 873
Anxiety???????????????????????????? 873
Prevalence?????????????????????????????????? 873
Associated factors?????????????????????????????????????????????????? 873
Treatments for anxiety?????????????????????????????????????????????????????????? 873
Eating disorders?????????????????????????????????????????????? 874
Prevalence?????????????????????????????????? 874
Associated factors?????????????????????????????????????????????????? 874
Treatments for eating disorders???????????????????????????????????????????????????????????????????????????? 874
Neurocognitive problems???????????????????????????????????????????????????????????? 875
Prevalence?????????????????????????????????? 875
Associated factors?????????????????????????????????????????????????? 875
Treatment???????????????????????????????? 875
Future research needs???????????????????????????????????????????????????????? 875
Recommendations for clinical practice???????????????????????????????????????????????????????????????????????????????????????? 875
Conclusions???????????????????????????????????? 876
References?????????????????????????????????? 876
Chapter 59 Glycated hemoglobin, serum proteins, and other markers as tools for monitoring???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 879
Introduction?????????????????????????????????????? 879
Glycation reactions???????????????????????????????????????????????????? 880
Glycation of hemoglobin???????????????????????????????????????????????????????????? 880
Nomenclature?????????????????????????????????????? 881
Glycation in individuals with normal glucose tolerance?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 881
Kinetics of glycation???????????????????????????????????????????????????????? 881
Glycated hemoglobin in nondiabetic populations?????????????????????????????????????????????????????????????????????????????????????????????????????????? 881
Standardization of the HbA1c assay?????????????????????????????????????????????????????????????????????????????????? 882
Estimated average glucose (eAG) reporting???????????????????????????????????????????????????????????????????????????????????????????????? 882
Mean blood glucose versus estimated average glucose???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 883
HbA1c as a screening test for diabetes?????????????????????????????????????????????????????????????????????????????????????????? 883
HbA1c used for risk stratification?????????????????????????????????????????????????????????????????????????????????? 883
HbA1c as a unique index of glycemic control in type 1 diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 884
HbA1c testing for diabetes screening and monitoring in pregnancy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 884
HbA1c and chronic complications of diabetes???????????????????????????????????????????????????????????????????????????????????????????????????? 885
Assays of glycated hemoglobin???????????????????????????????????????????????????????????????????????? 886
Methods based on charge difference?????????????????????????????????????????????????????????????????????????????????? 887
Methods measuring total glycated hemoglobin???????????????????????????????????????????????????????????????????????????????????????????????????? 887
Method based on immunoassay???????????????????????????????????????????????????????????????????? 887
Frequency of HbA1c testing?????????????????????????????????????????????????????????????????? 888
HbA1c testing affected by comorbid illnesses?????????????????????????????????????????????????????????????????????????????????????????????????????? 888
Hemoglobinopathies?????????????????????????????????????????????????? 888
Uremia?????????????????????????? 888
Other metabolic conditions?????????????????????????????????????????????????????????????????? 889
Glycation of serum proteins???????????????????????????????????????????????????????????????????? 889
Assay methods for glycated serum proteins???????????????????????????????????????????????????????????????????????????????????????????????? 890
Clinical usefulness of fructosamine analysis in diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 890
Monitoring of glycemia in pregnancy???????????????????????????????????????????????????????????????????????????????????? 890
1,5-Anhydroglucitol as a measure of glycemia?????????????????????????????????????????????????????????????????????????????????????????????????????? 891
Advanced glycosylation end-products and diabetic complications?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 891
Artificial pancreas???????????????????????????????????????????????????? 892
Acknowledgments???????????????????????????????????????????? 893
References?????????????????????????????????? 893
Section XI Complications of diabetes: general and microvasular?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 899
Chapter 60 Pathogenesis of diabetic microvascular complications???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 901
Introduction?????????????????????????????????????? 901
Gene regulation???????????????????????????????????????????? 902
Can our tissues remember????????????????????????????????????????????????????????????????? 902
MicroRNA?????????????????????????????? 903
Hyperglycemia-too much fuel or not enough??????????????????????????????????????????????????????????????????????????????????????????????????? 903
Glucose metabolism?????????????????????????????????????????????????? 904
Other cellular pathways for glucose metabolism?????????????????????????????????????????????????????????????????????????????????????????????????????????? 904
Impaired insulin signaling?????????????????????????????????????????????????????????????????? 905
Hemodynamic pathways?????????????????????????????????????????????????????? 905
The renin-angiotensin-aldosterone system (RAAS)???????????????????????????????????????????????????????????????????????????????????????????????????????????? 905
Obesity and dyslipidemia?????????????????????????????????????????????????????????????? 906
Adipokines?????????????????????????????????? 907
Protein modifications and turnover?????????????????????????????????????????????????????????????????????????????????? 907
Autophagy???????????????????????????????? 907
Posttranslational modifications of proteins???????????????????????????????????????????????????????????????????????????????????????????????????? 908
Oxidative imbalances?????????????????????????????????????????????????????? 909
Nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 909
Nitric oxide synthase???????????????????????????????????????????????????????? 910
Mitochondrial sources???????????????????????????????????????????????????????? 910
Antioxidants?????????????????????????????????????? 911
Inflammation?????????????????????????????????????? 911
Adhesion molecules?????????????????????????????????????????????????? 911
Inflammatory cell infiltration?????????????????????????????????????????????????????????????????????????? 911
Inflammatory cytokines?????????????????????????????????????????????????????????? 912
Nuclear transcription factor Kappa B (NF-?B) 912
Conclusion?????????????????????????????????? 912
References?????????????????????????????????? 912
Chapter 61 Diabetic retinopathy and other ocular complications?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 915
Introduction?????????????????????????????????????? 915
Prevalence of diabetic retinopathy?????????????????????????????????????????????????????????????????????????????????? 916
Incidence and progression of diabetic retinopathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 917
Time trends in the epidemiology of diabetic retinopathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 917
Risk factors?????????????????????????????????????? 918
Hyperglycemia, hypertension, and dyslipidemia???????????????????????????????????????????????????????????????????????????????????????????????????????? 918
Duration of diabetes?????????????????????????????????????????????????????? 918
Race?????????????????????? 918
Genetic factors???????????????????????????????????????????? 918
Gender?????????????????????????? 918
Cataract surgery?????????????????????????????????????????????? 918
Relationship with other complications???????????????????????????????????????????????????????????????????????????????????????? 918
Pathogenesis?????????????????????????????????????? 919
Biochemical changes???????????????????????????????????????????????????? 919
Retinal vascular changes?????????????????????????????????????????????????????????????? 920
Clinical features and assessment?????????????????????????????????????????????????????????????????????????????? 920
Investigations?????????????????????????????????????????? 921
Recommended timing and frequency of screening for diabetic retinopathy?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 923
Systemic treatment of diabetic retinopathy?????????????????????????????????????????????????????????????????????????????????????????????????? 924
Ocular therapy?????????????????????????????????????????? 925
Laser photocoagulation?????????????????????????????????????????????????????????? 925
Intraocular antivascular endothelial growth factor (VEGF) agents?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 926
Ocular and systemic safety of intraocular anti-VEGF therapy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 927
Intraocular steroids?????????????????????????????????????????????????????? 927
Surgical intervention???????????????????????????????????????????????????????? 928
Cataract surgery?????????????????????????????????????????????? 928
Other ocular complications?????????????????????????????????????????????????????????????????? 928
Cataract?????????????????????????????? 928
Refractive error?????????????????????????????????????????????? 928
Optic disc?????????????????????????????????? 928
Ocular motility disorders???????????????????????????????????????????????????????????????? 928
Glaucoma?????????????????????????????? 929
Corneal disorders???????????????????????????????????????????????? 929
Other retinal conditions?????????????????????????????????????????????????????????????? 929
Future directions???????????????????????????????????????????????? 929
References?????????????????????????????????? 929
Chapter 62 Diabetic nephropathy???????????????????????????????????????????????????????????????????????????? 937
Definition and classification of diabetic kidney disease (DKD)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 937
Aetiology of DKD?????????????????????????????????????????????? 938
Natural history of DKD?????????????????????????????????????????????????????????? 940
Type 1 diabetes???????????????????????????????????????????? 940
Type 2 diabetes???????????????????????????????????????????? 940
Predictive value of albuminuria below the microalbuminuric range?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 941
Hyperfiltration???????????????????????????????????????????? 941
Pathophysiology???????????????????????????????????????????? 941
Clinical studies?????????????????????????????????????????????? 942
Progression of DKD to ESRD?????????????????????????????????????????????????????????????????? 943
Gene variants in DKD?????????????????????????????????????????????????????? 943
Histologic changes of DN?????????????????????????????????????????????????????????????? 943
Glomerular changes?????????????????????????????????????????????????? 943
Tubulointerstitial changes?????????????????????????????????????????????????????????????????? 944
DKD in the absence of elevated AER?????????????????????????????????????????????????????????????????????????????????? 944
Non-DKD in people with diabetes???????????????????????????????????????????????????????????????????????????? 944
Prevention, screening, and monitoring of DKD?????????????????????????????????????????????????????????????????????????????????????????????????????? 944
Management of DKD???????????????????????????????????????????????? 945
Glucose control (Table )?????????????????????????????????????????????????????????????? 945
Blood pressure (BP) control (Table )?????????????????????????????????????????????????????????????????????????????????????? 946
Renin-angiotensin system (RAS) inhibition (Table )?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 947
Dyslipidemia (Table )???????????????????????????????????????????????????????? 947
Lifestyle factors???????????????????????????????????????????????? 948
Other interventions???????????????????????????????????????????????????? 948
Multifactorial interventions?????????????????????????????????????????????????????????????????????? 949
Novel interventions???????????????????????????????????????????????????? 949
References?????????????????????????????????? 949
Chapter 63 Pathology of human diabetic neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????? 952
Introduction?????????????????????????????????????? 952
Nerve biopsy?????????????????????????????????????? 952
Myelinated fibers???????????????????????????????????????????????? 952
Density???????????????????????????? 952
Axonal atrophy?????????????????????????????????????????? 954
Axoglial dysjunction?????????????????????????????????????????????????????? 955
Unmyelinated fibers???????????????????????????????????????????????????? 956
Microvessels?????????????????????????????????????? 956
Extracellular matrix?????????????????????????????????????????????????????? 956
Variants of diabetic neuropathy???????????????????????????????????????????????????????????????????????????? 957
Skin biopsy???????????????????????????????????? 958
Diagnostic yield of IENF quantification???????????????????????????????????????????????????????????????????????????????????????????? 958
Diabetic neuropathy???????????????????????????????????????????????????? 959
Sudomotor innervation???????????????????????????????????????????????????????? 959
Corneal confocal microscopy???????????????????????????????????????????????????????????????????? 959
References?????????????????????????????????? 960
Chapter 64 Autonomic neuropathy???????????????????????????????????????????????????????????????????????????? 965
Introduction?????????????????????????????????????? 965
Epidemiology of Diabetic Autonomic Neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????????? 965
Pathogenesis of Diabetic Autonomic Neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????????? 965
Cardiovascular autonomic neuropathy???????????????????????????????????????????????????????????????????????????????????? 967
Epidemiology of CAN???????????????????????????????????????????????????? 967
Clinical sequelae of CAN (Figure )?????????????????????????????????????????????????????????????????????????????????? 967
Gastrointestinal autonomic neuropathy???????????????????????????????????????????????????????????????????????????????????????? 970
Epidemiology of GAN???????????????????????????????????????????????????? 970
Pathogenesis of GAN???????????????????????????????????????????????????? 970
Diagnosis of GAN (Table )???????????????????????????????????????????????????????????????? 970
Clinical manifestations of GAN?????????????????????????????????????????????????????????????????????????? 971
Modulation of gastric emptying to improve glycemic control?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 972
Genitourinary autonomic neuropathy?????????????????????????????????????????????????????????????????????????????????? 972
Erectile / sexual dysfunction (Figure )???????????????????????????????????????????????????????????????????????????????????????????? 972
Bladder dysfunction???????????????????????????????????????????????????? 974
Sudomotor dysfunction (including gustatory sweating)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 974
Pupillary abnormalities???????????????????????????????????????????????????????????? 974
Autonomic neuropathy and the response to hypoglycemia???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 974
Conclusions???????????????????????????????????? 974
Conflict of interest disclosure???????????????????????????????????????????????????????????????????????????? 975
References?????????????????????????????????? 975
Chapter 65 Connective tissue disorders in diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 979
Introduction?????????????????????????????????????? 979
Skeleton?????????????????????????????? 979
Osteopenia?????????????????????????????????? 979
Hyperostosis?????????????????????????????????????? 980
Joints?????????????????????????? 980
Osteoarthritis?????????????????????????????????????????? 980
Osteolysis?????????????????????????????????? 980
Rheumatoid arthritis?????????????????????????????????????????????????????? 980
Skin and periarticular tissue???????????????????????????????????????????????????????????????????????? 981
Scleredema diabeticorum???????????????????????????????????????????????????????????? 981
Dupuytren disease???????????????????????????????????????????????? 981
Stiff hand syndrome???????????????????????????????????????????????????? 981
Carpal tunnel syndrome?????????????????????????????????????????????????????????? 981
Flexor tenosynovitis?????????????????????????????????????????????????????? 981
Adhesive capsulitis of the shoulder and shoulder-hand syndrome?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 981
Limited joint mobility (LJM)/Rosenbloom syndrome (RS)???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 982
Conclusion?????????????????????????????????? 987
References?????????????????????????????????? 987
Chapter 66 The diabetic foot?????????????????????????????????????????????????????????????????????? 990
Introduction?????????????????????????????????????? 990
Incidence and prevalence of diabetic foot ulcers?????????????????????????????????????????????????????????????????????????????????????????????????????????????? 990
Peripheral vascular disease???????????????????????????????????????????????????????????????????? 990
Diabetic peripheral neuropathy?????????????????????????????????????????????????????????????????????????? 991
Distal symmetrical sensorimotor peripheral neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 991
Peripheral sympathetic autonomic neuropathy???????????????????????????????????????????????????????????????????????????????????????????????????? 992
Other risk factors for foot ulceration?????????????????????????????????????????????????????????????????????????????????????????? 992
Nephropathy???????????????????????????????????? 992
Incidence of neuropathic foot ulcers?????????????????????????????????????????????????????????????????????????????????????? 993
The pathway to foot ulceration?????????????????????????????????????????????????????????????????????????? 993
Identification of the high-risk foot?????????????????????????????????????????????????????????????????????????????????????? 993
Assessment?????????????????????????????????? 993
Infection and diabetic foot ulcers?????????????????????????????????????????????????????????????????????????????????? 994
Management of diabetic foot ulcers?????????????????????????????????????????????????????????????????????????????????? 995
Debridement???????????????????????????????????? 995
Off-loading???????????????????????????????????? 995
Wound dressings???????????????????????????????????????????? 995
Negative pressure wound therapy???????????????????????????????????????????????????????????????????????????? 996
Growth factors and skin substitutes???????????????????????????????????????????????????????????????????????????????????? 996
Multidisciplinary team input?????????????????????????????????????????????????????????????????????? 996
Patient education???????????????????????????????????????????????? 997
Charcot neuroarthropathy?????????????????????????????????????????????????????????????? 998
Diagnosis of Charcot neuroarthropathy???????????????????????????????????????????????????????????????????????????????????????? 998
Medical management of Charcot neuroarthropathy?????????????????????????????????????????????????????????????????????????????????????????????????????????? 998
Surgical management of Charcot neuroarthropathy???????????????????????????????????????????????????????????????????????????????????????????????????????????? 999
Conclusion?????????????????????????????????? 999
References?????????????????????????????????? 999
Chapter 67 Erectile dysfunction in diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1001
Introduction?????????????????????????????????????? 1001
Epidemiology?????????????????????????????????????? 1001
Pathophysiology???????????????????????????????????????????? 1002
Changes within the corpus cavernosum?????????????????????????????????????????????????????????????????????????????????????? 1002
Neurologic factors?????????????????????????????????????????????????? 1003
Vascular factors?????????????????????????????????????????????? 1003
Hypogonadism?????????????????????????????????????? 1003
Other endocrine factors???????????????????????????????????????????????????????????? 1005
Drugs???????????????????????? 1005
Psychological factors???????????????????????????????????????????????????????? 1005
Lifestyle factors???????????????????????????????????????????????? 1005
Other factors???????????????????????????????????????? 1005
ED: a marker for cardiovascular disease (CVD)???????????????????????????????????????????????????????????????????????????????????????????????????????? 1006
Management?????????????????????????????????? 1006
Clinical assessment???????????????????????????????????????????????????? 1006
Treatment options???????????????????????????????????????????????? 1006
Conclusions???????????????????????????????????? 1011
References?????????????????????????????????? 1011
Chapter 68 Periodontal disease and diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1014
Introduction?????????????????????????????????????? 1014
Periodontal disease???????????????????????????????????????????????????? 1014
Diabetes?????????????????????????????? 1015
Periodontal diseases: assessment?????????????????????????????????????????????????????????????????????????????? 1015
Self-reported periodontal disease???????????????????????????????????????????????????????????????????????????????? 1018
Periodontal diseases and inflammation: localized and generalized?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1018
Conceptual model of pathways linking periodontitis to diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1019
Periodontal disease and diabetes mellitus: a two-way relationship???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1019
Oral-systemic evidence reviewed by experts from Europe and the USA?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1020
Effect of diabetes on periodontal disease???????????????????????????????????????????????????????????????????????????????????????????????? 1020
Type 1 diabetes???????????????????????????????????????????? 1021
Effect of diabetes intervention on periodontitis in type 2 diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1021
Effect of periodontal disease on diabetes???????????????????????????????????????????????????????????????????????????????????????????????? 1021
Effect of periodontal treatment on diabetes???????????????????????????????????????????????????????????????????????????????????????????????????? 1022
Effect of periodontal disease on diabetes complications???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1023
Periodontal disease and diabetes-related medical care costs???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1023
Medical care costs related to periodontal care?????????????????????????????????????????????????????????????????????????????????????????????????????????? 1023
Hospitalizations and physician office visits?????????????????????????????????????????????????????????????????????????????????????????????????????? 1024
Periodontal care and glycemic control???????????????????????????????????????????????????????????????????????????????????????? 1024
Guidelines for oral health in people with diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1024
International Diabetes Federation (IDF)???????????????????????????????????????????????????????????????????????????????????????????? 1024
American Diabetes Association (ADA)???????????????????????????????????????????????????????????????????????????????????? 1024
European Federation of Periodontology (EFP) and the American Academy of Periodontology (AAP)?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1025
Co-management of patients with diabetes by dental and medical care providers?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1025
Focus on oral health in medical practice: why medical health professionals should pay attention to the health of the mouth?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1025
Focus on diabetes in the dental office: should dental health professionals screen for diabetes????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1025
Future healthcare collaboration for diabetes prevention and lifelong management???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1027
References?????????????????????????????????? 1028
Section XII Complications of diabetes: macrovascular?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1031
Chapter 69 Epidemiology of macrovascular disease and hypertension in diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1033
Introduction?????????????????????????????????????? 1033
Hypertension?????????????????????????????????????? 1033
Prevalence and incidence?????????????????????????????????????????????????????????????? 1033
Proteinuria/Microalbuminuria and BP???????????????????????????????????????????????????????????????????????????????????? 1034
Hyperinsulinemia/insulin resistance and BP?????????????????????????????????????????????????????????????????????????????????????????????????? 1034
Hyperglycemia and BP?????????????????????????????????????????????????????? 1035
Diurnal blood pressure variability?????????????????????????????????????????????????????????????????????????????????? 1036
Atherosclerosis???????????????????????????????????????????? 1036
Coronary heart disease?????????????????????????????????????????????????????????? 1037
Prevalence and incidence?????????????????????????????????????????????????????????????? 1037
Mortality and case-fatality in AMI?????????????????????????????????????????????????????????????????????????????????? 1038
Risk factors for CHD in diabetic patients???????????????????????????????????????????????????????????????????????????????????????????????? 1039
Stroke and cerebrovascular diseases???????????????????????????????????????????????????????????????????????????????????? 1041
Incidence and mortality???????????????????????????????????????????????????????????? 1041
Risk factors for stroke in diabetic patients?????????????????????????????????????????????????????????????????????????????????????????????????????? 1042
Asymptomatic hyperglycemia and CVD risk???????????????????????????????????????????????????????????????????????????????????????????? 1043
REFERENCES?????????????????????????????????? 1046
Chapter 70 Atherogenesis, coronary heart disease and insulin resistance syndrome in diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1057
Diabetes mellitus and the burden of cardiovascular disease?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1057
Insulin resistance (metabolic) syndrome???????????????????????????????????????????????????????????????????????????????????????????? 1058
Hyperglycemia, glycemic control, and CVD?????????????????????????????????????????????????????????????????????????????????????????????? 1059
Diabetes and atherosclerosis?????????????????????????????????????????????????????????????????????? 1061
Pathogenesis linking metabolic syndrome, diabetes, and atherogenesis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1062
Hyperglycemia and glucotoxicity???????????????????????????????????????????????????????????????????????????? 1062
Insulin resistance and hyperinsulinemia???????????????????????????????????????????????????????????????????????????????????????????? 1064
Dyslipidemia, lipotoxicity, and lipid mediators of insulin resistance???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1064
Metabolic inflammation and adiposity?????????????????????????????????????????????????????????????????????????????????????? 1066
Conclusion?????????????????????????????????? 1068
References?????????????????????????????????? 1068
Chapter 71 Endothelial function and metabolic syndrome?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1072
Introduction: the metabolic syndrome?????????????????????????????????????????????????????????????????????????????????????? 1072
Endothelial dysfunction and MetS?????????????????????????????????????????????????????????????????????????????? 1072
Endothelial microparticles (EMP)?????????????????????????????????????????????????????????????????????????????? 1073
Endothelial microparticles and MetS???????????????????????????????????????????????????????????????????????????????????? 1073
Endothelial progenitor cells (EPC)?????????????????????????????????????????????????????????????????????????????????? 1073
EPC and cardiovascular events???????????????????????????????????????????????????????????????????????? 1073
EPC and MetS?????????????????????????????????????? 1074
Conclusion?????????????????????????????????? 1074
References?????????????????????????????????? 1075
Chapter 72 Hemostatic abnormalities in diabetes mellitus?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1077
Introduction?????????????????????????????????????? 1077
Mechanisms of thrombosis?????????????????????????????????????????????????????????????? 1078
The hemostatic system???????????????????????????????????????????????????????? 1078
Fibrinogen?????????????????????????????????? 1078
Factor XIII activation and fibrin cross-linking???????????????????????????????????????????????????????????????????????????????????????????????????????????? 1078
Fibrinolysis?????????????????????????????????????? 1078
Platelet activation???????????????????????????????????????????????????? 1078
Summary???????????????????????????? 1079
Mechanisms of thrombosis in diabetes?????????????????????????????????????????????????????????????????????????????????????? 1079
Fibrinolysis?????????????????????????????????????? 1079
Coagulation???????????????????????????????????? 1080
Fibrin structure in diabetes?????????????????????????????????????????????????????????????????????? 1081
The platelet in diabetes?????????????????????????????????????????????????????????????? 1081
The effects of glucose and glycation on thrombosis?????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1082
Inflammatory, thrombotic interactions???????????????????????????????????????????????????????????????????????????????????????? 1083
Circadian regulation of thrombotic mechanisms???????????????????????????????????????????????????????????????????????????????????????????????????????? 1083
Ameliorating thrombotic risk in diabetes?????????????????????????????????????????????????????????????????????????????????????????????? 1084
Hypoglycemic agents???????????????????????????????????????????????????? 1084
Aspirin???????????????????????????? 1084
Clopidogrel???????????????????????????????????? 1084
Prasugrel???????????????????????????????? 1084
Ticagrelol?????????????????????????????????? 1084
Dipyridamol and cilostazol?????????????????????????????????????????????????????????????????? 1085
Inhibitors of platelet-fibrinogen interaction???????????????????????????????????????????????????????????????????????????????????????????????????????? 1085
Coagulation inhibitors?????????????????????????????????????????????????????????? 1085
Summary and conclusions???????????????????????????????????????????????????????????? 1085
References?????????????????????????????????? 1086
Chapter 73 Clinical features and treatment of coronary heart disease in diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1090
Introduction?????????????????????????????????????? 1090
Key practical features of the relationship between CHD and diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1090
CHD at onset of diabetes?????????????????????????????????????????????????????????????? 1090
Duration of diabetes and CHD?????????????????????????????????????????????????????????????????????? 1091
Acute coronary syndromes and diabetes???????????????????????????????????????????????????????????????????????????????????????? 1091
Prognosis of CHD and diabetes???????????????????????????????????????????????????????????????????????? 1091
Screening for diabetes and prediabetes in patients with established CHD???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1092
Specific clinical features of CHD in diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????? 1093
Morphology of CHD???????????????????????????????????????????????? 1093
Symptomatology?????????????????????????????????????????? 1093
Cardiac autonomic neuropathy?????????????????????????????????????????????????????????????????????? 1093
Cardiomyopathy?????????????????????????????????????????? 1094
Heart failure???????????????????????????????????????? 1096
Microvascular disease of the heart?????????????????????????????????????????????????????????????????????????????????? 1096
Arrhythmias???????????????????????????????????? 1096
Cardiovascular risk related to diabetes therapy???????????????????????????????????????????????????????????????????????????????????????????????????????????? 1096
Defining the vulnerable patient with critical hypoglycemia?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1096
Mechanisms and links to cardiovascular complications during critically low glycemia???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1097
Coincidence of hypoglycemia and arrhythmias???????????????????????????????????????????????????????????????????????????????????????????????????? 1097
Impact of antidiabetic treatment on risk of hypoglycemia and arrhythmias?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1099
Conclusion?????????????????????????????????? 1099
Management aspects?????????????????????????????????????????????????? 1099
No clear evidence for routine screening, but for risk reduction???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1099
The diabetic patient after the cardiovascular event???????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1100
Lessons learned from revascularization trials???????????????????????????????????????????????????????????????????????????????????????????????????????? 1100
The metabolic component???????????????????????????????????????????????????????????? 1100
Concluding remarks?????????????????????????????????????????????????? 1101
References?????????????????????????????????? 1101
Chapter 74 Arterial hypertension in diabetes: etiology and treatment?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1105
Introduction?????????????????????????????????????? 1105
Genetics factors?????????????????????????????????????????????? 1106
Ion transport homeostasis???????????????????????????????????????????????????????????????? 1106
Extracellular sodium homeostasis?????????????????????????????????????????????????????????????????????????????? 1108
Sympathetic activity?????????????????????????????????????????????????????? 1108
Therapeutic considerations?????????????????????????????????????????????????????????????????? 1109
Conclusion?????????????????????????????????? 1112
References?????????????????????????????????? 1112
Chapter 75 Peripheral vascular and cerebrovascular disease in diabetes mellitus???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1117
Introduction?????????????????????????????????????? 1117
Diabetes and risk of vascular disease???????????????????????????????????????????????????????????????????????????????????????? 1117
Diabetes and peripheral arterial disease?????????????????????????????????????????????????????????????????????????????????????????????? 1117
Diagnosis???????????????????????????????? 1118
Treatment???????????????????????????????? 1119
Glycemia?????????????????????????????? 1120
Antiplatelet therapy?????????????????????????????????????????????????????? 1121
Lipids?????????????????????????? 1121
Blood pressure?????????????????????????????????????????? 1122
Lifestyle???????????????????????????????? 1122
Revascularization???????????????????????????????????????????????? 1123
Diabetes and cerebrovascular disease?????????????????????????????????????????????????????????????????????????????????????? 1123
Prevention of stroke?????????????????????????????????????????????????????? 1123
Blood pressure?????????????????????????????????????????? 1123
Lipids?????????????????????????? 1123
Antiplatelet therapy?????????????????????????????????????????????????????? 1123
Revascularization???????????????????????????????????????????????? 1124
Treatment of acute stroke???????????????????????????????????????????????????????????????? 1124
Conclusions???????????????????????????????????? 1125
References?????????????????????????????????? 1125
Section XIII Diabetes and public health???????????????????????????????????????????????????????????????????????????????????????????? 1129
Chapter 76 The diabetes challenge: from human and social rights to the empowerment of people with diabetes?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1131
Introduction?????????????????????????????????????? 1131
The right to health???????????????????????????????????????????????????? 1132
Human and social rights of people with diabetes???????????????????????????????????????????????????????????????????????????????????????????????????????????? 1133
Rights and responsibilities on diabetes information and education???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1134
Conclusion: the way forward???????????????????????????????????????????????????????????????????? 1136
References?????????????????????????????????? 1137
Chapter 77 The economics of diabetes care: a global perspective???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1139
Introduction?????????????????????????????????????? 1139
The scope of this chapter???????????????????????????????????????????????????????????????? 1139
The economic impact of diabetes???????????????????????????????????????????????????????????????????????????? 1140
Estimates of costs-from different perspectives?????????????????????????????????????????????????????????????????????????????????????????????????????????? 1140
Drivers of direct costs???????????????????????????????????????????????????????????? 1142
When individuals and families pay the cost of care themselves???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1142
The consequences of less-than-optimum therapy???????????????????????????????????????????????????????????????????????????????????????????????????????? 1143
The cost effectiveness and cost utility of interventions?????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1144
The cost-effectiveness plane?????????????????????????????????????????????????????????????????????? 1144
What do clinicians and policy makers need to know in terms of analytical studies in diabetes????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1145
What does the recent literature tell us about cost-saving and cost-effective interventions for primary prevention and for managing established diabetes??????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1145
The information that we have is not what we need most???????????????????????????????????????????????????????????????????????????????????????????????????????????????????????? 1147
Acknowledgments???????????????????????????????????????????? 1149
References?????????????????????????????????? 1149
Index???????????????????????? 1151
Supplemental Images???????????????????????????????????????????????????? 1179
EULA?????????????????????? 1203
| Erscheint lt. Verlag | 5.3.2015 |
|---|---|
| Sprache | englisch |
| Themenwelt | Sachbuch/Ratgeber ► Gesundheit / Leben / Psychologie |
| Medizinische Fachgebiete ► Innere Medizin ► Diabetologie | |
| Medizinische Fachgebiete ► Innere Medizin ► Endokrinologie | |
| Studium ► 1. Studienabschnitt (Vorklinik) ► Biochemie / Molekularbiologie | |
| Schlagworte | Diabetes • Diabetes, Endocrinology, Diabetes Mellitus, Diabetic, Insulin, Glucose Tolerance, Type 1 Diabetes, Type 2 Diabetes, Obesity, Diabetes Management, Diabetes Complications, Public Health, Diabetes Monitoring, Hypoglycaemia, Diabetic Nephropathy, Diabetic Retinopathy, Macrovascular. • Diabetes mellitus • endocrinology • Endokrinologie • Medical Science • Medizin |
| ISBN-13 | 9781118387689 / 9781118387689 |
| Informationen gemäß Produktsicherheitsverordnung (GPSR) | |
| Haben Sie eine Frage zum Produkt? |
PDF (Adobe DRM)Kopierschutz: Adobe-DRM
Adobe-DRM ist ein Kopierschutz, der das eBook vor Mißbrauch schützen soll. Dabei wird das eBook bereits beim Download auf Ihre persönliche Adobe-ID autorisiert. Lesen können Sie das eBook dann nur auf den Geräten, welche ebenfalls auf Ihre Adobe-ID registriert sind.
Details zum Adobe-DRM
Dateiformat: PDF (Portable Document Format)
Mit einem festen Seitenlayout eignet sich die PDF besonders für Fachbücher mit Spalten, Tabellen und Abbildungen. Eine PDF kann auf fast allen Geräten angezeigt werden, ist aber für kleine Displays (Smartphone, eReader) nur eingeschränkt geeignet.
Systemvoraussetzungen:
PC/Mac: Mit einem PC oder Mac können Sie dieses eBook lesen. Sie benötigen eine
eReader: Dieses eBook kann mit (fast) allen eBook-Readern gelesen werden. Mit dem amazon-Kindle ist es aber nicht kompatibel.
Smartphone/Tablet: Egal ob Apple oder Android, dieses eBook können Sie lesen. Sie benötigen eine
Geräteliste und zusätzliche Hinweise
Buying eBooks from abroad
For tax law reasons we can sell eBooks just within Germany and Switzerland. Regrettably we cannot fulfill eBook-orders from other countries.
aus dem Bereich
