Metabolic Syndrome and Cardiovascular Disease (eBook)

Metabolic Syndrome and Cardiovascular Disease 5
Contents 7
Preface 10
List of Abbreviations 11
1 The Metabolic Syndrome: A Relevant Concept? 17
2 Mitochondria 19
Background 19
Derivation 19
Implications of life with mitochondria 19
Structure 19
Number 21
Location 21
Dynamics 21
Function 21
Mitochondrial-cell communications 22
Cellular respiration 22
Metabolic phenotype 23
Respiration of glucose 23
Respiration of fatty acids 23
The tricarboxylic acid cycle 23
The electron transport chain 24
The mitochondrial membrane potential 24
Modulation of mitochondrial metabolic activity 25
Mitochondrial biogenesis 25
Mitochondrial removal 25
Mitochondrial uncoupling 25
Factors that affect mitochondrial number and activity 26
Nuclear transcriptional regulators of mitochondrial function 26
Other factors 26
Peroxisome proliferator–activated receptor gamma coactivator-1 27
Mitochondrial production of prooxidant species 28
Mitochondrial production of prooxidants 28
Increased mitochondrial ROS production 28
Regulation of mitochondrial ROS formation 29
Mitochondrial redox signaling pathways 29
Targets of mitochondrial prooxidant damage 30
Mitochondrial antioxidant defense 30
Mitochondria and nitric oxide 31
Mitochondrial NOS 31
Nitric oxide impact on metabolism 32
Mitochondrial calcium homeostasis 33
Calcium uptake 33
Functions of mitochondrial calcium 34
The mitochondrial permeability transition 34
Mitochondrial permeability transition pore structure 34
Function of the permeability transition pore 35
Conditions that promote MPTP patency 36
Inhibition of MPTP opening 36
Mode of MPTP patency 37
Apoptosis 38
Phases of apoptosis 38
Calcium release and propagation of permeability transition 38
Causes for mitochondrial dysfunction 38
Mitochondrial diseases 38
Stress 39
Inflammation 39
External stressors on mitochondrial function 42
Other factors 43
Implications of mitochondrial dysfunction 43
Metabolic deficit 43
Proinflammatory signaling 43
Tissue effects 43
Mitochondrial dysfunction and cardiovascular disease 43
Endothelial dysfunction 44
Hypertension 44
Coronary heart disease 44
Impaired preconditioning 44
Cardiac hypertrophy and cardiomyopathy 44
Electrophysiological dysfunction 45
Mitochondrial dysfunction and metabolic disease 45
Exercise capacity and insulin resistance 45
Skeletal muscle mitochondria 45
Sarcopenia 46
Insulin resistance and type 2 DM 46
Nonalcoholic fatty liver disease 48
Conclusion 48
Bibliography 50
3 Telomeres 56
Telomere structure 56
Telomere DNA 56
Telomere proteins 56
Telomere capping and uncapping 56
Measurement of telomere length 57
Telomere function 57
Telomere shortening 57
DNA replication and the end-replication problem 57
Critical telomere length 57
Telomere dysfunction 58
The DNA-damage response 58
Other causes of telomere dysfunction 58
Physiologic age 58
Determinants of telomere length 58
Marker of physiologic aging 59
Gender differences 59
Estrogen and telomeres 59
Estrogen and telomerase 59
Telomerase 59
Telomerase components 60
Telomerase activity 60
Telomerase activation 61
Telomerase inactivation 62
Telomerase deficiency 62
Cell senescence and apoptosis 62
Triggers of cell senescence 63
Pathways of cell senescence 64
Senescence phenotype and markers 64
Role of senescence 64
Apoptosis 65
Telomeres in aging 65
Premature aging syndromes 65
Aging tissues and phenotype 65
Mechanisms of aging 66
Telomeres and survival 66
Risk factors for cardiometabolic disease 67
Inactivity 67
Obesity 67
Chronic oxidative stress 67
Inflammation 68
Psychological stress 69
Cigarette consumption 69
Hypertension 69
Telomeres, senescence, and chronic disease 70
Cardiovascular disease 70
Telomere shortening in vascular cells 70
Vascular dysfunction 70
Telomeres and atherosclerosis 71
Aging heart and cardiomyopathy 73
Insulin resistance and type 2 DM 73
Senescent adipose tissue 73
Vascular disease 74
Cardiomyopathy 74
Hepatic steatosis 74
Conclusion 74
Bibliography 76
4 The FoxO Transcription Factors and Sirtuins 80
Forkhead transcription factors 80
FoxO nuclear activities 80
Control of FoxO via phosphorylation 81
Control of FoxO via acetylation 83
Functions of FoxO 84
Oxidative stress resistance 84
Antiinflammatory effect 85
Cell and tissue life cycle 85
Cardiovascular forkhead effects 86
Vascular FoxO effects 86
Cardiac effects 88
Metabolic forkhead effects 88
Mitochondrial function and PGC-1alpha 88
Insulin 88
Hepatic effects 88
Muscle effects 89
Adipose tissue effects 90
Histone acetylation and deacetylation 91
Transcriptional silencing 91
Nucleosomes 91
Histones 91
Histone control of gene expression 91
Histone acetylation and deacetylation 91
HATs and HDACs 92
Sirtuin deacetylases 92
Sir2 92
Sirt1 93
Sirt1–7 93
NAD+ and sirtuins 93
Sirtuin regulation 94
Sirtuin inhibition 94
Sirtuin activation 95
Antiinflammatory, cardiovascular, and myocyte sirtuin effects 96
Sirtuin effects on inflammation 96
Sirtuin effects on the vasculature 97
Sirtuin effects on the heart 97
Sirtuin effects on metabolism 97
Activation of PGC-1alpha 97
Mitochondrial biogenesis and activity 97
Activation of acetyl CoA synthetase 98
Adipose tissue effects 98
Sirtuin effects on muscle 98
Sirtuin effects on insulin and anabolic pathways 99
Sirtuins and cell longevity 99
Sirtuin effects on tissue stress response 99
Sirtuin effects on senescence 100
Sirtuin effects on cell death suppression 100
Negative sirtuin effects on longevity 100
Forkhead deregulation and insulin resistance 101
Selective insulin resistance 101
IR cardiovascular effects 101
IR mitochondrial effects 102
IR hepatic effects 102
IR muscle effects 103
IR adipose effects 103
IR pancreatic effects 103
Paradoxical effect of nutrition versus stress on cell death suppression 103
Growth and development 103
Cytoprotection 103
Stress-resistant states 104
FoxO effects on cell lifespan 104
FoxO versus Akt effects on cell lifespan 104
FoxO versus insulin effects on cell lifespan 105
Conclusion 105
Bibliography 106
5 Insulin and Insulin-Like Growth Factor 112
Anabolism and catabolism 112
Control of plasma glucose 112
Insulin 113
Structure 113
Synthesis 113
Secretion 113
Insulin receptor location 114
Caveolae 114
The Insulin receptor location in caveolae 116
Integrity of caveolae and insulin signaling 117
Metabolic insulin signaling 117
Insulin receptor signaling 117
Protooncogene c-Cbl metabolic insulin signaling 118
Insulin-mediated glucose uptake 119
Facilitated diffusion 119
GLUT proteins 119
Types of GLUT 119
GLUT4 119
Nutrient storage and metabolism 120
Insulin-mediated glucose disposal 120
Fatty acid uptake in adipose tissue 120
Amino acid uptake 121
Phosphate transport 121
Insulin effects on oxidative metabolism 121
Insulin contractile effects 121
Neurohormonal effects of insulin 122
Vascular and antiinflammatory effects 122
Endothelial function 122
Insulin antioxidant effects 122
Insulin antiinflammatory effects 122
Anticoagulant effects 122
Cytoprotective and antiapoptotic effects 122
Mitogenic action 123
Akt 123
Target of rapamycin 123
MAPK 124
Insulin-like growth factor 124
Structure and synthesis 124
IGF-1 levels 124
IGF-1 receptors 125
IGF-1 function 125
IGF-1 target organs 126
Insulin and IGF impact on cell longevity 127
Akt 128
Ras 128
Mitochondrial function 128
FoxO 128
Sirt1 128
Local versus systemic levels of IGF-1 128
Amylin 129
Glucagon 129
Cessation of insulin secretion 129
Secretion of glucagon 129
Hepatic and adipose tissue effects of glucagon 129
Conclusion 129
Bibliography 130
6 Oxidative Stress 136
Free radicals 136
Oxidases 136
NADH/NADPH oxidase 137
Xanthine oxidase 138
iNOS 138
Uncoupled eNOS 138
Myeloperoxidase 138
Lipoxygenase 139
Cyclooxygenase 139
Cytochrome P450 monooxygenase 139
Sources for free radicals 139
Mitochondria 139
Inflammation 139
Vascular stretch 140
Food intake 140
Hyperlipidemia 140
Free fatty acids 140
Hyperglycemia 140
Endogenous antioxidants 140
Glutathione peroxidases 140
Superoxide dismutase 141
Catalase 141
Bilirubin 141
Thioredoxins 141
Nitric oxide 141
Insulin 141
Antioxidants and longevity 142
Deficient antioxidant defenses 142
Physiologic functions of oxidative stress 142
Host defense 142
ROS as signaling molecules 142
Mechanisms of oxidative damage 143
Cellular stress-sensitive pathways 143
Nuclear Factor kappaB 144
Stress-activated protein kinases 144
Cellular targets of oxidative stress 144
Mitochondria 144
Telomeres 144
Forkhead transcription factors 145
Oxidative stress-related diseases 145
Endothelial dysfunction with oxidative stress 145
eNOS expression and activity 146
NO bioavailability and signaling 146
Cardiovascular disease 146
Risk factors 147
Increased vascular tone 147
Atherosclerosis 147
Insulin resistance and type 2 DM 147
Serine/threonine phosphorylation 148
Propagation of oxidative stress pathways 148
Hexosamine pathway 148
Advanced glycosylation endproducts 148
Pancreatic islet beta-cell dysfunction 149
Conclusion 149
Bibliography 150
7 Mental Stress 155
Stress responses 155
Central stress pathways 155
The hippocampus 155
The amygdala 156
The hypothalamus and brainstem 156
Peripheral stress pathways 156
The sympathetics 156
The HPA axis 157
The RAAS 157
Endothelin 157
Fight-flight-fright responses to acute stress 158
Active response 158
Passive response 158
Sequelae of sustained passive stress 158
Stress-sensitive conditions 158
Individual variability in stress sensitivity 158
Inflammatory effects of stress pathways 159
Inflammatory markers 159
Blunted immune response 159
Vascular and lipoprotein effects of stress pathways 159
Impaired endothelial function 159
Hypertension 160
Lipoprotein levels 160
Vascular disease 160
Stress impact on body weight 162
Weight loss 162
Weight gain 162
Metabolic effects of stress pathways 162
Glucocorticoid effects on insulin and insulin resistance 163
The sympatho-adrenal axis and insulin 164
RAAS effects 165
Endothelin-1 165
Examples of stress effects on metabolism 165
Depression and other mood disturbances 165
Neurohormonal changes with depression 166
Inflammatory activation with depression 166
Endothelial dysfunction with depression 166
Procoagulant status and impaired fibrinolysis 166
Cardiovascular disease 166
Cardiovascular mortality and sudden death 167
Insulin resistance 167
Hostility 167
Optimism 168
Conclusion 168
Bibliography 169
8 Sleep 175
Stages of sleep 175
Rapid eye movement sleep 175
Nonrapid eye movement sleep 176
Sleep stage progression 176
Cardiovascular parameters during normal sleep 176
Heart rate during sleep 176
Heart rate variability during sleep stages 176
Blood pressure during sleep 177
Function of sleep 177
Security 177
Neurobiology 178
Oxidative stress 178
Immunity and inflammation 179
Anabolism 179
Cardiovascular function 180
Metabolism 180
Sleep duration 180
Age-related optimal sleep duration 180
Sleep duration and health 181
Individual variability in sleep duration 181
Societal impact on sleep patterns 181
Circadian rhythm 181
Characteristics of circadian rhythms 181
Modulators of circadian rhythms 181
Circadian rhythms in pro- and eukaryotes 181
Clock genes 182
Clock cells 182
Circadian pacemaker 182
Photic interface with the circadian rhythm 182
Examples of circadian regulation 182
Circadian control of arousal and sleep 183
Cardiac circadian rhythm 184
Metabolic circadian rhythm 184
Circadian rhythm disturbance 184
Neurohormonal modulation of wakefulness 184
Histamine 185
Acetylcholine 185
Norepinephrine 185
The HPA axis 185
Neurohormonal modulation of sleep 186
Melatonin 186
Adenosine 187
Prostaglandins 187
Cytokines 187
Growth hormone and growth-hormone-releasing hormone 188
Sleep–arousal transitions 188
Orexins 188
Nitric oxide 190
Sleep deficit 190
Causes of inadequate sleep 190
Sleepiness versus fatigue 191
Sleep recovery 191
Pathophysiologic effects of sleep debt 191
Cognitive function and mood 191
Circadian rhythms 192
Oxidative stress 192
Stress 192
Immune effects 192
Hormonal effects 192
Sleep debt and risk of cardiometabolic disorder 193
Cardiovascular effects 193
Energy and metabolism 194
Insulin sensitivity and insulin secretion 195
Type 2 diabetes mellitus 195
Sleep disorders 195
Narcolepsy 195
Insomnia 196
Sleep apnea 197
Conclusion 198
Bibliography 199
9 Inflammation 208
Immune responses 208
Innate immunity 208
Adaptive immunity 209
Selected participants in the inflammatory response 209
Toll-like receptors 209
Nuclear factor kappaB 210
Cytokines 210
Chemokines 211
Rho, Rac, and other GTPase molecule 212
C-reactive protein 214
Inflammatory marker assays 214
C-reactive protein 214
The renin–angiotensin–aldosterone system and inflammation 215
The systemic RAAS 215
The local RAAS 215
Angiotensins 215
The mineralocorticoid aldosterone 217
Inflammation and chronic diseases 218
Inflammation, endothelial and vascular dysfunction 218
NF kappaB 218
TNF-alpha 218
Other cytokines 219
Rho-Rho kinase 219
C-Reactive protein 220
Angiotensin II 220
Aldosterone 220
Vascular stiffness 220
Antiinflammatory cytokines and endothelial function 221
Inflammation and atherosclerosis 221
Inflammatory markers in cardiovascular disease 221
Inflammation in the vessel wall 222
Atherogenesis 224
Acute inflammation, carbohydrate metabolism, and dyslipidemia 226
Dysregulated carbohydrate metabolism with inflammation 226
Protein metabolism with inflammation 228
Lipid metabolism with inflammation 228
Chronic inflammation and the metabolic syndrome 229
Inflammatory markers and the risk of metabolic syndrome and type 2 DM 229
Inflammation resulting from the metabolic syndrome 230
The metabolic syndrome and atherogenesis 230
Causes for systemic inflammation 231
Aging 231
Food intake 232
Obesity 232
Stress 233
Chronic inflammatory diseases 233
Chronic infectious diseases 233
Conclusion 234
Bibliography 235
10 Adipose Tissue and Overweight 244
Energy storage 244
Adipocytes 244
Lipogenesis 245
Lipolysis 246
Diverse fat depots 246
Brown adipose tissue 246
Subcutaneous adipose tissue 247
Visceral adipose tissue 247
Ectopic fat storage 249
Adipose tissue as immune organ 250
Adipose metabolic support of the immune response 250
Adipose tissue as an immune organ 250
Immune cells in adipose tissue 251
Adipose tissue as endocrine organ 252
Adipokines 252
Stimuli for adipokine release 252
Adipokine action 253
Adipokines with beneficial cardiometabolic effect 253
Leptin 253
Adiponectin 256
Apelin 259
Vaspin 260
Visfatin 260
Adipokines with detrimental cardiometabolic effect 260
Free fatty acids 260
Tumor necrosis factor-alpha 262
The renin–angiotensin–aldosterone system 264
Resistin 265
Interleukin-6 265
Vascular endothelial growth factor 265
Serum amyloid A3 266
Plasminogen activator inhibitor-1 266
Monocyte chemoattractant protein 266
Obesity comorbidities and cardiovascular disease 266
Endothelial dysfunction 266
Hypertension 267
Heart failure 267
Coronary heart disease 267
Lifespan 268
Obesity, insulin resistance, and diabetes 268
Diabetes mellitus 268
Insulin resistance 268
Inflamed adiposity and local insulin resistance 269
Conclusion 270
Bibliography 271
11 Weight Loss and Diet 282
Homeostatic responses to weight gain and weight loss 282
Weight gain 282
Weight loss 282
Adipose weight loss effects 283
Adipose mass and adipocyte size 283
Visceral-omental fat 283
Free fatty acids 283
Ectopic Fat 283
Antiinflammatory, vasculoprotective, and metabolic effects of weight loss 283
Antiinflammatory effects 283
Antioxidant effect 284
Parasympathetic tone 284
Vascular function 284
Insulin resistance 284
Dyslipidemia 285
Mortality 285
Dietary intervention for weight loss 285
The energy equation 285
Calorie calculators 286
Types of diet 286
Dietary goal 286
Calorie restriction 286
Implementation of calorie restriction 287
Cellular effects of caloric restriction 287
Metabolic adaptation 289
Antioxidant effects of calorie restriction 290
Immune and antiinflammatory effects of caloric restriction 290
Endocrine adaptations to caloric restriction 290
Lifespan effects 291
Organ and health effects of calorie restriction 292
Surgical intervention 293
Liposuction 293
Gastric pacing 293
Bariatric surgery 293
Diet 295
Foods to avoid 296
Dietary guidelines 297
The Mediterranean diet 297
Selected dietary components 298
Exercise as adjunct to weight loss 305
Conclusion 305
Bibliography 307
12 Skeletal Muscle and Exercise 319
Myocyte structure and function 319
Skeletal muscle adaptation to exercise 319
Mitogen-activated protein kinase 320
Histone modification 321
Metabolic adaptations in skeletal muscle 321
Normal skeletal muscle metabolism 321
Adenosine triphosphate 321
Glucose metabolism 321
Fatty acid oxidation 324
Mitochondria 326
Capillary density 327
Energy sensors 327
5’-AMP-activated protein kinase 327
Sirtuins and forkhead factors 330
PPAR-gamma coactivator-1 330
Peroxisome proliferator-activated receptor-alpha 330
Nitric oxide 331
Skeletal muscle in inflammation 333
Muscle atrophy 333
Contractile dysfunction 334
Blood perfusion 334
Insulin resistance 334
Skeletal muscle in insulin resistance 334
Structural changes in skeletal muscle 335
Loss of metabolic flexibility 335
Dysregulation of fatty acid metabolism 335
Glucose metabolism 335
Vascular insulin resistance 336
Impaired exercise capacity 336
Exercise effect on inflammation and oxidative stress 336
Inflammatory markers 336
Oxidative stress 337
Neurohormonal activation 337
Exercise effect on metabolism in obesity 338
Acute response 338
Chronic response 338
Exercise effect and cardiovascular health 338
Exercise capacity 338
Exercise and vascular aging 339
Cardiovascular effects 340
Exercise and insulin resistance 341
Muscle mass 341
Myofiber type and mitochondria 341
Intramyocellular lipid 341
Other fat depots 342
Exercise effects on glucose metabolism 343
Exercise and mortality 344
Mitochondria and telomeres 345
Adiposity and fitness 345
Older age and fitness 345
CHD and fitness 346
Metabolic syndrome and fitness 347
Type 2 diabetes and fitness 347
Exercise recommendation 347
Exercise prescription 347
Risks 348
Contraindications 348
Conclusion 348
Bibliography 350
13 Lipids, Atherogenic Dyslipidemia, and Therapy 363
Apolipoproteins 363
Lipoproteins 363
Apo A-containing lipoproteins 364
High-density lipoprotein 364
Reverse cholesterol transport 364
Beyond reverse cholesterol transport 366
Clinical impact of HDL plasma levels 368
Modulation of HDL function 369
Apo A-II 371
Apo B-containing lipoproteins 371
Chylomicrons 371
Very-low-density lipoproteins 372
Intermediate-density lipoproteins 372
Remnant lipoproteins 372
Low-density lipoproteins 372
Lipoprotein (a) 375
Apolipoproteins C, D, and E 376
Apolipoprotein C 376
Apolipoprotein D 376
Apolipoprotein E 376
The triglyceride lipase family 376
Lipoprotein lipase 376
Hepatic lipase 378
Endothelial lipase 379
Hormone-sensitive lipase 379
Lipoprotein-associated phospholipase A2 379
The normal metabolism of free fatty acids 379
Dietary fats 379
The liver and normal VLDL secretion 380
Peripheral fatty acid distribution and uptake 380
Fatty acid storage versus oxidation 380
Inflammation and hepatic insulin resistance 381
Dyslipidemia with infection and inflammation 381
Ectopic fat deposition in the liver and nonalcoholic fatty liver disease 381
Metabolic manifestations with fatty liver disease 384
Atherogenic dyslipidemia in insulin resistance 385
Hypertriglyceridemia in insulin resistance 385
Low HDL with insulin resistance 387
LDL changes with insulin resistance 387
VLDL changes with insulin resistance and remnant lipoproteins 388
Lipid-lowering therapy 388
Screening 388
Targets of lipid lowering therapy 389
The HMG CoA reductase inhibitors 390
Lipid-lowering effect 391
Impact of LDL reduction with statins in insulin resistant and diabetic populations 392
Statin effect on triglycerides 393
Statin effect on HDL 394
Lipid-independent beneficial effects of statins 394
Nicotinic acid 403
Mechanism of action 403
Insulin resistance 403
Cardiovascular effects 404
Other adverse effects 404
The fibric acid derivatives 404
Mechanism of action 404
Insulin resistance and new-onset diabetes mellitus 405
Cardiovascular effects 405
Potential adverse effects 407
Bile acid sequestrants 407
Ezetimibe 407
CETP inhibition 407
Conclusion 408
Bibliography 409
14 The Endothelium, Cardiovascular Disease, and Therapy 425
Endothelial function 425
Nitric oxide synthase and eNOS 425
Endothelial NO synthesis 426
eNOS abundance 427
Substrate and cofactor 427
eNOS activity 427
Specific enhancers of NO synthesis 429
Shear stress 430
High-density lipoprotein 430
Muscarinic agonists 430
Bradykinin 431
Peroxisome proliferator-activated receptors 431
Estrogen 431
Insulin 431
Functions of nitric oxide 431
NO bioavailability 431
NO signaling mechanisms 431
Mitochondrial biogenesis and metabolic effects 432
Insulin sensitivity 432
Glucose uptake 432
Vasodilation 432
Vascular repair and angiogenesis 433
Parasympathetic input 433
Inhibition of platelet activation 433
Antioxidant activities 433
Antiinflammatory and antiatherogenic activities 433
Cell protection 433
Cell senescence 434
Cell death 434
Shear stress and vascular function 434
Biochemical responses to flow 434
Shear-type determinants of endothelial response 434
Smooth muscle cells and vascular homeostasis 435
Mechanisms of endothelial dysfunction 436
Decreased eNOS expression 436
Decreased eNOS activity 436
Decreased NO half-life 437
Other factors 437
Insulin, insulin resistance, and endothelial dysfunction 440
Transendothelial insulin transport 440
Insulin stimulation of NO production 440
Vascular insulin effects 441
Insulin resistance and endothelial dysfunction 441
Endothelial dysfunction as precursor for insulin resistance 444
Implications of endothelial dysfunction 444
Time course of endothelial dysfunction 444
The impairment of endothelial dysfunction 444
Reversal of endothelial dysfunction 446
Assessment of endothelial function 446
Other venues for the assessment of vascular function 446
Hypertension 448
Classification and treatment aims 448
Insulin resistance and hypertension 448
Selective insulin resistance and hypertension 448
Cardiomyopathy 450
Normal myocardial metabolism 450
Abnormal myocardial metabolism 451
Obesity and cardiomyopathy 452
Insulin resistance and cardiomyopathy 453
Insulin resistance as a cause of cardiomyopathy 454
Heart failure as a cause for insulin resistance 455
Implications of insulin resistance in heart failure 456
Coronary and peripheral vascular disease 456
Incidence of vascular disease 457
Cardiovascular events and mortality 457
Insulin resistance factors contributing to vascular disease 458
Incidence of insulin resistance with CHD 459
Pharmacologic antagonism of the renin–angiotensin–aldosterone system and endothelin-1 459
Direct renin inhibition 459
Angiotensin-converting enzyme inhibition 460
Angiotensin II receptor blockade 462
The mineralocorticoid receptor antagonists 464
Endothelin-1 antagonists 464
Beta-adrenergic blockade 464
Antiatherogenic effect 465
Insulin sensitivity 465
Phosphodiesterase-5 inhibitors 465
Conclusion 466
Bibliography 467
15 Insulin Resistance, Metabolic Syndrome, and Therapy 484
Diagnostic criteria for the metabolic syndrome 484
Utility of the definition 484
Prevalence of the metabolic syndrome 486
Insulin resistance 486
Hyperinsulinemia with euglycemia 486
Prediabetes and type 2 diabetes mellitus 487
Multiorgan manifestations of insulin resistance 488
Other biomarkers of the metabolic syndrome 489
Diagnosis of insulin resistance 489
Causes of insulin resistance 490
Genetics 490
Physical inactivity 490
Aging 490
Overweight 490
Stress 491
Medications 491
Low birthweight 491
Pathways toward insulin resistance 492
Molecular mechanisms underlying insulin resistance 492
Pathways to insulin resistance 492
Vicious circles 495
The metabolic syndrome 496
Pharmacologic therapy to improve insulin sensitivity 496
AMPK-activators 497
PPAR-agonist 498
Conclusion 499
Bibliography 500
Index 507