Front Cover 1
Diabetes Mellitus:Associated Conditions 2
copyright 
3 
Contributors 4
Consulting Editor 4
Editors 4
Authors 4
Contents 8
Endocrinology And 
 
 
12 
Foreword 14
Preface 
18 
Metabolic Syndrome 20
Key points 20
Introduction 20
Definitions 21
Epidemiology 22
Consequences of MetS 27
Pathophysiology 29
Treatment 32
Controversies 34
Summary and future considerations 35
References 35
Cardiovascular Disease in Diabetes Mellitus 44
Key points 44
Introduction 44
Epidemiology 45
Assessing the risk of cardiovascular events 45
Pathophysiology 46
Mitigating the risks 47
Intensive Glycemic Control 47
Choosing the right agents 48
Lipids 50
Hypertension 51
Aspirin 52
Diagnosis of CHD in asymptomatic patients 52
Revascularization 53
Summary 53
Acknowledgments 54
References 54
The Relationships Between Cardiovascular Disease and Diabetes 60
Key points 60
Introduction 60
Diabetes and the vasculature 61
Oxidative Stress and the Vasculature 61
Diabetic Microvascular Dysfunction 63
Vascular Progenitor Cell Dysfunction and Diabetes 63
Impaired Reverse Cholesterol Transport 64
Summary of Relationships Between Diabetes and the Vasculature 64
Diabetes and the heart: diabetic cardiomyopathy 64
Mechanisms of Disease 65
Altered Substrate Metabolism 65
Activation of the Renin-angiotensin System 66
Cardiac Autonomic Neuropathy 66
Myocardial Fibrosis 67
Cardiovascular Findings 67
Diagnosing DCM 67
Diabetes and the cardiovascular patient 68
Coronary Artery Disease Risk Factors 68
Dyslipidemia 68
Hypertension 69
Glycemic control 69
Diabetes and Coronary Artery Disease 69
Heart Failure 71
Summary 71
References 72
Interventions for Coronary Artery Disease (Surgery vs Angioplasty) in Diabetic Patients 78
Key points 78
Introduction 78
Revascularization treatment options 79
Guidelines and other issues 82
Choice of conduit 82
Risk Scoring for CABG 83
Why is CABG Better than PCI? 84
Conclusions 85
Important Aspects of Perioperative Care: Glucose Control 85
What is the current role for PCI? 86
Summary 87
References 87
Mechanisms of Glucocorticoid-Induced Insulin Resistance 94
Key points 94
Introduction 94
Mechanisms of GC-induced insulin resistance 95
Tissue-specific regulation of insulin resistance 95
GC Regulation of Adipose Tissue Functionality, Mass, and Distribution 95
GC regulation of white adipose tissue lipolysis 95
GC regulation of de novo lipogenesis in white adipose tissue 97
GC regulation of insulin sensitivity in white adipose tissue 97
Chronic in vivo GC effects on adipogenesis and white adipose tissue mass and distribution in humans: studies on Cushing syn ... 98
GC regulation of the secretory profile of white adipose tissue 99
GC regulation of brown adipose tissue 100
Mechanisms of GC-Induced Insulin Resistance in Muscle 101
Mechanisms of GC-Induced Hepatic Insulin Resistance: Lipogenesis, Steatosis, and Circulating Lipids 101
GC Regulation of Circulating Lipids 102
Potential Effects of Brain GCs on Metabolic Homeostasis 103
11ß-HSD1 as a gatekeeper for intracellular GC availability 104
The Potential Role of 11ß-HSD1 Inhibition in Humans 105
The role of GCs in the development of common obesity 106
The paradox of GC anti-inflammatory yet diabetogenic actions: duration, location, or context? 106
Summary and future directions 107
References 108
Type 2 Diabetes Mellitus and Hypertension 122
Key points 122
Introduction 122
The burden 124
Epidemiology 124
Pathophysiology: converging pathways in coexisting DM and HTN 124
Role of oxidative stress 125
Insulin resistance and hyperinsulinemia 126
Treatment of HTN: rationale, strategies, and challenges in HTN 127
Impact of BP Control 127
BP Targets 127
Nonpharmacologic treatment: the role of therapeutic lifestyle intervention 128
Pharmacologic therapy 130
RAAS Blockade 130
CCBs 131
Diuretics 131
Incretin-based therapy and HTN: beyond glycemic control 132
Combined pharmacologic therapy 133
Perspectives 133
Telehealth 133
Renal Denervation 134
Acknowledgments 134
References 134
Polycystic Ovary Syndrome 142
Key points 142
History of polycystic ovary syndrome 142
Definition of PCOS 143
Clinical features of PCOS 144
Reproductive features of PCOS 144
Metabolic features of PCOS 145
Psychological features of PCOS 147
Risk factors for PCOS 147
Long-term consequences of PCOS 148
Insulin Resistance and Risk of Diabetes 148
Obesity 149
Hyperlipidemia 149
Cardiovascular Disease 149
Endometrial Cancer 150
Pregnancy Complications 150
PCOS in adolescence 150
Insulin resistance and PCOS 151
In Vitro Models 151
In Vivo Models 153
Genetics 153
Syndromes of Severe Insulin Resistance 154
Treatment of PCOS 155
Summary 157
References 157
Peripheral Arterial Disease 168
Key points 168
Introduction 168
Risk factors and pathogenesis 169
Risk Factors for PAD 169
Age, sex, and ethnicity 169
Cigarette smoking 169
Diabetes 169
Hypertension 170
Hyperlipidemia 170
Other factors 170
Atherosclerosis in PAD 170
Pathogenesis of the Complications of Diabetes in PAD 172
Hyperglycemia 172
Impaired lipid metabolism 173
Hypercoagulability and platelet dysfunction 173
Predictors of disease progression 173
C-reactive Protein 174
Fibrinogen 174
D-dimer 174
Hyperhomocysteinemia 174
Lipoprotein (a) 174
Clinical presentation 174
Intermittent Claudication 175
Critical Limb Ischemia 175
Diagnosis of PAD 176
Clinical Examination 176
ABPI Measurement 176
Treadmill Exercise Testing 177
Transcutaneous Oxygen Pressure Measurement 177
Duplex Ultrasound Scanning 178
Angiography 178
Management 178
Lifestyle and Risk Modifications 178
Cigarette smoking 178
Hyperglycemia 179
Hypercholesterolemia 179
Hypertension 180
Exercise 180
Drug Therapy 180
Antiplatelet agents 180
Vasoactive agents 180
Surgical Intervention 181
New therapies and future opportunities 181
Spinal Cord Stimulation 181
Intermittent Pneumatic Compression 182
Angiogenesis 182
Summary 182
References 182
Diabetes and Cancer 186
Key points 186
Introduction 186
Epidemiology of diabetes and cancer 187
Diabetes, Obesity, and the Metabolic Syndrome 187
Diabetes and Cancer Incidence 188
Diabetes and Cancer Mortality 189
Biologic mechanisms linking diabetes and cancer 190
IGF-1, insulin, and glucose 191
IGF-1 191
Insulin Resistance and Hyperinsulinemia 194
Hyperglycemia 195
Cytokines and adipokines 196
Inflammation 196
Adipokines 197
Summary 198
References 199
Obstructive Sleep Apnea 206
Key points 206
Introduction 206
Observational studies linking OSA with abnormalities of insulin and glucose metabolism and type 2 diabetes 207
Prevalence of OSA in subjects with type 2 diabetes 209
Insulin and glucose homeostasis assessment in patients with OSA 209
Impact of OSA on glycemic control in type 2 diabetes 210
Independent association of OSA with the metabolic syndrome 210
Pathophysiology of OSA and potential links to insulin resistance and type 2 diabetes 210
Chronic IH and insulin resistance 211
Chronic intermittent hypoxia, oxidative stress, and systemic inflammation 212
Impact of IH on pancreatic ß-cell function 213
Sympathetic neural activation 213
Adipose tissue hypoxia and systemic inflammation 213
Human studies linking IH and sleep fragmentation with insulin resistance and pancreatic ß-cell dysfunction 214
CPAP therapy in OSA and changes in insulin sensitivity 215
CPAP therapy in OSA and changes in glycosylated hemoglobin 216
Impact of CPAP therapy for OSA on the metabolic syndrome 216
Screening for OSA in patients with type 2 diabetes 217
Diagnosis and treatment of OSA 218
Summary 219
References 219
Vitamin D and Diabetes 224
Key points 224
Introduction 224
Review of vitamin D physiology 225
Classification of vitamin D status 225
Vitamin D intake requirements 226
Biologic plausibility of an association between vitamin D and type 2 diabetes 227
Vitamin D and Insulin Secretion 227
Vitamin D and Insulin Sensitivity 227
Vitamin D and Systemic Inflammation 228
Association between vitamin D status and type 2 diabetes 229
Cross-Sectional Studies 229
Longitudinal Studies 230
The influence of vitamin D supplementation on type 2 diabetes 236
Vitamin D and type 1 diabetes 244
Summary 245
References 246
Osteoporosis-associated Fracture and Diabetes 252
Key points 252
Introduction 252
T1D versus T2D and bone: similarities 253
T1D versus T2D and bone: differences 255
Quantifying risk of fracture associated with diabetes and osteoporosis 256
Management 257
Treatment 258
References 259
Relationships Between Diabetes and Cognitive Impairment 264
Key points 264
Introduction 264
Insulin signaling 265
The Master Hormone 265
Insulin-Stimulated Effects 265
IGFs 266
Insulin and IGF Signaling in the Brain 267
Insulin and IGF Signal Transduction 267
Insulin resistance and neurodegeneration 267
Insulin Resistance and its Consequences 267
AD Occurrence and Clinical Diagnosis 267
AD Neuropathology 268
AD is a Metabolic Disease with Brain Insulin/IGF Resistance 268
Brain Insulin and IGF Resistance and Deficiency in AD-Human Studies 271
Does AD = Type 3 Diabetes? 271
Experimental Evidence that Type 3 Diabetes = Sporadic AD 272
Metabolic Deficits in AD: the Starving Brain 272
Chronic Ischemic Cerebral Microvascular Disease 273
Brain metabolic derangements in other neurodegenerative diseases 275
Underlying causes of brain insulin resistance in AD 276
Aging 276
Lifestyle Choices and Aging 277
Obesity and Cognitive Impairment 277
T2DM 278
NAFLD/NASH 278
Metabolic Syndrome 278
Summary 279
References 279
Interactions Between Diabetes and Anxiety and Depression 288
Key points 288
Subtypes of diabetes and their relationship to anxiety and depression 289
Complex relationships between anxiety and depression and diabetes 289
Diabetes association with depression and anxiety 289
Depression and anxiety association with diabetes 290
Metabolic syndrome 291
Epigenetic risk 292
Treatment of depression: effect of medication 292
Antidepressants and antipsychotics: further analysis of risk/benefit 292
Treatment of diabetes as risk factor of depression and anxiety 294
Other biologic treatment modalities for depression 294
Cognitive behavioral therapy interventions 294
How to improve care for diabetes and anxiety and depression 295
Summary 296
References 297
Index 304