Microvascular disease in diabetes / edited by Francesco Tecilazich.

ABOUT THE AUTHOR
FRANCESCO TECILAZICH, MD, PhD, is a physician and scientist in the Endocrinology and Metabolic Diseases department of the Ospedale San Raffaele—Vita Salute San Raffaele University in Milan, Italy.

Includes bibliographical references and index.

TABLE OF CONTENTS
Foreword to: Microvascular Disease in Diabetes xv

Editor Biography xvii

List of Contributors xix

1 Introduction 1
Andrea Giustina and Stefano Frara

References 3

2 Pathophysiology 5
Francesco Tecilazich

Introduction 5

Anatomo-Physiology of Microvessels 5

Regulation of Microvascular Tone 6

Endothelial-Dependent Vasodilation 6

Endothelial-Independent Vasodilation 6

Nerve Axon Reflex (NARV) 7

Myogenic Response 7

Functional Hyperemia 7

Venoarteriolar Response (VAR) 8

Structural Changes in the Microcirculation 8

Functional Changes in the Microcirculation 8

Endothelial Dysfunction 8

VSMC Dysfunction 9

NARV Impairment 9

Defective Myogenic Response 10

Reduced Functional Hyperemia 10

Endothelial Dysfunction 11

Role of the Immune System and Leukostasis 11

Role of Hyperglycemia 12

AGEs 12

Polyol Pathway 12

Oxidative Stress 13

PKC 13

Transforming Growth Factor (TGF)-β 14

Hexosamine Pathway 14

PARP 14

ET-1 14

Vasoconstrictor Prostanoid Synthesis 15

Role of Insulin Resistance 15

Role of Inflammation 15

References 16

3 Genetics of Diabetic Microvascular Disease 23
Niina Sandholm and Carol Forsblom

Introduction 23

Genetics of DKD 23

Heritability of DKD 23

Candidate Genes for DKD 24

Linkage Studies for DKD 25

Genome-Wide Association Studies on DKD 25

Sequencing Efforts for DKD 29

Genetics of Diabetic Retinopathy 30

Heritability of Diabetic Retinopathy 30

Candidate Genes for Diabetic Retinopathy 30

Linkage Studies for Diabetic Retinopathy 31

GWAS on Diabetic Retinopathy 31

Sequencing Efforts for Diabetic Retinopathy 33

Genetics of Diabetic Neuropathy 33

Heritability of Diabetic Neuropathy 33

Candidate Genes for Diabetic Neuropathy 33

GWASs on Diabetic Neuropathy 34

Future Directions 34

Larger Studies are Needed 34

How to Define the Phenotype? 35

Variability in the Phenotypic Definitions 35

Criteria for Controls 36

Do Genetics of Microvascular Complications in T1D and T2D Differ? 36

Low-Frequency and Rare Variants May Affect Diabetic Complications 36

Sequencing of Rare and Low-Frequency Variants 36

Linkage Analysis with GWAS Data 37

Genetics May Reveal Biology and Infer Causality 37

Conclusions 37

References 37

4 Epigenetics of Diabetic Microvascular Disease 45
Luciano Pirola

Diabetic Complications Include Microvascular and Macrovascular Injury 45

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study in Type 1 Diabetic Patients, and the UKPDS Study in Type 2 Diabetic Patients, Support the Existence of the Hyperglycemic Memory Phenomenon 46

DCCT/EDIC Study 46

The UKPDS Study 46

Models of Hyperglycemic Memory 47

Animal Models 47

Cell Culture Models 48

The “Epigenetic Code” 48

DNA Methylation 49

Histone Methylation in Models of Hyperglycemic Variability 49

Epigenetic Changes in Microvascular Models of Glycemic Memory 50

MiRNAs Contribute to the Control of Glucose Homeostasis and are Dysregulated in Diabetes 52

Future Prospects 52

References 54

5 Diabetic Retinopathy – Clinical 59
Francesco Bandello, Rosangela Lattanzio, Alessandro Marchese, and Emanuela Aragona

Introduction 59

Epidemiology 60

Screening 60

Risk Factors 61

Clinical Patterns 61

Non-Proliferative Diabetic Retinopathy (NPDR) 61

Clinical Findings 62

Diagnostic Tools 64

Treatment Strategies 65

Proliferative Diabetic Retinopathy (PDR) 65

Clinical Findings 65

Diagnostic Tools 67

Treatment Strategies 67

Diabetic Macular Edema (DME) 69

Classification 70

Clinical Findings 71

Diagnostic Tools 71

Treatment Strategies 71

Conclusions 73

References 74

6 Diabetic Retinopathy – Research 79
Gopalan Gnanaguru

Retina and Induction of Hyperglycemia 79

Hyperglycemia and Retinal Microvasculature 80

Hyperglycemia and Reactive Gliosis 80

Hyperglycemia and Neurodegeneration 81

Hyperglycemia and Inflammation 81

References 82

7 Diabetic Nephropathy – Clinical 85
Gianpaolo Zerbini

Epidemiology 85

Natural History 86

Stages of DN 86

Morphologic Changes 87

Pathophysiology 88

Clinical Course 89

Treatment 90

Primary Prevention 90

Secondary Prevention 91

Tertiary Prevention 91

Perspectives 91

References 92

8 Diabetic Nephropathy – Research 97
Silvia Maestroni and Gianpaolo Zerbini

Essential Hypertension and DN 97

Role of Genetics in the Pathogenesis of DN 99

Polyol Pathway and Non-Enzymatic Glycation 100

Environment 100

Perspectives 101

Sodium–Glucose Cotransporter-2 (SGLT2) and DN 101

B7-1 and DN 101

Animal Models 102

DN in Induced Model of Type 1 Diabetes Mellitus (T1DM) 102

DN in Spontaneous Model of T1DM 103

Ins2Akita Mice 103

Non-Obese Diabetic (NOD) Mice 104

OVE26 Friend leukemia virus B (FVB) Mice 104

DN in Spontaneous Models of T2DM 105

db/db Mice 105

References 105

9 Diabetic Neuropathy – Clinical 111
Christopher H. Gibbons

Introduction 111

Classification of Diabetic Neuropathies 111

Distal Symmetric Polyneuropathy (DSPN) 112

Diagnosis 113

Management 113

Small Fiber Neuropathy 114

Diagnosis 115

Management 115

Autonomic Neuropathy 116

Diagnosis 117

Management 117

Treatment-Induced Neuropathy of Diabetes (TIND) 119

Diagnosis 119

Management 120

Diabetic Radiculoplexopathy 120

Diagnosis 120

Management 121

Mononeuropathies 121

Diagnosis 121

Management 121

Cranial Neuropathies 121

Diagnosis 121

Management 122

Screening for Neuropathy 122

Summary of Management of Diabetic Neuropathy 122

References 123

10 Diabetic Neuropathy – Research 129
Krish Chandrasekaran, Lindsay A. Zilliox, and James W. Russell

Basic and Translational Research in Diabetic Neuropathy 129

Animal Models of Diabetic Neuropathy 129

Basic Pathophysiology of Diabetic Neuropathy 131

Changes in Redox Potential 131

Role of Mitochondrial Dysfunction in Diabetic Neuropathy 133

Protein Kinase C (PKC) and Neuropathy 137

Advanced Glycation End Products 137

Modifying Molecular Chaperones 138

Inflammation and Neuropathy 138

TGF-β and Neuropathy 138

Metabotropic Glutamate Receptors (mGluRs) and Oxidative Injury 139

Growth Factors and Diabetes 139

Clinical Research in Diabetic Neuropathy 140

Treatment of Hypertension 141

Improved Glycemic Control 141

Diet and Lifestyle Interventions 142

Alpha-Lipoic Acid 144

Benfotiamine and Neuropathy 145

Treatment of Neuropathic Pain 145

Acknowledgments 146

References 147

11 Diabetic Foot – Clinical 157
Cristian Nicoletti

Introduction and Size of the Problem 157

Pathogenesis of Diabetic Foot Complications 158

Neuropathy 158

Peripheral Vascular Disease 158

Other Risk Factors 159

Prevention 159

Treatment 160

Treatment of Neuropathic Diabetic Foot Ulcers: Offloading 160

Treatment of PAD: Revascularization 161

Diabetic Foot Infections (DFIs) 163

Introduction 163

Diagnosis 163

Treatment 164

Wound Healing 166

Debridement 166

Dressings 167

Topical Negative Pressure Wound Therapy (NPWT) 167

Other Topical Treatments 167

References 167

12 Diabetic Foot – Research 173
Georgios Theocharidis and Aristidis Veves

Introduction 173

Anatomy of the Skin and Microcirculation 174

Structural Changes in the Microcirculation 174

Functional Changes in the Microcirculation 175

Functional Changes in the Diabetic Foot 176

Vasodilation 176

Endothelium-Dependent Vasodilation 177

Endothelium-Independent Vasodilation 178

Nerve Axon Reflex 179

Mechanisms of Endothelial Dysfunction 180

Endothelial Dysfunction and Hyperglycemia 180

Endothelial Dysfunction and Insulin Resistance 182

Endothelial Dysfunction and Inflammation 183

Pathophysiology of Diabetic Wound Healing 184

Hyperglycemia 184

Chronic Inflammation 184

Impaired Angiogenesis and Vasculogenesis 186

Hypoxia 186

Impaired Neuropeptide Signaling 186

Adjunctive Treatment Options 186

Bioengineered Skin Substitutes 187

Growth Factors 187

Hyperbaric Oxygen Therapy 188

Negative Pressure Wound Therapy 188

Electrical Stimulation and Shockwave Therapy 189

Future Therapeutic Perspectives 189

Gene Therapies 189

Stem Cell Therapies 189

Norleu3-Angiotensin-(1–7) 190

Neuropeptides 190

Cytokine Inhibition 190

Conclusion 191

References 191

13 Coronary Microvascular Dysfunction in Diabetes – Clinical and Research 201
Guglielmo Gallone, Francesco Moroni, and Marco Magnoni

Introduction 201

Clinical Classification and Mechanisms of CMD 202

CMD in Diabetic Patients 203

Clinical Assessment of CMD 205

Non-Invasive Imaging Technique for the Assessment of CMD 205

Transthoracic Doppler Evaluation 205

Contrast Echocardiography 206

Cardiovascular Magnetic Resonance (CMR) Imaging 206

Positron Emission Tomography (PET) 207

Invasive Techniques for the Evaluation of CBF 207

Indicator Dilution-Based Methods 207

Thermodilution 208

Gas Wash Out Method 208

Intracoronary Doppler Flow Wire 208

Treatment for CMD 210

The Effects of Glucose-Lowering Drugs on CMD 211

Future Perspectives for the Treatment of CMD in Diabetes 211

References 212

14 Cerebral Microvascular Disease in Diabetes – Clinical and Research 221
Eelco van Duinkerken and Richard G. IJzerman

Introduction 221

Postmortem Studies of the Brain in Diabetes 222

Cerebral Small Vessel Disease on MRI 223

MRI-Measured Cerebral Small Vessel Disease in Type 1 Diabetic Patients 224

White Matter Hyperintensities 224

Cerebral Microbleeds 226

Summary 226

Type 2 Diabetes and Cerebral Small Vessel Disease 227

Lacunar Infarcts 227

White Matter Hyperintensities 228

Cerebral Microbleeds 230

Synthesis 230

Clinical Impact of Cerebral Small Vessel Disease in Diabetes 231

Cognitive Functioning 231

Stroke 233

Dementia 234

The Influence of Microvascular Disease on the Structure and Functioning of the Diabetic Brain 235

Type 1 Diabetes 236

Type 2 Diabetes 237

Conclusions and Future Directions 239

References 240

Index 247

"Diabetes remains one of the main causes, in the western world, of legal blindness, end stage renal disease, and amputation, despite the implementation of tight glycemic control and the great progress in the management and care of our patients. In the perspective that clinical and basic-science knowledge are fundamental to clinicians as well as to researchers, this book is a valuable resource by integrating clinical information and research frontlines of the microvascular complications of diabetes. It will provide up-to-date diagnostic criteria, classifications, and therapeutic approaches and recent discoveries on mechanisms of disease, experimental therapeutic agents, and biomarkers of disease. The ultimate goal of this book is to provide a useful and handy tool to professionals and students in the field of diabetes and its microvascular complications. Will provide a much-needed resource synthesizing research and clinical applications to treating microvascular complications of diabetes. Covers all relevant microvascular systems. Provides current diagnostic criteria, classifications, and therapeutic approaches, as well as recent discoveries on the mechanisms of disease, experimental therapeutic agents, and biomarkers of disease"-- Provided by publisher.

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