Microvascular disease in diabetes /
edited by Francesco Tecilazich.
- 1 online resource
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
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"--