Microvascular Disease in Diabetes

Presents comprehensive coverage of the many microvascular complications of diabetes 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. This book provides a useful and handy tool to professionals and students in the field of diabetes and its microvascular complications by integrating information from clinical settings as well as from the frontlines of diabetic research. It provides readers with up-to-date diagnostic criteria, classifications, and therapeutic approaches. and recent discoveries on mechanisms of disease, experimental therapeutic agents, and biomarkers of disease.  Written by top experts in the field, Microvascular Disease in Diabetes offers in-depth chapters covering pathophysiology; the genetics of diabetic microvascular disease; and the epigenetics of diabetic microvascular disease. It then provides sections featuring both clinical and research information on diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, and diabetic foot. It also looks at coronary microvascular dysfunction and cerebral microvascular disease. Integrates new and accessible material on diabetic microvascular comorbidities Covers all relevant microvascular systems Provides a much-needed resource synthesizing research and clinical applications to treating microvascular complications of diabetes Presents current diagnostic criteria, classifications, and therapeutic approaches, as well as recent discoveries on the mechanisms of disease, experimental therapeutic agents, and biomarkers of disease Assembled in an easily consultable manner, Microvascular Disease in Diabetes is an excellent text for investigators, clinicians, and students looking to improve their understanding of diabetic complications.

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