Diabetic Neuropathy: Advances in Pathophysiology and Clinical Management

Description

In this updated edition, leading medical specialists critically review for the general practitioner the latest techniques for the clinical management of diabetic neuropathy. The contributors focus on the practical aspects of diabetic neuropathy and describe in detail the treatments that are currently available or expected to become available in the near future. They also include concise discussions of the pathogenesis of diabetic neuropathy. Contents Part I: Clinical Features and Diagnosis Introduction 1 Early History of the Diabetic Neuropathies 2 The Twentieth Century References The Epidemiology of Diabetic Neuropathy 1 Introduction 1.1 Strategy for Reviewing Relevant Literature 2 Diabetic Distal Symmetric Polyneuropathy 2.1 Issues to Consider When Evaluating Epidemiological Studies of DSPN 2.2 Prevalence of DSPN 2.3 Painful Diabetic Neuropathy 2.4 Incidence of DSPN 2.5 Risk Factors for DSPN and P-DSPN 2.6 DSPN Complications 3 Diabetic Autonomic Neuropathy 3.1 Cardiovascular Autonomic Neuropathy 3.2 Prevalence of CAN 3.2.1 Youth 3.2.2 Type 1 Diabetes 3.2.3 Type 2 diabetes 3.3 Incidence of CAN 3.4 Risk Factors for CAN 3.5 Other Forms of Autonomic Neuropathy 4 Other Forms of Diabetic Neuropathy References Clinical Features of Diabetes Neuropathies 1 Introduction 2 Epidemiology 3 Classification 4 Clinical Features of Diabetic Neuropathies 4.1 Diabetic Peripheral Neuropathy 4.1.1 Painful Diabetic Peripheral Neuropathy 4.1.2 Co-morbidities of Diabetic Peripheral Neuropathy 4.1.3 Differential Diagnosis of Diabetic Peripheral Neuropathy 4.2 Acute Painful-Distal Sensorimotor Polyneuropathies 4.2.1 Hyperglycaemia Induced Acute Painful Distal Sensorimotor Polyneuropathy 4.2.2 Treatment Induced Neuropathy of Diabetes 4.2.3 Autonomic Neuropathy 4.2.4 Cardiovascular Autonomic Neuropathy 4.2.5 Gastrointestinal Autonomic Neuropathy 4.2.6 Urogenital Autonomic Neuropathy 4.2.7 Sudomotor Dysfunction 4.3 Mononeuropathies 4.3.1 Microvasculitic Mononeuropathies 4.3.2 Entrapment Mononeuropathies 4.4 Radiculoplexus Neuropathies 5 Conclusions References Neuropathy in Type 1 and Type 2 Diabetes 1 Introduction 2 Clinical Features of DPN 3 Risk Factors for DPN 4 Clinical Trials in DPN References Clinical Diagnosis of Diabetic Peripheral Neuropathy 1 Introduction and Context 1.1 Diabetic Distal Symmetric Polyneuropathy (Diabetic DSP): A Brief Overview 1.2 Staging of Diabetic DSP 2 Key Clinical Considerations FOR Diabetic DSP Diagnosis 2.1 Clinical Risk Factors for Diabetic DSP Are Typically Present 2.2 The Impaired Protective Sensation of Diabetic DSP Represents Only One Component Cause of Foot Complications 2.3 Impaired Protective Sensation Shows Heterogeneity Between People with Diabetes 3 Asymptomatic Clinical Presentation: Screening for Diabetic DSP 4 Neuropathic Symptoms 5 Neuropathic Signs 6 Composite Symptom Scales, Sign Scales, and Combined Scales 7 The Michigan Neuropathy Screening Instrument (MNSI) 7.1 Scale Face Validity 7.2 Test Quality and Reliability 7.3 Diagnostic Accuracy: Concurrent 7.4 Diagnostic Accuracy: Predictive 7.5 Effect on Treatment Decisions, Impact on Patient Outcomes, Economic Analysis 8 Toronto Clinical Neuropathy Score (TCNS) 8.1 Scale Face Validity 8.2 Test Quality and Reliability 8.3 Diagnostic Accuracy: Concurrent 8.4 Diagnostic Accuracy: Predictive 8.5 Effect on Treatment Decisions, Impact on Patient Outcomes, Economic Analysis 9 Modified Toronto Clinical Neuropathy Score (mTCNS) 9.1 Scale Face Validity 9.2 Test Quality, Reliability, and Accuracy 9.3 Effect on Treatment Decisions, Impact on Patient Outcomes, Economic Analysis 10 Neuropathy Impairment Score of Lower Limbs (NIS-LL) 10.1 Scale Face Validity 10.2 Test Quality, Reliability, and Accuracy 10.3 Effect on Treatment Decisions, Impact on Patient Outcomes, Economic Analysis 11 Utah Early Neuropathy Scale 11.1 Scale Face Validity 11.2 Test Quality, Reliability, and Accuracy 11.3 Effect on Treatment Decisions, Impact on Patient Outcomes, Economic Analysis 12 Neuropathy Symptom Score (NSS) 12.1 Face Validity 12.2 Test Quality and Reliability 12.3 Diagnostic Accuracy: Concurrent 13 The Revised Neuropathy Disability Score (NDS) 13.1 Face Validity 13.2 Test Quality and Reliability 13.3 Diagnostic Accuracy: Concurrent 13.4 Diagnostic Accuracy: Predictive 14 Perspectives on the Comparison of Scales 15 Differential Diagnosis: A Diagnosis of Diabetic DSP Requires Consideration of Other Causes of Polyneuropathy 16 Concluding Overview References Diagnostic Techniques for Diabetic Peripheral Neuropathy 1 Introduction 2 Nerve Conduction Studies 2.1 Basic Principles and NCS Abnormalities in DPN 2.2 Clinical Utility of NCS in DPN Diagnosis 2.3 Research Applications for NCS 3 Skin Biopsy with Measurement of Intraepidermal Nerve Fiber Density (IENFD) 3.1 Skin Anatomy and Epidermal Innervation 3.2 Selection of Biopsy Site, Processing Technique, and Quantification of Skin Nerve Fibers 3.3 Skin Biopsy Abnormalities in DPN 3.4 Clinical Application of Skin Biopsy 3.5 Research Application of Skin Biopsy 4 Quantitative Sensory Testing 4.1 Point of Care QST Devices 4.2 Application of QST in Clinical Trials 5 Sudomotor Testing 5.1 Quantitative Sudomotor Axon Reflex Testing (QSART) 5.2 Thermoregulatory Sweat Testing 5.3 Neuropad: Indicator Plaster Test 5.4 Electrochemical Sweat Conductance (ESC) 6 Corneal Confocal Microscopy 7 Conclusion References Sensory Profiles and Diabetic Neuropathy 1 Introduction 2 The DFNS Protocol of Sensory Profiling 2.1 The DFNS Protocol of Quantitative Sensory Testing 2.1.1 Small Fiber Function (C-/A-delta): Thermal Thresholds 2.1.2 A-Beta-Fiber-Function: Mechanical Detection Thresholds 2.1.3 A-Delta Fiber Function and Central Sensitization: Pinpricks and Pressure Pain Threshold, Dynamic Mechanic Allodynia 2.1.4 Z-transformation and Reference Values 2.1.5 Advantages and Disadvantages of QST 2.2 Sensory Profiling According to the DFNS QST Protocol 2.2.1 The DFNS QST Protocol 2.3 Sensory Profiling in Diabetic Neuropathy 3 Patient Stratification for Mechanism-Based Treatment 3.1 Clustering Approach 3.2 Sensory Testing as Predictor of Treatment Response 3.3 Sensory Profiling Using Patient Reported Outcome Measures References Neurotrophic Factors in the Pathogenesis and Treatment of Diabetic Neuropathy 1 Introduction 2 The Neurotrophin Family 3 GDNF Family Ligands 4 IL-6 Cytokine Family 5 Insulin, C-Peptide, and Insulin-Like Growth Factors 6 Morphogens and Axonal Guidance Factors 7 VEGF 8 Erythropoietin 9 Will Neurotrophic Factors Ever Be a Viable Therapy for Diabetic Neuropathy? References Treatment Induced Neuropathy of Diabetes 1 Historical Background 2 Clinical Features 3 Pathophysiology 4 Epidemiology 5 Risk Factors 6 Complications 7 Long-Term Outcomes 8 Disease Management References Asymmetric Diabetic Neuropathy: Radiculoplexus Neuropathies, Mononeuropathies, and Cranial Neuropathies 1 Introduction 2 Diabetic Radiculoplexus Neuropathies (DRPN) 3 Diabetic Lumbosacral Radiculoplexus Neuropathy (DLRPN) 3.1 Historical Perspective 3.2 Epidemiology 3.3 Clinical Presentation 3.4 Pathophysiology 3.5 Diagnosis 3.6 Management 3.7 Outcome and Prognosis 4 Diabetic Cervical Radiculoplexus Neuropathy (DCRPN) 5 Diabetic Thoracic Radiculoneuropathy (DTRN) 6 Entrapment Neuropathy 7 Median Mononeuropathy Across the Wrist (MNW) 8 Ulnar Mononeuropathy Across the Elbow (UNE) 9 Fibular Mononeuropathy Across the Fibular Head (FN) 10 Lateral Femoral Cutaneous Mononeuropathy [Meralgia Paresthetica (MP)] 11 Cranial Neuropathies 12 Ocular Motor Mononeuropathies (OMM) 13 Facial Paralysis References Motor Neuropathy in Diabetes 1 Introduction 2 Clinical Presentation 3 Pathophysiology 4 Neurogenic Muscle Weakness 5 Diabetic Myopathy 6 Diagnostic Approach 7 Motor Nerve Dysfunction 8 Electromyography 9 Muscle Strength in Diabetic Distal Symmetric Polyneuropathy 10 Assessment of Muscle Strength 11 Imaging of Muscular Atrophy and Motor Neuropathy 12 Motor Function, Postural Stability, and Falls 13 Interventions 14 Conclusions References Cardiovascular Autonomic Neuropathy 1 Cardiovascular Autonomic Neuropathy 2 Epidemiology 3 Pathophysiology 4 Clinical Impact and Implications 5 Diagnostic 5.1 Screening and Diagnosis in Clinical Care 5.1.1 Symptoms of CAN 5.1.2 Clinical Signs of CAN 5.2 Diagnosis for Clinical Research 6 Treatment 6.1 Prevention 6.2 Symptomatic Treatment 7 Conclusions References Psychosocial Aspects of Diabetic Neuropathy: From Description to Interventions 1 Introduction 2 The Impact of DPN on Physical and Mental Functioning, and QoL 3 The Effects of Pain Medication on Psychosocial Outcomes: Sleep and Mental Health 4 The Role of Psychosocial Factors in Pain Experience and Response to Treatment 5 Pathways Linking DPN and Its Symptoms to Depression and Anxiety 6 Generalized Anxiety Vs. Specific Fears 7 Measuring QoL in DPN: Generic, DPN-Specific or Combined Approach? 7.1 Limitations of the Generic Health status/QoL Instruments 7.2 The Shift from Generic to DPN-Specific QoL Assessments 8 How to Manage Psychological Problems of Persons with DPN in Clinical Care? 9 Psychological Treatment Options for People with Painful DPN 10 Concluding Remarks and Directions for Future Research References Part II: Pathophysiology The Genomics of Diabetic Neuropathy 1 Introduction 2 A Brief Introduction to Diabetes Genetics 3 The Genomics of Diabetic Neuropathy in Humans 3.1 Insights into Diabetic Neuropathy Provided by Gene Variants Associated with Charcot-Marie-Tooth 3.2 Insights Provided into Diabetic Neuropathy from Transcriptional Profiling in Humans 4 The Genomics of Neuropathic Pain in Diabetic Neuropathy in Humans 4.1 Sodium Channel Variants and Painful Diabetic Neuropathy 5 Conclusion References Metabolic Mechanisms in Diabetic Neuropathy 1 Introduction 2 Role of Aldose Reductase and Polyol Pathway 3 Non-enzymatic Glycation 4 Hexosamine and Protein Kinase C 5 Oxidative and Nitrosative Stress 6 Additional Mechanisms and Treatment Options 7 Conclusion References Mechanisms of Nerve Injury in Diabetes: Dyslipidemia, Bioenergetics, and Oxidative Damage 1 Introduction 2 Bioenergetics and Nutrient Overload in the Nerve and PN 2.1 Introduction to Nerve Bioenergetics 2.2 Axo-glial Metabolic Interactions in the Nerve 2.3 Mitochondrial Dynamics in the Nerve and PN 2.4 Mitochondrial Oxidative Stress in the Nerve and PN 2.5 Glucose Excess and Inflammation in the Nerve and PN 3 Dyslipidemia Is Associated with PN 3.1 Global Energy Imbalance and Metabolic Disruption During Dyslipidemia 3.2 De Novo Lipogenesis in the Nerve and PN 3.3 Lipid Uptake in the Nerve and PN 3.4 Dyslipidemia, Lipid Metabolism, and Lipotoxic Species in the Nerve During PN 3.5 Dyslipidemia-Induced Inflammation in the Nerve During PN 3.6 Dyslipidemia Impairs Mitochondrial Bioenergetics and Dynamics in the Nerve During PN 4 Disease-Modifying Therapies for PN Associated with Dyslipidemia 4.1 Exercise 4.2 Dietary Interventions 4.3 Weight Loss 4.4 Lipid-Lowering Agents 5 Conclusions References Targeting the Mitochondrion in Diabetic Neuropathy 1 Introduction 2 Mitochondrial Mechanisms and Potential Drug Targets in DN 2.1 Role of Mitochondrial Dysfunction in DN 2.2 Changes in Redox Potential in the Mitochondrion in DN 2.3 Advanced Glycation End Products and the Mitochondrion in DN 2.4 Mitochondrial Regulation of Molecular Chaperones in DN 2.5 TGF-β and DN 2.6 Metabotropic Glutamate Receptors, Oxidative Injury, and DN 2.7 Mitophagy, the Inflammasome, and Innate Immune Pathways in DN 3 Current Treatment Approaches That Target Mitochondrial Function in DN 3.1 Lifestyle Modification and Improvement in Mitochondrial Function in DN 3.2 Improved Glycemic Control and DN 3.3 Diet and Lifestyle Interventions in DN 3.4 Alpha-Lipoic Acid and DN 3.5 Benfotiamine and DN 4 Conclusion References Diabetic Sensory Neurons, Dorsal Root Ganglia, and Neuropathy 1 Introduction 2 Structure and Physiology of Dorsal Root Ganglia 3 DRG Responses to Injury 4 Dorsal Root Ganglia and Diabetes Mellitus 5 Sensory Neurons in Diabetes 6 Regrowth Strategies for Sensory Neurons 7 Sensory Neurons and Pain 8 Conclusions References Micro- and Macrovascular Disease in Diabetic Neuropathy 1 Introduction 2 Microvascular Disease: Overview and Anatomic Changes 3 Pathophysiology of Microvascular Disease and Endothelial Dysfunction in Diabetes 3.1 Functional Changes 3.2 Microvascular Dysfunction and Diabetic Neuropathy 3.2.1 Endothelium Dysfunction 3.3 Autonomic Denervation 3.4 Nerve Axon Reflex 4 Lower Extremity Arterial Disease and Diabetes 5 Conclusions References The Spinal Cord in Diabetic Neuropathy 1 Introduction 2 Inflammation 2.1 Microglia Activation in Type 1 Diabetes 2.2 Proinflammatory Peptides and Cytokines 2.3 Inflammation in Type 2 Diabetes 3 Molecular Mechanisms 3.1 Mitochondrial Function 3.2 Synaptic Plasticity 3.3 Receptors and Ion Channels 3.3.1 Glutamatergic Receptors 3.3.2 Adrenergic Receptors 3.3.3 Ligand-Gated Channels 3.3.4 Voltage-Gated Sodium Channels 3.3.5 Voltage-Gated Calcium Channels 3.4 Oxidative Stress 3.5 Serotonin/Noradrenaline Reuptake Inhibitors 4 Spinal Disinhibition 5 Spinal Cord Stimulation 6 Summary/Conclusions References Brain Changes in Diabetes and Cognitive Dysfunction 1 Stages of Cognitive Dysfunction: Definitions 2 Stages of Cognitive Dysfunction in Diabetes 2.1 Type 1 Diabetes 2.2 Type 2 Diabetes 3 Mechanisms: Structural Brain Changes and Dementia Aetiologies 3.1 Diabetes and Alzheimer Pathologies 3.2 Diabetes and Vascular Brain Injury 3.3 Diabetes and Neurodegeneration/Global Brain Injury 3.4 Markers of Cerebral Blood Flow and Metabolism 4 Implications for Clinical Practice 4.1 Emerging Clinical Guidelines 4.2 Diagnosing Cognitive Dysfunction in People with Diabetes 4.3 Treatment References Lifestyle and Dietary Modifications: Relevance in the Management of Diabetic Neuropathy 1 Introduction 2 Pharmacologic Treatment of Diabetic Peripheral Neuropathy 3 Obesity and Diabetic Peripheral Neuropathy 4 High-Fat Diets as a Tool to Study Diabetic Peripheral Neuropathy 5 Dietary Interventions to Improve Diabetic Peripheral Neuropathy 5.1 Mediterranean Diets 5.2 Ketogenic Diets 5.2.1 Addressing Health Concerns of Using a Ketogenic Diet in Patients with Diabetes 5.2.2 Ketogenic Diet and Neural Disease 5.2.3 Ketone Bodies as Signaling Molecules 5.2.4 Ketogenic Diets and TRP Channels 5.2.5 Ketones and Modulation of ATP-Gated Ion Channels 5.2.6 Exogenous Ketone Supplementation as a Tool to Treat Diabetic Peripheral Neuropathy 6 Dietary Influences on the Microbiome Relevant to Diabetic Peripheral Neuropathy 7 Exercise and Physical Activity to Improve Diabetic Peripheral Neuropathy 7.1 Exercise Benefits on Non-neuronal Tissues 7.2 Exercise Benefits on Neuronal Tissues 8 Conclusion References Pathophysiology of Neuropathic Pain 1 Introduction 2 Peripheral Mechanisms of Painful Diabetic Neuropathy 2.1 Endothelial Dysfunction and Inflammation 3 Central Mechanisms of Painful Diabetic Neuropathy 4 Conclusions References Central Nervous System Involvement in Painful Diabetic Neuropathy 1 Painful Diabetic Neuropathy 2 CNS Changes in Response to Peripheral Nerve Injury and How These Changes Result in Chronic Pain in Diabetes 2.1 Changes in the Spinal Cord 2.2 Changes in the Brain 2.2.1 Structural/Metabolic 2.2.2 Functional 3 Clinical Implications 4 Future Direction 5 Conclusions References Part III: Clinical Consequences and Treatments Characteristics and Treatment of Painful Diabetic Neuropathy 1 Definition, Epidemiology, Diagnosis, and Characteristics 2 Treatment of P-DPN 3 Pharmacological Treatment 3.1 Pathogenesis Orientated Treatment 3.2 Symptomatic Treatment 3.3 Guideline Recommendations 3.4 Modes of Action, Recommended Dose, and Side Effects 3.5 Other Pharmacological Treatment Options 3.6 Emerging Treatment Possibilities 4 Nonpharmacological Treatment 5 Conclusion References Orthostatic Hypotension and Sudomotor Dysfunction in Diabetes 1 Introduction 2 Orthostatic Hypotension 3 Clinical Presentation and Initial Evaluation 3.1 Symptoms 3.2 Initial Steps 3.3 Evaluation for Additional Causes of OH 3.4 Additional Autonomic Testing 3.4.1 Valsalva Maneuver 3.4.2 Tilt Table 4 Treatment 5 Medication Review and Adjustment 6 Nonpharmacological Interventions 6.1 Lifestyle 6.1.1 Volume Repletion: Increase Hydration and Salt Intake 6.1.2 Avoid Warm, Humid Environments and Increase in Core Body Temperature 6.1.3 Remain Active 6.1.4 Purposeful Movement 6.1.5 Eat Small, Low Carbohydrate Meals 6.1.6 Avoid Alcohol and Caffeine 6.1.7 Sleep with Head of Bed Elevated 6.1.8 Compression Garments 7 Pharmacologic Interventions 7.1 Treatment of Anemia 7.2 Fludrocortisone 7.3 Midodrine 7.4 Droxidopa 7.5 Norepinephrine Reuptake Inhibitors 7.6 Other 8 Special Considerations 8.1 Neurogenic Supine Hypertension 8.2 Postprandial Hypotension 9 Sudomotor Dysfunction 10 The Anatomy and Pathophysiology of Sudomotor Function 11 Clinical Presentation 12 Diagnostics 12.1 Quantitative Sudomotor Axon Reflex Test (QSART) 12.2 Quantitative Direct and Indirect Axon Reflex Testing (QDIRT) 12.3 Silicone Impressions 12.4 Acetylcholine Sweat-Spot 12.5 Thermoregulatory Sweat Testing (TST) 12.6 Sympathetic Skin Response (SSR) 13 Treatment References Gastrointestinal Neuropathy 1 Introduction 2 Assessment of Gastrointestinal Symptoms and Autonomic Function in Diabetes 3 Oesophagus 3.1 Diagnosis 3.2 Pathophysiology 3.3 Treatment 4 Stomach 4.1 Diagnosis 4.2 Pathophysiology 4.3 Effects of the Glycaemic Environment on Gastric Emptying 4.4 Treatment 5 Gallbladder 6 Small and Large Intestine 6.1 Diagnosis 6.2 Pathophysiology 6.3 Treatment 7 Modulation of Gastric Emptying and Small Intestinal Motility to Improve Glycaemic Control 8 Relevance of Gastric Emptying and Small Intestinal Motility to Postprandial Hypotension 9 Conclusions References Diabetic Neuropathy: Clinical Management—Genitourinary Dysfunction in Diabetes 1 Introduction 2 Bladder Dysfunction in Diabetes 2.1 Epidemiology of Diabetic Bladder Dysfunction 2.1.1 Bladder Dysfunction in Men 2.1.2 Bladder Dysfunction in Women 2.1.3 Urinary Tract Infections 2.2 Physiology of Micturition 2.3 Pathophysiology of Diabetic Bladder Dysfunction 2.3.1 Diabetic Neuropathy 2.3.2 Neurotrophins 2.3.3 Detrusor Smooth Muscle Dysfunction 2.3.4 Urothelial Dysfunction 2.3.5 Urethra Dysfunction 2.4 Clinical Manifestations of Diabetic Bladder Dysfunction 2.4.1 Manifestations in Men and Women 2.4.2 Urinary Tract Infections 2.5 Diagnosis of Diabetic Bladder Dysfunction 2.5.1 History, Questionnaires, and Diaries 2.5.2 Physical Examination 2.5.3 Laboratory Investigations 2.5.4 Instrumental Diagnostic 2.5.5 Invasive Urodynamics and Urethrocystoscopy 2.5.6 Uro-Neurophysiological Tests 2.6 Treatment of Diabetic Bladder Dysfunction 2.6.1 Lifestyle Interventions 2.6.2 Treatment of Symptoms Related to Benign Prostatic Hyperplasia 2.6.3 Treatment of Urgency, Detrusor Overactivity, and Urgency Incontinence 2.6.4 Treatment of Detrusor Underactivity 2.6.5 Treatment of Stress Urinary Incontinence 2.7 Barriers to Effective Management of Diabetic Bladder Dysfunction 3 Male Sexual Dysfunction in Diabetes 3.1 Epidemiology of Diabetic Erectile Dysfunction 3.1.1 Prevalence of Diabetic Erectile Dysfunction 3.1.2 Clinical Correlates, Comorbidities, and Risk Factors of Diabetic Erectile Dysfunction Depression and QoL Cardiovascular Disease Mechanisms Linking Erectile Dysfunction and Cardiovascular Risk Diabetic Neuropathy Mechanisms Linking Erectile Dysfunction and Diabetic Neuropathy 3.2 Physiology and Pathophysiology of Erectile Function 3.3 Multifactorial Pathogenesis of Diabetic Erectile Dysfunction 3.3.1 Hypogonadotropic Hypogonadism 3.4 Diagnosis of Diabetic Erectile Dysfunction 3.4.1 History and Questionnaires 3.4.2 Physical Examination 3.4.3 Laboratory Investigations 3.4.4 Instrumental Procedures 3.5 Treatment of Diabetic Erectile Dysfunction 3.5.1 Lifestyle Interventions 3.5.2 Psychosexual Strategies 3.5.3 Pharmacological Treatment: PDE5Is 3.5.4 Pharmacological Treatment: Testosterone 3.5.5 Pharmacological Treatment: Intracavernosal and Intraurethral Therapy 3.5.6 Mechanical Devices 3.5.7 Surgery 3.5.8 Future Treatments 3.6 Novel Antihyperglycemic Drugs and Male Sexual Function 4 Ejaculation Dysfunction in Diabetes 4.1 Epidemiology of Ejaculation and Orgasmic Dysfunction in Diabetes 4.2 Premature Ejaculation in Diabetes 4.2.1 Pathophysiology of Premature Ejaculation 4.2.2 Management of Premature Ejaculation 4.3 Retrograde Ejaculation in Diabetes 4.3.1 Pathophysiology of Retrograde Ejaculation 4.3.2 Management of Retrograde Ejaculation 5 Female Sexual Dysfunction in Diabetes 5.1 Definition and Epidemiology of Diabetic Female Sexual Dysfunction 5.2 Physiology and Pathophysiology of Female Sexual Function 5.3 Pathogenesis of Diabetic Female Sexual Dysfunction 5.4 Diagnosis of Diabetic Female Sexual Dysfunction 5.4.1 Questionnaires and Clinical Assessment 5.4.2 Laboratory Testing 5.4.3 Instrumental Procedures 5.5 Treatment of Diabetic Female Sexual Dysfunction 5.5.1 Lifestyle Intervention 5.5.2 Antihyperglycemic Treatment 5.5.3 Pharmacological Options 6 Conclusions on Diabetic Genitourinary Dysfunction References Index