Diabetes Complications, Comorbidities and Related Disorders

Series Preface
Volume Preface
Contents
About the Editors
Contributors
1 Diabetes and Obesity
	Introduction
	Definition of Obesity
	Definition and Classification of Diabetes
	Epidemiology of Obesity and Diabetes
	Pathophysiology of Obesity and Diabetes
	Genetics of Obesity and Diabetes
	Obesity: A Major Risk Factor for Type 2 Diabetes
	Role of Glucose Toxicity
	Role of Lipotoxicity
	Role of Insulin Resistance
	Body Fat Distribution and Risk for Type 2 Diabetes
	Role of Adipose Tissue Dysfunction: A Mechanistic Link Between Obesity and Type 2 Diabetes
	Prevention of Obesity and Type 2 Diabetes
	Management of Obesity
	Treatment of Obesity in Patients with Type 2 Diabetes
	Behavior Modifications
	Diets for Weight Loss
	Increasing Physical Activity
	Antidiabetic Medications and Body Weight
	Pharmacotherapy of Obesity
	Bariatric and Metabolic Surgery
	Conclusions
	References
2 Diabetes and Dyslipidemia
	Introduction
	Lipoprotein Composition
	Transport of Dietary Lipids on apo B48-Containing Lipoproteins in Diabetes Mellitus
	Transport of Endogenous Lipids on apo B100-Containing Lipoproteins in Diabetes Mellitus
		VLDL
		LDL
	Transport of apo A-Containing Lipoproteins in Diabetes Mellitus
		HDL
	Treatment of Diabetic Dyslipidemia
		Nonpharmacologic Therapies
	Lipid Lowering Therapies
		Current Treatment Guidelines
		Statins
	Summary
	References
3 Metabolic Syndrome
	Introduction
	Proposed Underlying Causes of Metabolic Syndrome
		Insulin Resistance
		Obesity
		Overnutrition and Energy Imbalance
	Effects of Overnutrition on Specific Tissues
		Adipose Tissue
		Pancreatic Beta Cells
		Skeletal Muscle
		Liver
		Kidney
		Heart
	Adverse Effects of Carbohydrate Overnutrition
	Timeline for Development of the Metabolic Syndrome
	Obesity Without Metabolic Syndrome
	Metabolic Syndrome Without Obesity
	Lifestyle Intervention on Metabolic Syndrome
	Management of Individual Metabolic Risk Factors
		Atherogenic Dyslipidemia
		Hypertension
		Hyperglycemia
		Pro-inflammatory State
		Prothrombotic State
	References
4 Hypertension and Diabetes
	Introduction
	Pathophysiology of Hypertension and Diabetes Mellitus
	Goals of Blood Pressure Treatment
	Effect of Antihypertensive Agents on Diabetes
	Approach to Treatment
	Summary
	References
5 Diabetes and the Cardiovascular System
	Introduction
	Mechanisms of Vascular Damage in Diabetes
	Impaired Vascular Repair in Diabetes
	Screening for Coronary Artery Disease in Diabetic Patients
	Diabetic Cardiomyopathy and Heart Failure
	Cerebrovascular Disease
	Peripheral Artery Disease
	Therapeutic Multifactorial Approach to Diabetic Macroangiopathy
	Setting Glycemic Targets for the Prevention of Macroangiopathy
	Glucose-Lowering Medications and Prevention of Macroangiopathy
	Summary
	References
6 Pathogenesis of Microvascular Complications
	Introduction
	Role of the Polyol Pathway
	The Role of the Glycation Modification of Proteins in Diabetic Microvascular Complications
	Oxidative Stress in the Pathogenesis of Diabetic Microvascular Complications
	Activation of Protein Kinase C in Vascular Tissues
	Evidence for the Activation of Diacylglycerol (DAG)-PKC Pathway in Diabetes
	PKC Activation in the Development of Diabetic Nephropathy
	Clinical Studies Using RBX for Treatment of DN
	PKC Activation in the Development of Diabetic Retinopathy
	Role of PKC in the Development of Diabetic Peripheral Neuropathy (DPN)
	PKCδ Activation in Fibroblasts and Wound Healing
	Renin-Angiotensin System (RAS) in the Pathogenesis of Diabetic Microvascular Complications
	Role of Endoplasmic Reticulum (ER) Stress in Diabetic Microvascular Complications
	Role of Kallikrein-Bradykinin System in the Development of Diabetic Microvascular Complications
	Role of the Kallikrein-Kinin System in Diabetic Retinopathy
	Protective Factors
		Insulin: Concept of Selective Insulin Resistance on the Vessel Wall in Diabetes
		Antioxidant Enzymes
		SHP-1 Activation and Its Inhibitory Effects of PDGF and VEGF
		TGF-β
		VEGF
		Activated Protein C (APC)
		Vascular Progenitor Cells (VPC)
	Summary
	References
7 Diabetes and the Kidney
	Epidemiology
	Clinical Presentation
		Natural History of Diabetic Kidney Disease: The Classical View
		Stage I
		Stage II
		Stage III
		Stage IV
		Stage V
			Alternative Presentation of Diabetic Nephropathy
		Additional Renal Complications
	Management of the Renal Damage in Diabetes
		The Role of the Glucose Control
		Insulin Treatment
		Glomerular Hemodynamic and Blood Pressure Control
	Diabetic Nephropathy and Cardiovascular Disease
		Epidemiology
		Mechanisms of Macrovascular Damage in Patients with Diabetes and CKD
	References
8 Diabetes and the Eye
	Introduction
		Eye Involvements in Diabetes
			Orbit
			Nerves: Extraocular Muscles
			Ocular Appendages
			Cornea
			Iris: Trabecular Meshwork
			Ciliary Body
			Pupil
			Lens
			Optic Nerve
	Diabetic Retinopathy
		Epidemiology and Risk Factors
		Natural History and Classification of Diabetic Retinopathy
		Pathogenesis
		Clinical Assessment of Diabetic Retinopathy
			Fundus Photography
			Grading Diabetic Retinopathy from Color Fundus Photographs
			Monitoring the Initial Stages of Diabetic Retinopathy Progression: Microaneurysm Turnover
			Wide Field Fundus Angiography
			Fluorescein Angiography
			Optical Coherence Tomography (OCT)
			OCT Angiography
			Electrophysiological Testing
			Oscillatory Potentials (OPs)
			Multifocal Electroretinography
		Current Options for Medical Treatment
		New Perspectives for Medical Treatment
		Ophthalmological Treatment
			Laser and Surgical Interventions for Severe Nonproliferative and Proliferative Diabetic Retinopathy
				Panretinal Laser Photocoagulation
				Surgical Vitrectomy for Vitreous Hemorrhage and Proliferative Diabetic Retinopathy
				Intravitreal Antiangiogenic Agents
			Laser and Surgical Interventions for Diabetic Macular Edema
				Focal Laser Treatment
				Sub-threshold Laser
				Surgical Vitrectomy for Diabetic Macular Edema
			Intravitreal Corticosteroids
			Intravitreal Antiangiogenic Agents
		Review of Approaches for the Treatment of Diabetic Macular Edema
			Recommendations for the Treatment of Diabetic Macular Edema
			Characterization of Responders to Treatment
		Role of Early Screening for Diabetic Retinopathy in Patients with Diabetes Mellitus
			Screening for High-Risk Diabetic Retinopathy
			Criteria for Review and Referral
			Screening Tests for Diabetic Retinopathy
			Automated Computer-Aided Analysis of Fundus Digital Photographs in Diabetic Retinopathy Screening
			Role of Telemedicine in Eye Care in Diabetes
	Conclusions
	References
9 Diabetes and the Nervous System
	Introduction and Scope of the Problem
	Central Nervous System and Diabetes
		Structural Changes
		Functional Changes
		Epidemiologic Evidence of CNS Dysfunction in DM
		Mechanisms of CNS Changes in Diabetes
		Cognition and Behavior
	Peripheral Nervous System and Diabetes
	Pathogenesis of Diabetic Neuropathies
	Classification of Diabetic Neuropathies
	Clinical Presentation
		Focal and Multifocal Neuropathies
		Radiculopathies or Polyradiculopathies
		Acute Painful Treatment-Induced Neuropathy
		Distal Symmetric Polyneuropathy (DSPN)
			DSPN Is Strongly Linked to Falling
			What Interventions Work Best for Reducing Falls Risk?
	Screening and Diagnosis of Diabetic Neuropathies
		Toronto Classification of DSPN (Tesfaye et al. 2010)
		Clinical Assessment of DSPN
		Conditions Mimicking Diabetic Neuropathy
		Objective Devices for the Diagnosis of Neuropathy
	Cardiac Autonomic Neuropathy
	Treatment of Diabetic Polyneuropathies
		Treatment of Specific Underlying Pathogenic Mechanisms
			Glycemic and Metabolic Control
			Oxidative Stress
			Growth Factors
		Treatment of Symptoms and Improvement in QoL
			The Diagnostic Workup for Pain
			Pathogenetic Mechanism of Neuropathic Pain
			Distinction Between Nociceptive and Non-nociceptive Pains
			Pain and Its Comorbidities
			Epidemiology of Neuropathic Pain
			The Diagnosis of Neuropathic Pain
			Management of Neuropathic Pain
			Pharmacological Treatment of Pain
			Topical Agents
			Opioids
			Antidepressants and Monoamine Reuptake Inhibitors
			Natural Products
			Lifestyle Interventions
			Botulinum Toxin
			Psychological Support
			Physical Measures
			Acupuncture
			Electrical Stimulation
			Surgical Decompression
			Guidelines for Treatment of Painful Neuropathy
	References
10 Diabetic Foot
	Introduction
	Diabetic Peripheral Neuropathy (DPN)
		Distal Symmetrical Sensorimotor Peripheral Neuropathy
		Peripheral Sympathetic Autonomic Neuropathy
	Other Long-Term Risk Factors for Foot Ulceration
	Peripheral Vascular Disease
	Epidemiology of Diabetic Foot Problems
	Prevention of Diabetes-Related Foot Complications
	Identification of the High-Risk Foot
		Assessment
		History
		Clinical Examination
		Neurological Assessment
		Vascular Assessment
		The High-Risk Patient
		Wound Classification
	Management of Diabetic Foot Ulceration
		Neuropathic Ulcers
		Debridement
		Off-Loading
		Neuro-Ischemic Ulcers
		Infection
		Wound Dressings
		Negative-Pressure Wound Therapy
		Growth Factors and Skin Substitutes
		Hyperbaric Oxygen Therapy
		Charcot Neuroarthropathy
		Patient Education
		Multidisciplinary Team Input
		Summary
	Conclusions
	References
11 Diabetes and Cancer
	Introduction
	Diabetes-Cancer Association: Epidemiology
		Diabetes and Cancer Incidence in Different Tissues
			Other Cancers in Diabetes
		Type 1 Diabetes and Cancer
		Cancer-Related Mortality and Diabetes
	Mechanisms of the Cancer-Promoting Effect of Diabetes
		General Mechanisms
		Site-Specific Mechanisms
		Mechanisms of Increased Cancer-Related Mortality in Diabetes
	Antidiabetes Drugs and Cancer Risk
		Insulin Analogs
			In Vitro Experimental Evidences
			Clinical Studies on Insulin Analogs and Cancer
		Oral Antidiabetic Drugs
			New Antidiabetes Drugs
	Cancer Drugs Causing Hyperglycemia and Insulin Resistance
		Glucocorticoids
		Antiandrogens and Other Hormonal Therapies
		Cancer Drugs Targeting the Insulin Signaling Pathways
		Approach to Hyperglycemia Induced by Cancer Treatment
	References
12 Bone and Diabetes
	Definition of Diabetic Bone Disease
	Epidemiology of Fracture in Patients with Diabetes
		Burden of Fracture in Patients with Diabetes
		Bone Mineral Density
		Other Fracture Predictors
		Medication Associated with Osteoporosis
		FRAX
	Bone Remodeling and Pathophysiology of Osteoporosis
		Regulation of Bone Remodeling
		Pathogenesis of Osteoporosis
	Pathophysiology of Diabetic Bone Disease
		Bone Remodeling
		Insulin and Incretins
		Advanced Glycation End Products and HbA1c
		Falls, Hypoglycemia, and Diabetes Complications
	Antidiabetic Drugs and Diabetic Bone Disease
		Lipid-Lowering Drugs
		Antihypertensives
	Potential Predictors of Diabetic Bone Disease
		Comorbidities
		Recent Scanning Modalities
		Microindentation
		Bone Turnover Markers
	Diagnostic Approach to Diabetic Bone Disease
	Treatment of Diabetic Bone Disease
	Future Perspectives
	Implications
	Summary
	Cross-References
	References
13 Diabetes and the Skin
	Introduction
	Specific Cutaneous Markers of Diabetes Mellitus
		Acanthosis Nigricans
		Necrobiosis Lipoidica Diabeticorum
		Generalized Granuloma Annulare
		Bullous Disease of Diabetes
		Scleredema Diabeticorum
		Diabetic Foot
		Eruptive Xanthomas
	Non-specific Skin Conditions Associated with Diabetes
		Psoriasis
		Acrochordons
		Yellow Skin and Nails
		Generalized Pruritus
		Rubeosis Faciei
		Diabetic Dermopathy and Pigmented Purpura
		Skin Infections
	Conclusions
	References
14 Diabetes and Periodontal Disease
	Introduction
	The Effects of Diabetes on Periodontal Disease
		Pathogenesis of Periodontal Disease
		Periodontal Disease as a Complication of Diabetes
	The Bidirectional Relationship Between Diabetes and Oral Health
	The Role of Periodontal Disease on Glycemic Status for Patients with Type 2 Diabetes
	Diabetes and Dental Implant Therapy
	Summary
	References
15 Diabetes and Sexual Disorders
	Introduction
	Erectile Dysfunction
		ED and Diabetes: Epidemiology and Risk Factors
		Physiology of Penile Erection
		Pathogenesis of ED in Diabetes
			Hyperglycemia
			Vasculopathy
			Neuropathy
			Visceral Adiposity
			Hypogonadism
			Psychological Issues
		Diagnosis
		Treatment
			Lifestyle Changes
			Pharmacologic Therapy
	Female Sexual Dysfunction
		FSD and Diabetes: Epidemiology and Risk Factors
		Physiology of Female Sexual Response
		Pathogenesis of FSD in Diabetes
			Hyperglycemia
			Vascular and Nerve Dysfunctions
			Endocrinological Disorders
			Psychological Factors
		Diagnosis
		Treatment
			Lifestyle Change
			Hormonal Therapy
			Other Drugs
			Mechanical Device
			Psychological Issue Treatment
	Summary
	Appendix 1
	References
16 Diabetes and NAFLD
	Introduction
	Diagnosis of NAFLD
	Epidemiology and Natural History of NAFLD in Patients with Diabetes
	Association Between NAFLD and Poor Glycemic Control
	Association Between NAFLD and Risk of Liver-Related Mortality and Morbidity
	Association Between NAFLD and Risk of Chronic Kidney Disease and Other Microvascular Diabetic Complications
	Association Between NAFLD and Risk of Cardiovascular, Cardiac, and Arrhythmic Complications
	Putative Mechanisms Linking NAFLD with Cardiovascular, Cardiac, and Kidney Complications
	Management of NAFLD in Patients with Diabetes
	Treatment Options for NAFLD in Patients with Diabetes
	Summary
	References
17 Diabetes Secondary to Pancreatic Diseases
	Definition and Prevalence
	Causes
		Pancreatitis
		Pancreatic Cancer
		Pancreatic Surgery
		Other Causes
	Clinical Diagnosis
	Management
	Conclusion
	References
18 Impact of Drugs on Diabetes Risk and Glycemic Control
	Introduction
	Glucocorticoids and Other Hormones
	Insulin Resistance
		Liver
		Skeletal Muscle
		Adipose Tissue
	Insulin Secretion
		Oral Contraceptives
		Growth Hormone
		Somatostatin Analogues
	Antihypertensives
		Thiazide Diuretics
		Beta-Blocking Agents
		CCBs
	Lipid-Modifying Agents
		Statins
		Nicotinic Acid
	Antiarrhythmics
	Anti-infectives
		Antibiotics
		Antimycobacterials
		Antivirals
		Antiprotozoals
	Drugs Affecting the Nervous System
		Antiepileptics
		Antipsychotic Drugs
		Antidepressant Drugs
	Antineoplastic Agents
	Immunosuppressive Agents
	Summary
	References
19 Diabetes Secondary to Endocrine Disorders and PCOS
	Introduction
	Diabetes Secondary to Hypersecretion of Counterregulatory Hormones
		Glucagonoma
		Pheochromocytoma
		Cushing´s Syndrome
		Acromegaly
	Other Endocrine Disorders Associated with Diabetes
		Somatostatinoma
		Thyroid Dysfunction
		Hyperaldosteronism
		Hyperparathyroidism
		Male Hypogonadism
	Polycystic Ovary Syndrome and Diabetes
	Summary
	References
20 Hyperglycemic Crises: Diabetic Ketoacidosis and Hyperglycemic Hyperosmolar State
	Introduction
	Pathogenesis
	Precipitating Causes
	Diagnosis
		Symptoms and Signs
	Laboratory Findings
	Laboratory Pitfalls
	Management of Hyperglycemic Crises
	Fluid Therapy
	Insulin Therapy
	Potassium
	Bicarbonate
	Phosphate
	Transition to Subcutaneous Insulin
	Prevention
	References
21 Hypoglycemia
	Introduction
	Frequency of Hypoglycemia
	Definition of Hypoglycemia
	Brain Metabolism and Glucosensors
	Liver and Kidneys as Sources of Endogenous Glucose Production
	Neuroendocrine Responses to Hypoglycemia
	Pathophysiology of Hypoglycemia
		Responses to Hypoglycemia in Elderly People
		Impaired Awareness of Hypoglycemia (or Hypoglycemia Unawareness)
	Hypoglycemia-Associated Autonomic Failure (HAAF - ``Cryer Syndrome´´)
	Consequences of Hypoglycemia
	Cardiovascular Risk of Hypoglycemia
	The Economic Burden of Hypoglycemia
	General Principles of Preventing Hypoglycemia
	Prevention of Hypoglycemia in Intensively Treated Type 1 Diabetes
	Prevention of Hypoglycemia in Intensively Treated Type 2 Diabetes
	Treatment of Hypoglycemia Unawareness
	Treatment of Hypoglycemia
	Conclusions
	References
22 Pregnancy and Diabetes
	Introduction
	Epidemiology
	Pathophysiology
	Classification and Diagnosis of Hyperglycemia in Pregnancy
	Adverse Pregnancy Outcomes in Pregnancies Complicated by Diabetes
	Management of Gestational Diabetes Mellitus
	Postpartum Management
	References
23 Diabetes, Depression, and Cognitive Disorders
	Introduction
	Diabetes and Depression
	Epidemiology of Diabetes and Depression
		Depression or Distress
		Specific Populations
	Etiology of Diabetes and Depression
		Which People with Diabetes Are at Risk of Depression?
		Why Do People with Diabetes Develop Depression?
		Why Do People with Depression Develop Diabetes?
		Do Common Antecedents Explain the Association Between Diabetes and Depression?
	Consequences of Depression in Diabetes
	Management of People with Diabetes and Depression
		Screening and Diagnosis of Depression
		Treatment of Depression in People with Diabetes
		Psychological Treatment
		Pharmacotherapy
		Models of Care
	Cognitive Function
	Diabetes and Cognition
		Cognitive Dysfunction in Children and Adolescents
		Cognitive Dysfunction in Adults with Diabetes
	Dementia
	Diabetes and Dementia
	Clinical Implications of Dementia in People with Diabetes
		Prevention of Dementia
		Diagnosis of Dementia
		Treatment of Dementia
		Management of Diabetes in Someone with Dementia
	Conclusions
	References
Index