From Obesity to Diabetes

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Preface: From Obesity to Diabetes Contents Part I: Obesity Epidemiology of Obesity 1 Introduction: Why Obesity Matters 2 Definition of Obesity by Its Relation to Health Effects 3 Obesity Subtypes, Body Fat Distribution, Ectopic Depositions 4 Prevalence and itsDependencies of Multilevel Geography, Sex and Age 5 The Energy-Balance Theorem: Eaten Too Much and Moved Too Little 6 Within and Between Population Risk Factors for Obesity 7 Familial Risk, Genetics and Shared Environment 8 General - Family Independent - Environmental Risk Factors 9 Risk Factors vs. Modifiable and Non-modifiable Causal Factors of Obesity 10 Trans-Generational and Perinatal - Epigenetically Mediated - Risk Factors 11 Life-Course Approach, Life-Long Challenges 12 Multilevel Social Risk Factors 13 Development of the Obesity Epidemic and Future Predictions 14 Presumed Drivers of the Obesity Epidemic 15 Epilogue References The Circadian Clock and Obesity 1 Introduction 2 The Biological Clock 3 The Molecular Clock Machinery 3.1 Core Clock Transcriptional Regulation 3.2 Post-Translational Clock Regulation 4 Circadian Clock and Metabolism Interplay 4.1 Peripheral Clocks 4.2 Circadian Clock and Nutrient Sensing 4.3 Circadian Regulation of Hormones 5 Circadian Control of Energy Homeostasis and Metabolic Consequences of Clock Disruption 5.1 Adipose Tissue Clock and Obesity 5.2 Circadian Glucose Homeostasis and Diet-Induced Obesity-Associated Metabolic Disorders 5.3 The Liver Clock, Lipid Metabolism, and Obesity-Associated Liver Disease 6 Clock Desynchronization and Metabolic Syndrome in Humans 7 Pathological Consequences of Altered Feeding Patterns and Potential Beneficial Impact of Time-Restricted Feeding/Eating to D... 7.1 Feeding Patterns and Impact of Time-Restricted Feeding (TRF) on Metabolic Control in Rodents 7.2 Feeding Pattern and Metabolic Control in Humans: Potential Beneficial Impact of Time-Restricted Feeding/Eating to Decrease... 8 Conclusion/Perspectives References Nutrition and Microbiome 1 Introducing the Role of the Microbiome for Human Health 1.1 The Definition of Microbiome 1.2 Observational Studies in Humans Identified the Diet as a Strong Modulator of the Gut Microbiome 1.3 Nutritional and Metabolic Disorders Are Associated with Microbiome Changes 2 Targeting the Microbiome for Improving Metabolic Health in Humans 2.1 Inulin-Type Fructans 2.2 Galacto-Oligosaccharides 2.3 beta-Glucans 2.4 Arabinoxylans 2.5 Resistant Starch 3 Can the Gut Microbiome Predict the Efficacy of Dieting in Humans? 4 Conclusion and Perspectives References From Obesity to Diabetes: The Role of the Adipose Organ 1 White and Brown Adipose Tissues 1.1 White Adipose Tissue 1.2 Brown Adipose Tissue 2 The Adipose Organ 3 Adipose Organ Plasticity 4 The Adipose Organ in Obesity Disease 5 Adipose Organ Dysfunction, Inflammation, and T2DM in Obesity 6 New Browning Drugs 7 Conclusion References Targeting Epicardial Fat in Obesity and Diabetes Pharmacotherapy 1 Introduction 2 EAT and Diabetes Mellitus 3 EAT and Obesity 4 EAT and GLP-1A 5 EAT and DPP4i 6 EAT and SGLT2i 7 EAT and TZDs 8 EAT and Metformin 9 EAT and Insulin 10 EAT and Statins 11 Conclusions References The Enteroendocrine System in Obesity 1 Introduction 2 Glucagon-Like Peptide 1 (GLP-1) 2.1 Intestinal GLP-1 Secretion 2.2 GLP-1 and the Incretin Effect 2.3 Anorexigenic Effects of GLP-1 2.4 Gastrointestinal Effects of GLP-1 2.5 Additional Actions of GLP-1 3 Other Intestinal Proglucagon-Derived Peptides 3.1 GLP-2 3.2 Oxyntomodulin 4 Glucose-Dependent Insulinotropic Polypeptide (GIP) 5 Peptide YY (PYY) 6 Cholecystokinin (CCK) 7 Dysregulation of Gut Hormones in Obesity 7.1 Alteration of EEC Expression Profiles by Diet or Obesity 7.2 Maintained Gut Hormone Function in Obesity 8 Conclusion References Insights from Studies of White Adipose Tissue Using Single-Cell Approaches 1 Introduction 2 Single-Cell Technologies: A Rapidly Evolving Field 3 Platforms to Study White Adipose Tissue Heterogeneity 4 Exposures of Interest in Single-Cell Studies of White Adipose Tissue 5 Results Related to Specific White Adipose Tissue Resident Cells 5.1 Adipocyte Progenitors 5.2 Immune Cells 5.3 Mature Adipocytes 6 Future Perspectives References Obesity-Related Insulin Resistance: The Central Role of Adipose Tissue Dysfunction 1 Introduction 2 Adipose Tissue Metabolism, Composition, and Insulin Resistance 2.1 Impact of Insulin on Lipogenesis and Adipose Tissue Expansion 2.2 Impact of Insulin on Lipolysis 2.3 Impact of Adipose Tissue Composition on IR 3 Impact of Adipose Tissue Distribution and Ectopic Fat Accumulation on IR 4 Obesity and Hepatic Insulin Resistance 5 Obesity and Muscle Insulin Resistance 6 Conclusions References Obesity, Senescence, and Senolytics 1 Introduction 2 Obesity 3 Adipose Tissue 4 Cellular Senescence 5 Cellular Senescence in Obesity 6 Inducers of Cellular Senescence in Obesity 7 Implications of Cellular Senescence in Obesity 8 Senolytic Therapies in Obesity References Obesity and Obstructive Sleep Apnea 1 Introduction 2 Epidemiology 3 Studies on Adipose Tissue 4 Effects of CPAP Treatment 5 New Drugs to Treat Obesity: Effects in OSA Patients 6 Conclusions References Part II: Diabetes and Complications Inter-Organ Crosstalk in the Development of Obesity-Associated Insulin Resistance 1 From Obesity to Diabetes: The Role of Inter-Organ Crosstalk 2 Mediators of Communication: Soluble Factors of Inter-Organ Crosstalk 2.1 Adipokines 2.2 Myokines and Hepatokines: Toward the Organokine Concept 2.3 EVs as Shuttle of Biological Information 2.4 Other Circulating Messengers (miRNA, lncRNA, Fatty Acids) 3 Organ Crosstalk 3.1 AT-Liver Crosstalk 3.2 AT-Skeletal Muscle Crosstalk 3.3 AT-Pancreas Crosstalk 3.4 Interaction Between AT and the Cardiovascular System 3.5 Interaction Between Gut Microbiota, Liver, and AT 4 Perspective: Taming Inter-Organ Mediators to Control Obesity? References Islet Inflammation and beta Cell Dysfunction in Type 2 Diabetes 1 Introduction 2 T2D Etiology and Pathogenesis of beta Cell Failure 2.1 Definition of T2D 2.2 beta Cells at the Center of T2D 3 Islet-Resident Macrophages at Homeostasis 4 Islet Inflammation and Immune Cells in T2D Patients 4.1 Immune Cells in T2D Islets 4.2 Transcriptomic Analyses of T2D Islets 4.3 Islet Inflammation During the Progression of T2D 4.4 Islets in the Single-Cell Era 5 Islet Homeostasis During Metabolic Stress in Rodents 5.1 Islet Inflammation and Immune Cells in Obese and Diabetic Rodents 5.2 Phenotype of Mouse Islet Macrophages During Obesity and T2D 6 Interactions Between Macrophages and beta Cells in Islets 6.1 Cytokines and beta Cell Function 6.2 Macrophages and beta Cell Function 6.3 Macrophages and Islet Remodeling 7 Other Parameters Regulating Islet Inflammation and beta Cell Dysfunction 7.1 Islet Amyloid Deposition 7.2 Pancreatic Steatosis 7.3 Aging 8 In Vitro Exploration of Islet Glucolipotoxicity 9 Conclusions and Perspectives References NAFLD and NASH: The Metabolically Diseased Liver 1 Definition 2 Epidemiology 3 Pathophysiology 4 Diagnostics 5 Management 5.1 Lifestyle 5.2 Pharmacotherapy References Diabetic Kidney Disease: From Pathogenesis to Novel Treatment Possibilities 1 Introduction 1.1 Definition 1.2 Diagnosis 2 Pathogenesis of DKD 3 Current Therapies for DKD 3.1 Lifestyle Changes 3.2 Blood Glucose and Blood Pressure Control 3.2.1 Blood Glucose SGLT-2 Inhibitors GLP-1 Receptor Agonists Incretin Therapies 3.2.2 Blood Pressure Angiotensin-Converting Enzyme (ACE) Inhibitors Angiotensin II Receptor Blockers Mineralocorticoid Receptor Antagonists 3.3 Lipid Management 4 Novel Experimental Drug Targets for DKD 4.1 Carbonyl and Oxidative Stress 4.1.1 AGE-RAGE AGE Formation Inhibitors RAGE Inhibitors 4.1.2 NOX NOX4 as a New Target in DKD NOX5 as a New Target in Human DKD NOX Inhibitors 4.1.3 Xanthine Oxidoreductase 4.1.4 Mitochondrial ROS 4.1.5 Antioxidants Nrf2-KEAP 4.2 Inflammation 4.2.1 Inflammasome Activation of NLRP3 Inflammasome TLR4-NFκB-ROS Signaling Pathway 4.2.2 Novel Inflammation Inhibitors 4.2.3 Chemokines and Cytokines 4.2.4 JAK-STAT 4.2.5 Phosphodiesterase 5 Outlook References Diabetic Peripheral Neuropathy 1 Introduction 2 Large- and Small Nerve Fibre Diabetic Neuropathy 3 Early Detection of Diabetic Peripheral Neuropathy 4 Pathophysiology of Diabetic Peripheral Neuropathy 5 Treating Diabetic Peripheral Neuropathy 6 Diabetic Foot Ulcers 7 Pathophysiology of Neuropathic Pain in Diabetes 8 Conventional Treatment of Neuropathic Pain in Diabetes 9 Pathogenic Treatment of Neuropathic Pain in Diabetes References Part III: Lifestyle Modifications and Future Treatments Weight Loss Strategies 1 Introduction 2 Energy Intake and Energy Expenditure in Different Approaches of Weight Loss 3 Lifestyle Interventions for Weight Management 3.1 Traditional Lifestyle Interventions 3.2 Alternative Lifestyle Interventions 4 Time-Restricted Eating Patterns 5 Diet Composition Focused Interventions 6 Effects of Age on Weight Management 7 Weight Loss Interventions for Underrepresented Groups 8 Summary and Roadmap for Future Personalization Weight Loss Strategies References Physical Activity, Obesity and Weight Loss Maintenance 1 Introduction 2 Physical Activity and Weight Loss 3 Maintenance of Weight Loss 4 Physical Activity and Appetite: Are There an Additional Effect Beyond Burning Calories? 5 Physical Activity, Fitness and Fat Distribution 6 Myokines: Effect on Adipose Tissue and Brain 6.1 Muscle-Adipose Crosstalk 6.2 Muscle-Brain Crosstalk 6.3 Muscle-Muscle Crosstalk 7 Conclusion References Bariatric/Metabolic Surgery 1 Laparoscopic Bariatric/Metabolic Surgery 1.1 Sleeve Gastrectomy 1.2 Roux-en-Y Gastric Bypass 1.3 Biliopancreatic Diversion With or Without Duodenal Switch 1.4 Single Anastomosis Duodeno-Ileal Bypass 1.5 Effects on Life Expectancy 1.6 Effects on Type 2 Diabetes 1.7 Effects on Hypertension and Cardiovascular Diseases 1.8 Effects on Cancer 2 Endoscopic Bariatric Surgery 2.1 Intragastric Balloons 2.2 Hydrogel 2.3 Endoluminal Vertical Gastroplasty 2.4 Incisionless Magnetic Anastomosis System 2.5 Gastric Aspiration 2.6 Gastrointestinal Liner 2.7 Duodenal Mucosa Resurfacing 3 New Anti-obesity Medications 4 Conclusions References Drugs for Treating Obesity 1 Introduction and Rationale for Anti-obesity Medications 2 Anti-obesity Medications Recently Brought to Market: Semaglutide 2.4 mg and Setmelanotide 2.1 Semaglutide 2.4 mg 2.2 Setmelanotide 3 Older Anti-obesity Medications 3.1 Orlistat 3.2 Naltrexone SR/Bupropion SR 3.3 Liraglutide 3.0 mg 3.4 Phentermine/Topiramate Extended Release (ER) (Available in the USA, But Not Available in the EU) 4 Obesity Pharmacotherapy for the Next Decade 4.1 Tirzepatide 4.2 Bimagrumab 4.3 Cagrilintide + Semaglutide 5 The Way Forward in Obesity Pharmacotherapy References Novel Drugs for Diabetes Therapy 1 Introduction 2 GLP-1 Receptor Co-agonists 2.1 Background 2.2 Combinations of GLP-1 Agonists and Glucagon 2.3 Combinations of GLP-1 Agonists and GIP 2.4 Other Dual- or Triple Agonists with GLP-1 3 Novel Insulin Preparations 3.1 Once-Weekly Insulins 3.1.1 Insulin Icodec 3.1.2 Basal Insulin Fc (BIF) 3.1.3 Pharmacology 3.1.4 Clinical Data 3.2 Oral Insulins 3.2.1 Background 3.2.2 Prandial Oral Insulins 3.2.3 Basal Oral Insulins 4 Summary and Conclusions References Novel Approaches to Restore Pancreatic Beta-Cell Mass and Function 1 Introduction 2 Lifestyle Intervention 2.1 Lifestyle Intervention and Diabetes Remission 2.2 Mechanisms Underlying the Effects of Lifestyle Intervention on Glycemic Control 3 Pharmacological Approaches 3.1 Insulin 3.2 Metformin, Sulfonylurea, Thiazolidinediones 3.2.1 Effects on Glycemic Control and Beta-Cell Function in Individuals with T2DM 3.3 GLP-1 Receptor Agonists and DPP-4 Inhibitors 3.3.1 The Physiological Effects of GLP-1 3.3.2 Effects on Beta-Cell Function and Mass in Preclinical Models 3.3.3 Effects on Glycemic Control and Beta-Cell Function in Individuals with T2DM 3.4 Twincretins 3.5 SGLT2 Inhibitors 3.5.1 Effects on Beta-Cell Function and Mass in Preclinical Models 3.5.2 Effects on Glycemic Control and Beta-Cell Function in Individuals with T2DM 4 Bariatric/Metabolic Surgery 5 Conclusion and Outlook References Precision Medicine and Obesity 1 Introduction 2 Obesity Phenotypes Based on Pathophysiologic Traits 2.1 Characterization of Obesity Phenotypes 2.2 Obesity Phenotyping as a Tool for Prediction and Treatment for Weight Loss 3 Psycho-Behavioral Phenotyping of Obesity: The Six-Factor Questionnaire (6FQ) 4 The Role of Post-Prandial Glucose Metabolism on Weight Management: Glycemic Dips 5 Pharmacotherapy for Monogenic Mutations Associated with Obesity 6 Other Precision Medicine for Obesity Initiatives 7 Conclusion References Targeting the Enteroendocrine System for Treatment of Obesity 1 Introduction 2 Gut Hormone Mimetics: GLP1R Agonism and Beyond 2.1 GLP-1 Receptor Agonists 2.2 DPP4 Inhibitors 2.3 GLP1R/GCGR Co-agonism 2.4 GLP1R/GIPR Co-agonism 2.5 GLP1R/GCGR/GIPR Triple Agonism 2.6 GLP1R/NPY2R Co-agonism 2.7 CCK1R Agonism 2.8 Co-administration of GLP-1 and Amylin Receptor Agonists 2.9 Summary of Gut Hormone Mimetic Treatments 3 Bariatric Surgery 4 Stimulating Endogenous EEC Secretion 4.1 Nutrient Encapsulation 4.2 Pharmacological Targeting of Enteroendocrine GPCRs 4.3 FFA1 (GPR40) Agonists 4.4 GPR119 Agonists 4.5 GPBAR1 (TGR5) Agonists 4.6 Bile Acid Sequestrants and ASBT Inhibitors 4.7 Slowing Macronutrient Digestion 4.8 SGLT1 Inhibitors 4.9 Somatostatin Receptor Antagonists 4.10 Future Directions in Manipulating Endogenous EEC Secretion 5 Enhancing EEC Number 6 Conclusion References