Diabetes - Perspectives in Drug Therapy (eBook)

Preface 6
Contents 10
Contributors 12
Targeting Type 2 Diabetes 16
1 Inflamed About Obesity: Adipose Tissue and Insulin Resistance 17
2 The Lipotoxicity Concept 22
3 beta-Cell Failure: Link to Hyperglycaemia and T2DM 25
4 Role of the CNS in Glucose Homeostasis 27
5 Nutrient-Sensing Pathways in Calorie Restriction 29
6 Current Therapy 30
6.1 Published Algorithms 30
6.2 Metformin 31
6.3 Thiazolidinediones 32
6.4 GLP-1 Agonists and DPP-4 Inhibitors 33
7 Conclusions 34
References 35
Dual Acting and Pan-PPAR Activators as Potential Anti-diabetic Therapies 49
1 Introduction 50
2 PPAR-gamma 51
3 PPAR-a 52
4 PPAR-delta 53
5 Logic for Dual and Triple PPAR Activators in the Treatment of Diabetes and Insulin Resistance 53
6 The Bezafibrate Experience 54
7 Use of Combined Therapy with Fenofibrate and Glitazones 55
8 Dual PPAR-a/gamma Activator Drugs 56
9 Outlook for Dual PPAR-a/gamma Activators 58
10 PPAR-Pan Activators and PPAR-delta Dual Activators 59
11 Cancer Liability of PPAR Activators 60
12 Concluding Remarks 60
References 61
GLP-1 Agonists and Dipeptidyl-Peptidase IV Inhibitors 66
1 Type 2 Diabetes, Its Epidemiology, and the Need for Further Treatment Options 67
2 Incretin Hormones 67
2.1 GLP-1 Actions 69
2.2 Dipeptidyl-Peptidase IV 70
3 GLP-1 Receptor Agonists 71
3.1 Exenatide 72
3.2 Liraglutide 74
4 DPP-4 Inhibitors 75
4.1 Sitagliptin 76
4.2 Vildagliptin 77
4.3 Saxagliptin 77
5 Incretin-Based Therapies: Common Characteristics and Differences 78
6 Indications for Incretin-Based Therapies and Their Placement in Treatment Guidelines for Type 2 Diabetes 79
7 Incretin-Based Therapies and Type 1 Diabetes 81
References 82
Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes 88
1 A Brief Introduction to the Endocannabinoid System 89
2 Central Endocannabinoid Control of Energy Balance 91
3 Peripheral Endocannabinoid Control of Energy Balance 95
4 Regulation and Dysregulation of the Endocannabinoid System in the Control of Metabolism 97
4.1 Role of Dysregulated Endocannabinoid Signaling in Type 2 Diabetes and Obesity-Related Metabolic and Cardiovascular Disorders 101
4.2 Endocannabinoid Dysregulation in Human Abdominal Obesity and Hyperglycemia: Relationship with Cardiometabolic Risk Factors and Type 2 Diabetes 105
5 Clinical Use of CB1 Receptor Antagonists/Inverse Agonists Against Type 2 Diabetes 106
6 Plant Cannabinoids and Type 1 Diabetes 109
6.1 Type 1 Diabetes Mellitus 109
7 Concluding Remarks 110
References 111
SGLT Inhibitors as New Therapeutic Tools in the Treatment of Diabetes 118
1 Preface 119
2 The Sodium-d-Glucose Cotransporter as Target 119
2.1 Role of Sodium-d-Glucose Cotransport in Transepithelial Sugar Transport 119
2.2 Molecular Basis of Sodium-d-Glucose Cotransport 121
2.3 Sugar Binding Sites of the SGLT 122
2.3.1 Substrate Specificity of the Sodium-d-Glucose Cotransporters 122
2.3.2 Sugar Binding Site(s) of the Sodium-d-Glucose Cotransporter 124
3 The Prototype of SGLT Inhibitors: Phlorizin 124
3.1 General Remarks 124
3.2 SGLT as Phlorizin Receptor 125
3.2.1 Binding Studies on Brush Border Membranes 125
3.2.2 Interactions of Phlorizin with the Isolated Transporter and Its Subdomains 125
3.2.3 Differences Between hSGLT1 and hSGLT2 126
3.3 Pharmacophore Analysis and Dimensions of the Phlorizin Binding Pocket 126
4 Synthesis and Screening of Derivates of Phlorizin 127
4.1 O-glucosides, C-arylglucosides, N-glucosides and S-glycosides 127
4.2 Screening Methods 129
4.2.1 Cellular Assays 129
4.2.2 Animal Models 130
5 Therapeutic Efficacy of SGLT Inhibitors 130
5.1 In Vitro Studies on Sugar Transport by Cultured Transfected Cells 130
5.2 Effect of SGLT Inhibitors in Preclinical and Clinical Studies 131
5.2.1 Urinary Glucose Excretion 131
5.2.2 Effect on Plasma Glucose Levels 132
5.2.3 Effect on Fasting Hypoglycaemia 132
6 Benefits and Pitfalls of SGLT Inhibitors 133
6.1 Benefits 133
6.2 Pitfalls 133
7 Current State and Future Developments 134
References 135
Inhibitors of 11beta-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy 140
1 Glucocorticoid Metabolism and Action 141
2 Glucocorticoid Excess and the Development of the Metabolic Syndrome 142
3 Association of 11beta-HSD1 with Obesity and Insulin Resistance 144
4 11beta-HSD1 Biochemistry and Regulation 146
5 Non-selective 11beta-HSD1 Inhibitors as Tools 148
6 Studies with Selective 11beta-HSD1 Inhibitors 149
7 Clinical Experience with 11beta-HSD1 Inhibitors 152
8 Potential Therapeutic Challenges with 11beta-HSD1 Inhibitors 152
9 Concluding Remarks 153
References 154
Nampt and Its Potential Role in Inflammation and Type 2 Diabetes 160
1 Introduction 161
2 Nampt and Metabolic Disorders 162
2.1 eNampt and iNampt: Regulation of Pancreatic beta-Cell Function 162
2.2 eNampt in Human Circulation: A Biomarker for Obesity and T2DM? 165
2.3 Role of Hepatic Nampt in T2DM 166
3 eNampt: A Link Between T2DM and Inflammation 168
4 Concluding Remarks and Future Aspects 170
References 171
Inhibition of Ganglioside Biosynthesis as a Novel Therapeutic Approach in Insulin Resistance 178
1 Introduction 179
2 Ganglioside GM3 Is an Inducer of Insulin Resistance 179
3 Caveolae Microdomains and Insulin Signaling 181
4 Insulin Resistance as a Membrane Microdomain Disorder 183
5 Serum GM3 Levels as a New Biomarker of Metabolic Syndrome 187
6 A Possible Therapeutic Intervention of Metabolic Syndrome by Inhibiting Ganglioside Synthesis 188
7 Concluding Remarks 188
References 189
Overcoming Insulin Resistance with Ciliary Neurotrophic Factor 192
1 Introduction 193
2 Current Therapeutics for Obesity and Type 2 Diabetes 193
3 Leptin: A Flash in the Pan 194
4 Leptin Receptor Versus gp130 Receptor Signalling 195
5 gp130 Receptor Ligands 197
6 CNTF 198
7 Metabolic Effects of CNTF 200
7.1 Central Effects of CNTF 200
7.2 Peripheral Metabolic Effects of CNTF 203
8 Future Directions for gp130 Ligands 206
References 207
Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy 213
1 Introduction 214
2 Rationale: Why Target Thermogenesis? 216
2.1 Obesity and Diabetes 216
2.2 Exercise in the Treatment of Diabetes 216
2.3 Exercise in the Treatment of the Metabolic Syndrome 217
2.4 Mitochondrial Function and Capacity for Fat Oxidation in Diabetes 217
2.5 Lessons from beta-Adrenoceptor Agonists 218
3 Current and Recent Drugs 220
3.1 Diabetes Drugs 220
3.2 Obesity Drugs 221
3.2.1 Sibutramine 221
3.2.2 Rimonabant 221
4 Targets in Hormonal Systems 224
4.1 Sympathetic Nervous System 224
4.2 Zn-a2-Glycoprotein 224
4.3 Thyroid Hormones 225
4.4 TGR5: A Bile Acid Receptor 226
4.5 Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase-1 227
4.6 Leptin 228
4.7 Fibroblast Growth Factor 21 229
4.8 Ghrelin 230
4.9 Ciliary and Brain-Derived Neurotrophic Factors 231
4.10 Adiponectin 232
5 Targets in Lipid Metabolism 234
5.1 Acetyl-CoA Carboxylase 234
5.2 Fatty Acid Synthase 235
5.3 Stearoyl-CoA Desaturase-1 235
5.4 Acetyl-CoA:Diacylglycerol Acyltransferase (DGAT) 237
6 Other Intracellular Targets 238
6.1 AMP-Activated Protein Kinase 238
6.2 Peroxisome Proliferator-Activated Receptor beta/delta 241
6.3 Sirtuin1 242
7 Perspectives and Implications for Drug Discovery and Development 243
7.1 Detection of Thermogenesis 244
7.2 Manipulation of Energy Expenditure Data 245
7.3 Translation from Rodents to Humans 246
References 247
Interleukin-Targeted Therapy for Metabolic Syndrome and Type 2 Diabetes 268
1 Introduction: The IL-1 Family 269
2 IL-1beta Links Obesity and Diabetes 269
2.1 IL-1beta in Adipocytes 271
2.2 IL-1beta in the Liver 271
2.3 IL-1beta in the Brain 272
3 IL-1beta Signaling in the beta-Cell 273
4 IL-1beta Secretion 276
5 Blocking IL-1beta Signals Protects the beta-Cell 277
5.1 Lessons from IL-1 Mouse Models 279
5.2 Blocking IL-1beta Signals In Vivo Inhibits Diabetes Progression 280
References 281
Fructose-1, 6-Bisphosphatase Inhibitors for Reducing Excessive Endogenous Glucose Production in Type 2 Diabetes 290
1 Introduction 291
2 Endogenous Glucose Production in Type 2 Diabetes 292
3 Enzyme targets in the Gluconeogenic Pathways 293
4 Structure and function of FBPase 295
5 Discovery of inhibitors of FBPase 296
5.1 Competitive and Uncompetitive Inhibitors 296
5.2 Noncompetitive Inhibitors ZMP
5.3 Noncompetitive Inhibitors Design of MB05032
5.4 Discovery of CS-917 299
6 Mechanism of Action, Efficacy, and Safety of CS-917 300
6.1 Mechanism of Action 300
6.2 Efficacy 302
6.2.1 Monotherapy 302
6.2.2 Combination Therapy 303
6.3 Safety 306
7 Clinical Development of FBPase Inhibitors 307
7.1 CS-917 307
7.2 MB07803 308
8 Conclusions and Perspectives 308
References 309
AMP-Activated Protein Kinase and Metabolic Control 313
1 Introduction 314
2 Rational for a Pharmacological Management of T2D by Targeting AMPK 315
3 Structure and Regulation of AMPK 317
4 Beneficial Metabolic Effects of Targeting AMPK Pathway 318
4.1 Mimicking the Beneficial Effects of Physical Exercise 318
4.2 Mimicking the Beneficial Effects of Calorie/Dietary Restriction 321
4.3 Mimicking the Beneficial Effects of Hypoglycemic Agents 322
4.3.1 AMPK Action in Liver 322
4.3.2 AMPK Action in Skeletal Muscle 323
4.3.3 AMPK Action in beta-Cells 324
4.4 Mimicking the Beneficial Effects of Hypolipidemic Agents 325
4.5 Mimicking the Beneficial Effects of an Antiobesity Drug 328
5 Benefits of Targeting AMPK Pathway for Metabolic Complications 329
5.1 AMPK and Ischemic Heart 329
5.2 AMPK and Endothelial Dysfunction 330
6 Conclusion 331
References 332
Mitochondria as Potential Targets in Antidiabetic Therapy 341
1 Introduction 342
2 Mitochondrial Abnormalities in Diabetes 343
2.1 Pancreas 345
2.2 Skeletal Muscle 347
2.3 Cardiac Muscle 349
2.4 Liver 350
2.5 Nervous Tissue 351
3 Mitochondria as Potential Targets 353
3.1 Insulin and Insulin-Sensitizing Drugs 353
3.2 Metabolic Antioxidants 355
3.3 Mitochondria-Targeted Antioxidants and SS Peptides 357
4 Conclusions 359
References 360
Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects 367
1 Introduction to the problem 368
2 Finding New Drug Targets from Exploring T2DM, Hyperinsulinism, and Glucose Homeostasis Generally 369
3 Slow Evolution of the Idea That Glucokinase Might Serve as Glucose Sensor and as Drug Receptor 373
4 Biological Systems Analysis of GK (GK in Pancreatic Islet Beta-Cells, Liver, and Neuroendocrine Cells Is Central to Understanding Glucose Homeostasis and GKA Action) 378
5 Glucokinase Disease and the Status of GK in Type I and II Diabetes 383
6 Discovery of GKAs by High-Throughput Screening 384
7 What Are GKAs Chemically? 385
8 How Do GKAs Activate GK at the Molecular Level? 388
9 Effects of GKAs at the Cellular and Organ Levels 392
10 Effects of GKAs on Glucose Homeostasis of Normal and Diabetic Laboratory Animals and Humans 393
11 Critical Assessment of GKA´s Potential for Diabetes Therapy 398
12 Addendum at the time of Revision (Fall 2010) 401
References 402
References for Addendum 410
Index 412