Schwanstecher Diabetes - Perspectives in Drug Therapy

Perspectives in Drug Therapy (Handbook of Experimental Pharmacology, Vol 203)
1. Auflage 2011
ISBN: 978-3-642-17214-4
Verlag: Springer
Format: PDF
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 408 Seiten

The chapters of this book report cutting-edge research on molecular events in adiposity and type 2 diabetes, thus opening the way for innovative drug-based therapeutic strategies. It addresses all those who wish to keep in touch with recent developments in the field.

Autoren/Hrsg.

Schwanstecher, Mathias

Inhaltsverzeichnis

1;Preface;6
2;Contents;10
3;Contributors;12
4;Targeting Type 2 Diabetes;16
4.1;1 Inflamed About Obesity: Adipose Tissue and Insulin Resistance;17
4.2;2 The Lipotoxicity Concept;22
4.3;3 beta-Cell Failure: Link to Hyperglycaemia and T2DM;25
4.4;4 Role of the CNS in Glucose Homeostasis;27
4.5;5 Nutrient-Sensing Pathways in Calorie Restriction;29
4.6;6 Current Therapy;30
4.6.1;6.1 Published Algorithms;30
4.6.2;6.2 Metformin;31
4.6.3;6.3 Thiazolidinediones;32
4.6.4;6.4 GLP-1 Agonists and DPP-4 Inhibitors;33
4.7;7 Conclusions;34
4.8;References;35
5;Dual Acting and Pan-PPAR Activators as Potential Anti-diabetic Therapies;49
5.1;1 Introduction;50
5.2;2 PPAR-gamma;51
5.3;3 PPAR-a;52
5.4;4 PPAR-delta;53
5.5;5 Logic for Dual and Triple PPAR Activators in the Treatment of Diabetes and Insulin Resistance;53
5.6;6 The Bezafibrate Experience;54
5.7;7 Use of Combined Therapy with Fenofibrate and Glitazones;55
5.8;8 Dual PPAR-a/gamma Activator Drugs;56
5.9;9 Outlook for Dual PPAR-a/gamma Activators;58
5.10;10 PPAR-Pan Activators and PPAR-delta Dual Activators;59
5.11;11 Cancer Liability of PPAR Activators;60
5.12;12 Concluding Remarks;60
5.13;References;61
6;GLP-1 Agonists and Dipeptidyl-Peptidase IV Inhibitors;66
6.1;1 Type 2 Diabetes, Its Epidemiology, and the Need for Further Treatment Options;67
6.2;2 Incretin Hormones;67
6.2.1;2.1 GLP-1 Actions;69
6.2.2;2.2 Dipeptidyl-Peptidase IV;70
6.3;3 GLP-1 Receptor Agonists;71
6.3.1;3.1 Exenatide;72
6.3.2;3.2 Liraglutide;74
6.4;4 DPP-4 Inhibitors;75
6.4.1;4.1 Sitagliptin;76
6.4.2;4.2 Vildagliptin;77
6.4.3;4.3 Saxagliptin;77
6.5;5 Incretin-Based Therapies: Common Characteristics and Differences;78
6.6;6 Indications for Incretin-Based Therapies and Their Placement in Treatment Guidelines for Type 2 Diabetes;79
6.7;7 Incretin-Based Therapies and Type 1 Diabetes;81
6.8;References;82
7;Cannabinoids and Endocannabinoids in Metabolic Disorders with Focus on Diabetes;88
7.1;1 A Brief Introduction to the Endocannabinoid System;89
7.2;2 Central Endocannabinoid Control of Energy Balance;91
7.3;3 Peripheral Endocannabinoid Control of Energy Balance;95
7.4;4 Regulation and Dysregulation of the Endocannabinoid System in the Control of Metabolism;97
7.4.1;4.1 Role of Dysregulated Endocannabinoid Signaling in Type 2 Diabetes and Obesity-Related Metabolic and Cardiovascular Disorders;101
7.4.2;4.2 Endocannabinoid Dysregulation in Human Abdominal Obesity and Hyperglycemia: Relationship with Cardiometabolic Risk Factors and Type 2 Diabetes;105
7.5;5 Clinical Use of CB1 Receptor Antagonists/Inverse Agonists Against Type 2 Diabetes;106
7.6;6 Plant Cannabinoids and Type 1 Diabetes;109
7.6.1;6.1 Type 1 Diabetes Mellitus;109
7.7;7 Concluding Remarks;110
7.8;References;111
8;SGLT Inhibitors as New Therapeutic Tools in the Treatment of Diabetes;118
8.1;1 Preface;119
8.2;2 The Sodium-d-Glucose Cotransporter as Target;119
8.2.1;2.1 Role of Sodium-d-Glucose Cotransport in Transepithelial Sugar Transport;119
8.2.2;2.2 Molecular Basis of Sodium-d-Glucose Cotransport;121
8.2.3;2.3 Sugar Binding Sites of the SGLT;122
8.2.3.1;2.3.1 Substrate Specificity of the Sodium-d-Glucose Cotransporters;122
8.2.3.2;2.3.2 Sugar Binding Site(s) of the Sodium-d-Glucose Cotransporter;124
8.3;3 The Prototype of SGLT Inhibitors: Phlorizin;124
8.3.1;3.1 General Remarks;124
8.3.2;3.2 SGLT as Phlorizin Receptor;125
8.3.2.1;3.2.1 Binding Studies on Brush Border Membranes;125
8.3.2.2;3.2.2 Interactions of Phlorizin with the Isolated Transporter and Its Subdomains;125
8.3.2.3;3.2.3 Differences Between hSGLT1 and hSGLT2;126
8.3.3;3.3 Pharmacophore Analysis and Dimensions of the Phlorizin Binding Pocket;126
8.4;4 Synthesis and Screening of Derivates of Phlorizin;127
8.4.1;4.1 O-glucosides, C-arylglucosides, N-glucosides and S-glycosides;127
8.4.2;4.2 Screening Methods;129
8.4.2.1;4.2.1 Cellular Assays;129
8.4.2.2;4.2.2 Animal Models;130
8.5;5 Therapeutic Efficacy of SGLT Inhibitors;130
8.5.1;5.1 In Vitro Studies on Sugar Transport by Cultured Transfected Cells;130
8.5.2;5.2 Effect of SGLT Inhibitors in Preclinical and Clinical Studies;131
8.5.2.1;5.2.1 Urinary Glucose Excretion;131
8.5.2.2;5.2.2 Effect on Plasma Glucose Levels;132
8.5.2.3;5.2.3 Effect on Fasting Hypoglycaemia;132
8.6;6 Benefits and Pitfalls of SGLT Inhibitors;133
8.6.1;6.1 Benefits;133
8.6.2;6.2 Pitfalls;133
8.7;7 Current State and Future Developments;134
8.8;References;135
9;Inhibitors of 11beta-Hydroxysteroid Dehydrogenase Type 1 in Antidiabetic Therapy;140
9.1;1 Glucocorticoid Metabolism and Action;141
9.2;2 Glucocorticoid Excess and the Development of the Metabolic Syndrome;142
9.3;3 Association of 11beta-HSD1 with Obesity and Insulin Resistance;144
9.4;4 11beta-HSD1 Biochemistry and Regulation;146
9.5;5 Non-selective 11beta-HSD1 Inhibitors as Tools;148
9.6;6 Studies with Selective 11beta-HSD1 Inhibitors;149
9.7;7 Clinical Experience with 11beta-HSD1 Inhibitors;152
9.8;8 Potential Therapeutic Challenges with 11beta-HSD1 Inhibitors;152
9.9;9 Concluding Remarks;153
9.10;References;154
10;Nampt and Its Potential Role in Inflammation and Type 2 Diabetes;160
10.1;1 Introduction;161
10.2;2 Nampt and Metabolic Disorders;162
10.2.1;2.1 eNampt and iNampt: Regulation of Pancreatic beta-Cell Function;162
10.2.2;2.2 eNampt in Human Circulation: A Biomarker for Obesity and T2DM?;165
10.2.3;2.3 Role of Hepatic Nampt in T2DM;166
10.3;3 eNampt: A Link Between T2DM and Inflammation;168
10.4;4 Concluding Remarks and Future Aspects;170
10.5;References;171
11;Inhibition of Ganglioside Biosynthesis as a Novel Therapeutic Approach in Insulin Resistance;178
11.1;1 Introduction;179
11.2;2 Ganglioside GM3 Is an Inducer of Insulin Resistance;179
11.3;3 Caveolae Microdomains and Insulin Signaling;181
11.4;4 Insulin Resistance as a Membrane Microdomain Disorder;183
11.5;5 Serum GM3 Levels as a New Biomarker of Metabolic Syndrome;187
11.6;6 A Possible Therapeutic Intervention of Metabolic Syndrome by Inhibiting Ganglioside Synthesis;188
11.7;7 Concluding Remarks;188
11.8;References;189
12;Overcoming Insulin Resistance with Ciliary Neurotrophic Factor;192
12.1;1 Introduction;193
12.2;2 Current Therapeutics for Obesity and Type 2 Diabetes;193
12.3;3 Leptin: A Flash in the Pan;194
12.4;4 Leptin Receptor Versus gp130 Receptor Signalling;195
12.5;5 gp130 Receptor Ligands;197
12.6;6 CNTF;198
12.7;7 Metabolic Effects of CNTF;200
12.7.1;7.1 Central Effects of CNTF;200
12.7.2;7.2 Peripheral Metabolic Effects of CNTF;203
12.8;8 Future Directions for gp130 Ligands;206
12.9;References;207
13;Thermogenesis and Related Metabolic Targets in Anti-Diabetic Therapy;213
13.1;1 Introduction;214
13.2;2 Rationale: Why Target Thermogenesis?;216
13.2.1;2.1 Obesity and Diabetes;216
13.2.2;2.2 Exercise in the Treatment of Diabetes;216
13.2.3;2.3 Exercise in the Treatment of the Metabolic Syndrome;217
13.2.4;2.4 Mitochondrial Function and Capacity for Fat Oxidation in Diabetes;217
13.2.5;2.5 Lessons from beta-Adrenoceptor Agonists;218
13.3;3 Current and Recent Drugs;220
13.3.1;3.1 Diabetes Drugs;220
13.3.2;3.2 Obesity Drugs;221
13.3.2.1;3.2.1 Sibutramine;221
13.3.2.2;3.2.2 Rimonabant;221
13.4;4 Targets in Hormonal Systems;224
13.4.1;4.1 Sympathetic Nervous System;224
13.4.2;4.2 Zn-a2-Glycoprotein;224
13.4.3;4.3 Thyroid Hormones;225
13.4.4;4.4 TGR5: A Bile Acid Receptor;226
13.4.5;4.5 Glucocorticoids and 11beta-Hydroxysteroid Dehydrogenase-1;227
13.4.6;4.6 Leptin;228
13.4.7;4.7 Fibroblast Growth Factor 21;229
13.4.8;4.8 Ghrelin;230
13.4.9;4.9 Ciliary and Brain-Derived Neurotrophic Factors;231
13.4.10;4.10 Adiponectin;232
13.5;5 Targets in Lipid Metabolism;234
13.5.1;5.1 Acetyl-CoA Carboxylase;234
13.5.2;5.2 Fatty Acid Synthase;235
13.5.3;5.3 Stearoyl-CoA Desaturase-1;235
13.5.4;5.4 Acetyl-CoA:Diacylglycerol Acyltransferase (DGAT);237
13.6;6 Other Intracellular Targets;238
13.6.1;6.1 AMP-Activated Protein Kinase;238
13.6.2;6.2 Peroxisome Proliferator-Activated Receptor beta/delta;241
13.6.3;6.3 Sirtuin1;242
13.7;7 Perspectives and Implications for Drug Discovery and Development;243
13.7.1;7.1 Detection of Thermogenesis;244
13.7.2;7.2 Manipulation of Energy Expenditure Data;245
13.7.3;7.3 Translation from Rodents to Humans;246
13.8;References;247
14;Interleukin-Targeted Therapy for Metabolic Syndrome and Type 2 Diabetes;268
14.1;1 Introduction: The IL-1 Family;269
14.2;2 IL-1beta Links Obesity and Diabetes;269
14.2.1;2.1 IL-1beta in Adipocytes;271
14.2.2;2.2 IL-1beta in the Liver;271
14.2.3;2.3 IL-1beta in the Brain;272
14.3;3 IL-1beta Signaling in the beta-Cell;273
14.4;4 IL-1beta Secretion;276
14.5;5 Blocking IL-1beta Signals Protects the beta-Cell;277
14.5.1;5.1 Lessons from IL-1 Mouse Models;279
14.5.2;5.2 Blocking IL-1beta Signals In Vivo Inhibits Diabetes Progression;280
14.6;References;281
15;Fructose-1, 6-Bisphosphatase Inhibitors for Reducing Excessive Endogenous Glucose Production in Type 2 Diabetes;290
15.1;1 Introduction;291
15.2;2 Endogenous Glucose Production in Type 2 Diabetes;292
15.3;3 Enzyme targets in the Gluconeogenic Pathways;293
15.4;4 Structure and function of FBPase;295
15.5;5 Discovery of inhibitors of FBPase;296
15.5.1;5.1 Competitive and Uncompetitive Inhibitors;296
15.5.2;5.2 Noncompetitive Inhibitors; ZMP;296
15.5.3;5.3 Noncompetitive Inhibitors; Design of MB05032;298
15.5.4;5.4 Discovery of CS-917;299
15.6;6 Mechanism of Action, Efficacy, and Safety of CS-917;300
15.6.1;6.1 Mechanism of Action;300
15.6.2;6.2 Efficacy;302
15.6.2.1;6.2.1 Monotherapy;302
15.6.2.2;6.2.2 Combination Therapy;303
15.6.3;6.3 Safety;306
15.7;7 Clinical Development of FBPase Inhibitors;307
15.7.1;7.1 CS-917;307
15.7.2;7.2 MB07803;308
15.8;8 Conclusions and Perspectives;308
15.9;References;309
16;AMP-Activated Protein Kinase and Metabolic Control;313
16.1;1 Introduction;314
16.2;2 Rational for a Pharmacological Management of T2D by Targeting AMPK;315
16.3;3 Structure and Regulation of AMPK;317
16.4;4 Beneficial Metabolic Effects of Targeting AMPK Pathway;318
16.4.1;4.1 Mimicking the Beneficial Effects of Physical Exercise;318
16.4.2;4.2 Mimicking the Beneficial Effects of Calorie/Dietary Restriction;321
16.4.3;4.3 Mimicking the Beneficial Effects of Hypoglycemic Agents;322
16.4.3.1;4.3.1 AMPK Action in Liver;322
16.4.3.2;4.3.2 AMPK Action in Skeletal Muscle;323
16.4.3.3;4.3.3 AMPK Action in beta-Cells;324
16.4.4;4.4 Mimicking the Beneficial Effects of Hypolipidemic Agents;325
16.4.5;4.5 Mimicking the Beneficial Effects of an Antiobesity Drug;328
16.5;5 Benefits of Targeting AMPK Pathway for Metabolic Complications;329
16.5.1;5.1 AMPK and Ischemic Heart;329
16.5.2;5.2 AMPK and Endothelial Dysfunction;330
16.6;6 Conclusion;331
16.7;References;332
17;Mitochondria as Potential Targets in Antidiabetic Therapy;341
17.1;1 Introduction;342
17.2;2 Mitochondrial Abnormalities in Diabetes;343
17.2.1;2.1 Pancreas;345
17.2.2;2.2 Skeletal Muscle;347
17.2.3;2.3 Cardiac Muscle;349
17.2.4;2.4 Liver;350
17.2.5;2.5 Nervous Tissue;351
17.3;3 Mitochondria as Potential Targets;353
17.3.1;3.1 Insulin and Insulin-Sensitizing Drugs;353
17.3.2;3.2 Metabolic Antioxidants;355
17.3.3;3.3 Mitochondria-Targeted Antioxidants and SS Peptides;357
17.4;4 Conclusions;359
17.5;References;360
18;Research and Development of Glucokinase Activators for Diabetes Therapy: Theoretical and Practical Aspects;367
18.1;1 Introduction to the problem;368
18.2;2 Finding New Drug Targets from Exploring T2DM, Hyperinsulinism, and Glucose Homeostasis Generally;369
18.3;3 Slow Evolution of the Idea That Glucokinase Might Serve as Glucose Sensor and as Drug Receptor;373
18.4;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
18.5;5 Glucokinase Disease and the Status of GK in Type I and II Diabetes;383
18.6;6 Discovery of GKAs by High-Throughput Screening;384
18.7;7 What Are GKAs Chemically?;385
18.8;8 How Do GKAs Activate GK at the Molecular Level?;388
18.9;9 Effects of GKAs at the Cellular and Organ Levels;392
18.10;10 Effects of GKAs on Glucose Homeostasis of Normal and Diabetic Laboratory Animals and Humans;393
18.11;11 Critical Assessment of GKA´s Potential for Diabetes Therapy;398
18.12;12 Addendum at the time of Revision (Fall 2010);401
18.13;References;402
18.13.1;References for Addendum;410
19;Index;412