| Contributors | p. xv |
| Preface | p. xxi |
| The Human Insulin Superfamily of Polypeptide Hormones | p. 1 |
| Introduction | p. 2 |
| Relaxin Peptide Hormone Subfamily | p. 10 |
| Concluding Remarks | p. 22 |
| Acknowledgments | p. 22 |
| References | p. 22 |
| The Structure and Function of Insulin: Decoding the TR Transition | p. 33 |
| Introduction | p. 34 |
| Structure-Activity Relationships | p. 38 |
| Implications for the Genetics of Diabetes Mellitus | p. 44 |
| Concluding Remarks | p. 45 |
| Acknowledgments | p. 46 |
| References | p. 46 |
| Molecular Mechanisms of Differential Intracellular Signaling From the Insulin Receptor | p. 51 |
| Overview | p. 52 |
| Insulin and the IR | p. 53 |
| Modulation of IR Activity | p. 57 |
| Differential Activation of the IR | p. 63 |
| Conclusions/Final Words | p. 67 |
| References | p. 68 |
| c-Abl and Insulin Receptor Signalling | p. 77 |
| Introduction | p. 78 |
| Insulin and IGF-IRs | p. 79 |
| Metabolic Versus Mitogenic Effect of IR | p. 83 |
| c-Abl Tyrosine Kinase | p. 87 |
| c-Abl and IR Signalling | p. 93 |
| Concluding Remarks | p. 98 |
| Acknowledgments | p. 99 |
| References | p. 99 |
| CXCL14 and Insulin Action | p. 107 |
| Introduction | p. 108 |
| Basic Properties ofCXCL14 | p. 109 |
| Biological Activities of CXCL14 | p. 113 |
| Novel Functions ofCXCL14 Revealed by Knockout Mice | p. 115 |
| Signal Cross-Talk Between CXCL14and Insulin | p. 119 |
| CXCL14as a Metabolic Regulator | p. 119 |
| Conclusions | p. 121 |
| References | p. 121 |
| Crosstalk Between Growth Hormone and Insulin Signaling | p. 125 |
| Introduction | p. 126 |
| GH Signaling | p. 127 |
| Insulin Signaling | p. 130 |
| Regulation of GH Signaling by Insulin | p. 131 |
| Regulation of Insulin Signaling by Chronic GH | p. 140 |
| Conclusions | p. 142 |
| Acknowledgments | p. 143 |
| References | p. 143 |
| Intracellular Retention and Insulin-Stimulated Mobilization of <$$$> Glucose Transporters | p. 155 |
| Introduction | p. 156 |
| <$$$> Storage Vesicles (GSVs) | p. 158 |
| Insulin-Regulated Aminopeptidase (IRAP) | p. 162 |
| Stability and Trafficking of <$$$> and IRAP | p. 164 |
| TUG, an Essential Component of a Retention Receptor for <$$$> | p. 166 |
| From What Membranes do GSVs Originate? | p. 174 |
| A General Mechanism for the Regulated Targeting of Membrane Proteins | p. 176 |
| Conclusions | p. 179 |
| Acknowledgments | p. 179 |
| References | p. 179 |
| Compartmentalization and Regulation of Insulin Signaling to <$$$> by the Cytoskeleton | p. 193 |
| Introduction | p. 194 |
| Insulin Signaling to <$$$> Vesicles | p. 195 |
| <$$$> Vesicle Membrane Trafficking | p. 200 |
| <$$$> Vesicle Fusion | p. 205 |
| Conclusions | p. 208 |
| Acknowledgments | p. 208 |
| References | p. 208 |
| Nutrient Modulation of Insulin Secretion | p. 217 |
| Introduction | p. 218 |
| Overview of Insulin Secretion | p. 219 |
| Nutrient Regulation of Insulin Secretion | p. 224 |
| References | p. 238 |
| How Insulin Regulates Glucose Transport in Adipocytes | p. 245 |
| Introduction | p. 246 |
| Historical Perspective | p. 250 |
| Current Views and Controversies | p. 265 |
| Conclusions and Future Directions | p. 277 |
| References | p. 278 |
| Spatio-Temporal Dynamics of Phosphatidylinositol-3,4,5-Trisphosphate Signalling | p. 287 |
| Introduction | p. 288 |
| Synthesis and Degradation of <$$$> | p. 289 |
| Real-Time Measurements of <$$$> in Living Cells | p. 292 |
| Spatio-Temporal Patterns of <$$$> Signals | p. 295 |
| <$$$> Oscillations and Autocrine Insulin Signalling in ß-Cells | p. 297 |
| Significance of <$$$> Oscillations | p. 300 |
| Concluding Remarks | p. 302 |
| Acknowledgments | p. 303 |
| References | p. 303 |
| Serine Kinases of Insulin Receptor Substrate Proteins | p. 313 |
| Introduction | p. 314 |
| Insulin and IGF-1 Signaling | p. 314 |
| Regulation of Insulin and IGF-1 Signaling: Role of Ser/Thr Phosphorylation of IRS Proteins | p. 319 |
| The Consequences of Ser Phosphorylation of IRS Proteins | p. 328 |
| Ser Phosphorylation of IRS Proteins as an Array Phenomenon | p. 333 |
| Summary | p. 336 |
| References | p. 337 |
| Phosphorylation of IRS Proteins: Yin-Yang Regulation of Insulin Signaling | p. 351 |
| Introduction | p. 352 |
| Discovery of the IRS Proteins | p. 353 |
| Molecular Structure of the IRS Proteins | p. 354 |
| Biological Function of IRS Proteins in Insulin Action | p. 364 |
| The Role of IRS Serine Phosphorylation in Mediating the Crosstalk with Other Signaling Pathways | p. 366 |
| Mechanisms Underlying IRS Serine Phosphorylation-Induced Insulin Resistance | p. 369 |
| Conclusion | p. 372 |
| References | p. 373 |
| IRS-2 and Its Involvement in Diabetes and Aging | p. 389 |
| Introduction | p. 390 |
| Identification of IRS-2 Protein | p. 391 |
| Basic Structure of IRS Family Proteins | p. 392 |
| Involvement of IRS Proteins in Other Signaling Pathways | p. 392 |
| IRS-2 Protein is Well Conserved Across Species | p. 393 |
| IRS-2, and Its Regulation in Energy Homeostasis | p. 393 |
| Searching for the Regulatory Factor of IRS-2 Transcription | p. 395 |
| Phenotype of IRS-2 Null Mice | p. 397 |
| The Role of IRS-2 in Female Reproduction | p. 400 |
| The Putative Role of IRS-2 in Aging Process | p. 400 |
| Summary | p. 402 |
| References | p. 403 |
| Glucose-Dependent Insulinotropic Polypeptide (Gastric Inhibitory Polypeptide; GIP) | p. 409 |
| Introduction | p. 410 |
| Glucose-Dependent Insulinotropic Polypeptide (GIP) | p. 412 |
| The GIP Gene and Precursor | p. 415 |
| GIP Secretion and Metabolism | p. 417 |
| The GIP Receptor | p. 421 |
| Actions of GIP | p. 425 |
| GIP-Activated Signal-Transduction Pathways | p. 432 |
| Pathophysiology of GIP | p. 439 |
| Acknowledgments | p. 444 |
| References | p. 444 |
| Insulin Granule Biogenesis, Trafficking and Exocytosis | p. 473 |
| Introduction | p. 474 |
| Section I | p. 476 |
| Section II | p. 480 |
| Section III | p. 484 |
| Section IV | p. 491 |
| References | p. 494 |
| Glucose, Regulator of Survival and Phenotype of Pancreatic Beta Cells | p. 507 |
| Scope | p. 508 |
| Beta Cell Handling of Glucose: Metabolic Specializations to Ensure Low-Affinity/High Capacity Glucose Sensing | p. 509 |
| Glucose as Regulator of the Differentiated Beta Cell Phenotype | p. 512 |
| Glucose Regulation of Beta Cell Number | p. 518 |
| Beta Cell Handing of Threatening High and Low Glucose Levels | p. 521 |
| Acknowledgments | p. 530 |
| References | p. 530 |
| Matrix Metalloproteinases, T Cell Homing and ß-Cell Mass in Type 1 Diabetes | p. 541 |
| Matrix Metalloproteinases and Their Natural Protein Inhibitors | p. 542 |
| T Cell Membrane Type-1 Matrix Metalloproteinase | p. 547 |
| Rodent Model of Human Type 1 Diabetes | p. 550 |
| T Cell MT1-MMP and CD44 in T1D | p. 552 |
| Acknowledgment | p. 556 |
| References | p. 556 |
| Role of Wnt Signaling in the Development of Type 2 Diabetes | p. 563 |
| Introduction | p. 564 |
| Wnt Signaling | p. 565 |
| TCF7L2 Variants and Type 2 Diabetes Risk | p. 570 |
| Functional Relationship Between Wnt Signaling and Type 2 Diabetes In Vitro | p. 574 |
| Conclusions and Future Directions | p. 575 |
| References | p. 578 |
| Retinal Insulin Receptor Signaling In Hyperosmotic Stress | p. 583 |
| Introduction | p. 584 |
| Experimental Procedures | p. 586 |
| Results | p. 590 |
| Discussion | p. 603 |
| Acknowledgments | p. 607 |
| References | p. 608 |
| Interleukin-6 and Insulin Resistance | p. 613 |
| Introduction | p. 614 |
| Insulin Signaling and Insulin Resistance | p. 615 |
| IL-6 and Insulin Resistance | p. 619 |
| Conclusions | p. 625 |
| Acknowledgment | p. 626 |
| References | p. 627 |
| Structure, Function, and Regulation of Insulin-Degrading Enzyme | p. 635 |
| Introduction | p. 636 |
| Structure of IDE | p. 637 |
| The Regulation of IDE Activity | p. 642 |
| Conclusion | p. 645 |
| Acknowledgments | p. 645 |
| References | p. 645 |
| Modification of Androgen Receptor Function by Igf-1 Signaling: Implications in the Mechanism of Refractory Prostate Carcinoma | p. 649 |
| Androgen Receptor Signaling | p. 651 |
| IGF Signaling and Foxo-1 | p. 653 |
| Interaction between AR and Insulin/IGF-1 Signaling | p. 654 |
| Clinical Implications of Interactions between IGF-1 Signaling and AR | p. 659 |
| Conclusion | p. 662 |
| Acknowledgments | p. 663 |
| References | p. 663 |
| Insulin-Like Growth Factor-2/Mannose-6 Phosphate Receptors | p. 667 |
| Introduction | p. 668 |
| The IGF-2/M6P Receptor | p. 671 |
| Functions of the IGF-2/M6P Receptor | p. 678 |
| Conclusions | p. 685 |
| References | p. 685 |
| Interactions of IGF-II with the IGF2R/Cation-Independent Mannose-6-Phosphate Receptor: Mechanism and Biological Outcomes | p. 699 |
| Introduction | p. 700 |
| The Mechanism of the IGF2R:IGF-II Interaction | p. 701 |
| Conclusion | p. 713 |
| References | p. 714 |
| Index | p. 721 |
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