Islets of Langerhans (eBook)

Preface 8
Contents 10
Contributors 14
1 Microscopic Anatomy of the Human Islet of Langerhans 21
1.1 Introduction 21
1.2 The Islets of Langerhans 22
1.3 Embryology and Fetal Development 23
1.4 Endocrine Cell Types 23
1.4.1a-Cells 24
1.4.2 ß-Cells 24
1.4.3 D-Cells 26
1.4.4 PP Cells 27
1.4.5 Epsilon Cells 27
1.5 Islet Anatomy 28
1.6 Non-endocrine Islet Cells 29
1.7 Islet Vasculature 29
1.8 Innervation 30
1.9 Islet in Type 1 Diabetes 30
1.10 Islets in Type 2 Diabetes 33
References 34
2 The Comparative Anatomy of Islets 40
2.1 Introduction 40
2.2 Invertebrates 41
2.2.1 Agnatha-Cyclostomes -- First Appearance of an Islet Organ 44
2.2.2 Chondrichthyes (Jawed Fish) 44
2.2.3 Osteichthyes (Lungfish and Teleost Fish) 45
2.2.4 Amphibia 46
2.2.5 Reptilia (Turtles, Crocodiles, Lizards, Snakes) 46
2.2.6 Aves 48
2.2.7 Mammals 49
2.2.7.1 Rodents 49
2.2.7.2 Carnivora 50
2.2.7.3 Artiodactyls (Even-Toed Ungulates) 50
2.2.7.4 Marsupials 51
2.2.7.5 Archonta -- Bats, Primates, Tree Shrews 51
2.3 Conclusion 52
References 52
3 Approaches for Imaging Islets: Recent Advances and Future Prospects 57
3.1 Introduction 58
3.2 Optical Imaging Modalities for Islet Imaging 59
3.2.1 Laser Scanning Microscopy (LSM) 59
3.2.2 Optical Projection Tomography 61
3.2.3 Bioluminescence Imaging 63
3.3 Nuclear Imaging Modalities for ß-Cell Imaging 64
3.3.1 Magnetic Resonance Imaging 64
3.3.2 Imaging with Radioactive Tracer Molecules 68
3.3.2.1 Positron Emission Tomography 68
3.3.2.2 Single Photon Emission Computed Tomography 68
3.3.2.3 Radiotracer Development 69
3.3.2.4 Radiotracer Imaging of -Cells 70
3.4 Emerging Technologies for Islet Imaging 71
3.5 Concluding Remarks 72
References 73
4 Islet Cell Development 76
4.1 Introduction 76
4.2 Overview of Pancreas Development 77
4.3 Transcriptional Control in Pancreas Development 79
4.3.1 Regulators of Pancreatic Progenitors 79
4.3.1.1 Pdx1 79
4.3.1.2 Ptf1a/p48 80
4.3.2 Establishment of the Endocrine Pancreas 81
4.3.2.1 Ngn3 81
4.3.3 Endocrine Lineages Specification 82
4.3.3.1 Pax/Arx 82
4.3.3.2 Nkx Transcription Factors 82
4.3.4 Maintenance of -Cell Identity 83
4.3.4.1 NeuroD/BETA2 83
4.3.4.2 MafA 83
4.3.4.3 Pdx1 84
4.4 Human Islet Cell Development 84
4.5 Lessons from Islet Development for Cell Replacement Therapy in Diabetes 85
References 86
5 High Fat Programming of ß-Cell Failure 93
5.1 Introduction 93
5.2 Critical Programming Windows 94
5.3 HFP Concept 95
5.4 ß-Cell Regulation 97
5.5 HFP May Induce ß-Cell Failure Via Glucolipotoxicity 98
5.6 HFP Degrades ß-Cell Integrity 100
5.7 HFP: Potential Mechanism of Induction of Type 2 Diabetes 101
5.8 Perspectives 103
References 103
6 Nutrient Regulation of Insulin Secretion and ß-Cell Functional Integrity 106
6.1 Overview of ß-Cell Stimulus-Secretion Coupling 107
6.2 Phases and Pulsatility of Insulin Secretion 110
6.3 Primary Metabolic Factors Regulating Glucose-Stimulated Insulin Secretion 111
6.4 Investigating Nutrient Regulation of -Cell Metabolism and Insulin Secretion 112
6.5 Mechanisms Underlying ß-Cell Actions of Glucose 112
6.6 Mechanisms Underlying ß-Cell Actions of Lipids 116
6.7 Mechanisms Underlying ß-Cell Actions of Amino Acids 117
6.8 Overview of Nutrient Regulation of ß-Cell Gene Expression 121
6.9 Nutrient-Induced ß-Cell Desensitization, Dysfunction, and Toxicity 122
6.10 Conclusion 123
References 124
7 Electrophysiology of Islet Cells 130
7.1 ß-cells 131
7.1.1 Ion Channels 131
7.1.1.1 K ATP Channels 131
7.1.1.2 Ca 2+ Channels 140
7.1.1.3 Kv and KCa Channels 144
7.1.1.4 Other Ion Channels 148
7.1.2 Cell Membrane Potential (Vm) 150
7.1.2.1 Regulation by Glucose 150
7.1.2.2 Regulation by Hormones and Neurotransmitters 153
7.2 a-Cells 155
7.2.1 Ion Channels 155
7.2.2 Regulation of Electrical Activity 157
7.3 -Cells 158
References 159
8 ATP-Sensitive Potassium Channels in Health and Disease 179
8.1 Introduction 180
8.2 Role of K ATP Channels in the Pancreas and Other Tissues 181
8.3 Molecular Structure and Functional Properties of the -Cell K ATP Channel 182
8.3.1 Recent Structural Advances 185
8.4 Congenital Hyperinsulinism of Infancy 185
8.4.1 ABCC8 and CHI 186
8.4.2 KCNJ11 and CHI 186
8.4.3 Therapeutic Implications 187
8.5 Neonatal Diabetes Mellitus 187
8.5.1 KCNJ11 and NDM 188
8.5.2 Location of NDM Mutations in the Kir6.2 Subunit 188
8.5.3 Functional Effects of Kir6.2 Mutations Causing NDM 189
8.5.4 Heterozygosity of Kir6.2 Mutations 193
8.5.5 ABCC8 and PNDM 194
8.5.6 Mouse Models of PNDM 195
8.5.7 Implications for Therapy 197
8.5.8 Kir6.2 and Type 2 Diabetes 198
8.6 Conclusions and Future Directions 199
References 199
9 Role of Mitochondria in ß-cell Function and Dysfunction 207
9.1 Introduction 207
9.2 Overview of MetabolismSecretion Coupling 208
9.3 Mitochondrial NADH Shuttles 208
9.4 Mitochondria as Metabolic Sensors 211
9.5 A Focus on Glutamate Dehydrogenase 212
9.6 Mitochondrial Activation Results in ATP Generation 213
9.7 The Amplifying Pathway of Insulin Secretion 214
9.8 Mitochondria Promote the Generation of Nucleotides Acting as Metabolic Coupling Factors 214
9.9 Fatty Acid Pathways and the Metabolic Coupling Factors 215
9.10 Mitochondrial Metabolites as Coupling Factors 216
9.11 Reactive Oxygen Species Participate to -Cell Function 218
9.12 Mitochondria Can Generate ROS 218
9.13 Mitochondria are Sensitive to ROS 218
9.14 ROS May Trigger -Cell Dysfunction 219
9.15 Mitochondrial DNA Mutations and -Cell Dysfunction 220
9.16 Conclusion 221
References 221
10 Basement Membrane in Pancreatic Islet Function 231
10.1 Introduction 231
10.2 Basement Membrane Components 232
10.2.1 Collagen IV 232
10.2.2 Laminin 234
10.2.3 Nidogen/Entactin 234
10.2.4 Heparan Sulfate Proteoglycans (HSPGs) 234
10.3 Cell Surface Receptors 235
10.3.1 Integrins 235
10.3.2 Dystroglycan 235
10.3.3 Lutheran Glycoprotein 237
10.4 The Vascular Basement Membrane and its Role in Pancreatic Islets 238
10.5 Control of -Cell Function by Vascular Basement Membrane 239
10.6 Specific Basement Membrane/Cell Surface Interactions That Control -Cell Function 239
10.7 Conclusion 240
10.8 Outlook 241
References 242
11 Calcium Signaling in the Islets 249
11.1 Introduction 250
11.2 Human -Cells as a Group Are Never Resting 250
11.3 Biphasic Insulin Secretion Is an Experimental Epiphenomenon 251
11.4 Glucose Increases Insulin Secretion by Increasing [Ca 2+ ] i and by Providing ATP in the Face of Energy-Consuming Processes Triggered by Ca 2+ Influx Through the Voltage-Gated Ca 2+ Channels (VGCC) 252
11.5 Mechanism of Initial Depolarization of -Cells by Glucose 253
11.6 TRP Channels 254
11.7 Store-Operated Ca2+ Entry (SOCE) 257
11.8 Voltage-Gated Ca2+ Channels of ß-Cells 258
11.9 Intracellular Ca2+ Channels of ß-Cells 259
11.10 Cyclic ADP Ribose (cADPR) and Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) 260
11.11 Ca2+-Induced Ca2+ Release (CICR) 261
11.12 [Ca2+] i Oscillation in ß-Cells 264
References 266
12 Electrical Bursting, Calcium Oscillations, and Synchronization of Pancreatic Islets 274
12.1 The Role of Calcium Feedback 276
12.2 Metabolic Oscillations 277
12.3 The Dual Oscillator Model for Islet Oscillations 278
12.4 Glucose Sensing in the Dual Oscillator Framework 281
12.5 Functional Role for Compound Oscillations 283
12.6 Islet Synchronization 284
References 287
13 Cyclic AMP Signaling in Pancreatic Islets 293
13.1 Introduction 293
13.2 Control of cAMP Levels in the -Cell 294
13.2.1.1 Adenylyl Cyclases in the Pancreatic Islet -Cell 296
13.2.3 Dynamics of cAMP Formation and Destruction 298
13.2.4 Intracellular Compartmentalization of cAMP Formation, Action and Degradation 299
13.3 Functions of Cyclic AMP in the Pancreatic Islet -Cell 300
13.3.1 Insulin Secretion 301
13.3.1.1 Effects on the -Cell ATP-Sensitive Potassium Channel 301
13.3.1.2 Voltage-Sensitive Potassium Channels 301
13.3.1.3 Elevations in Intracellular Calcium [Ca 2+ ] i 302
13.3.1.4 Direct Effect on Exocytosis 303
13.3.1.5 Activation of Protein Kinase C 303
13.4 Role of cAMP in Insulin Synthesis and in -Cell Differentiation, Proliferation, and Survival 304
13.4.1 Immediate Early Response Genes 304
13.5 Possible Roles of cAMP in Other Islet Cell Types 305
13.6 Conclusion 306
References 307
14 Exocytosis in Islet ß-Cells 317
14.1 Introduction 317
14.2 Measurements of Exocytosis 320
14.2.1 Electrophysiological Approaches and Quantification 320
14.2.2 TIRF Imaging and ''Docking'' of Granules 321
14.2.3 Two-Photon Imaging and the Spatial Organization of Exocytosis 322
14.2.3.1 TEP (Two-Photon Extracellular Polar-Tracer) Imaging 322
14.2.3.2 Spatial Organization of Exocytosis: Docking, Priming, and the Readily Releasable Pool of Vesicles 323
14.3 Insulin Exocytosis 325
14.3.1 Single Insulin Granule Exocytosis 325
14.3.2 Fusion Pore Kinetics and ''Kiss-and-Run'' Exocytosis 327
14.3.3 Fusion Pore Compositions and Fusion Mechanisms 329
14.3.4 Lateral Diffusion of SNARE Proteins 331
14.4 Regulation of Insulin Exocytosis 331
14.4.1 Biphasic Insulin Exocytosis and Protein Kinase A 331
14.4.2 Actions of Glucose and cAMP 332
14.4.3 Molecular Mechanisms of Insulin Exocytosis 334
14.5 Exocytosis of Synaptic-Like Microvesicles (SLMVs) 336
14.5.1 Historical Perspective 336
14.5.2 Regulation by cAMP 339
14.5.3 Functional Role of SLMV Exocytosis in -Cells 340
14.6 Perspectives 341
References 342
15 The Novel Roles of Glucagon-Like Peptide-1, Angiotensin II, and Vitamin D in Islet Function 351
15.1 Introduction 351
15.2 Glucagon-Like Peptide-1 in Islet Function 352
15.3 Angiotensin II in Islet Function 355
15.4 Vitamin D in Islet Function 357
15.5 GLP-1-Angiotensin II-T2DM Axis 359
15.6 Vitamin D-Angiotensin II-T2DM Axis 363
15.7 Summary 365
References 366
16 Proteomics and Islet Research 374
16.1 Introduction 374
16.2 Proteome and Proteomics 375
16.3 Application of Proteomics in Islet Research 380
16.3.1 Protein Profiling of Pancreatic Islets 380
16.3.2 Comparative and Quantitative Islet Proteomics 384
16.3.3 Glucolipotoxicity and Islet Proteomics 386
16.3.4 Type 1 Diabetes and Islet Proteomics 391
16.3.5 Pharmacoproteomics and Pancreatic Islets 392
16.4 Conclusion 393
References 394
17 Wnt Signaling in Pancreatic Islets 402
17.1 The Diabetes Problem 402
17.2 Wnt Signaling Pathways 403
17.2.1 The Canonical Wnt Signaling Pathway 405
17.2.2 Noncanonical Wnt Signaling 406
17.3 Wnt Signaling in Pancreas Development and Regeneration 406
17.3.1 Wnt Signaling Loss-of-Function Studies 407
17.3.2 Wnt Signaling Gain-of-Function Studies 408
17.4 Role of Wnt Signaling in -Cell Growth and Survival 409
17.5 Roles of Non-Wnt Hormonal Ligands in the Activation of the Wnt Signaling Pathway in Islets 409
17.5.1 Downstream Wnt Signaling Requirement for GLP-1-Induced Stimulation of -Cell Proliferation 410
17.5.2 Downstream Wnt Signaling Requirement for SDF-1-Induced Promotion of -Cells Survival 411
17.5.3 Potential Mechanisms by Which GLP-1 and SDF-1 May Act Cooperatively on Wnt Signaling to Enhance -Cell Growth and Survival 413
17.6 Type 2 Diabetes Genes 414
17.6.1 Genes Associated with Islet Development/Function and Wnt Signaling 414
17.6.1.1 TCF7L2 (Transcription Factor 7-Like 2) 414
17.6.1.2 FTO (Fat Mass and Obesity-Associated Protein) 417
17.6.1.3 NOTCH2 417
17.6.1.4 IGF2BP2 (Insulin-Like Growth Factor 2 Binding Protein 2) 418
17.6.1.5 HHEX (Hematopoietically Expressed Homeobox) 418
17.6.1.6 TCF2 (Hepatocyte Nuclear Factor 1 Beta, HNF1beta, MODY 5 Gene) 418
17.6.1.7 CDKN2A/B (Cyclin-Dependent Kinase Inhibitor 2A/B, ARF, p16INK4a) 418
17.6.2 Genes Associated with Islet Development/Function, Wnt Signaling Unknown 419
17.6.2.1 PPARgamma (Peroxisome Proliferator-Activated Receptor Gamma) 419
17.6.2.2 KCNJ11 (Inward Rectifying Potassium Channel) 419
17.6.2.3 WFS1 (Wolfram Syndrome 1) 419
17.6.2.4 CDKAL1 (CDK5 Regulatory Subunit-Associated Protein-1-Like 1) 420
17.6.2.5 SLC30a8 (Solute Carrier 30a8) 420
17.6.2.6 KCNQ1 (Potassium Channel Q1) 420
17.6.2.7 MTNR1B (Melatonin Receptor 1B) 420
17.6.3 Genes Not Known to be Involved in Either Islet Development/Function or Wnt Signaling 421
17.6.3.1 TSPAN8/LGR5/GPR49 421
17.6.3.2 JAZF1 (Zinc Finger 1, TIP27) 421
17.6.3.3 CDC123/CAMK1D 421
17.6.3.4 THADA (Thyroid Adenoma Associated) 421
17.6.3.5 ADAMTS9 422
17.7 Future Directions 422
References 423
18 Molecular Pathways Underlying the Pathogenesis of Pancreatic -Cell Dysfunction 431
18.1 The Pancreatic a-Cell and Glucagon 431
18.1.1 The Pancreatic a-Cell 431
18.1.2 Functions of Glucagon 432
18.2 Dysregulation of a-Cell Function in Diabetes 434
18.2.1 Excess Glucagon Secretion 434
18.2.2 Defective Glucagon Response to Hypoglycemia 434
18.2.3 Defective a-Cell Function in Islet Transplantation Grafts 435
18.2.4 Glucagonoma Syndrome 435
18.3 Mechanisms Regulating Glucagon Expression and Secretion 435
18.3.1 Regulation of Glucagon Processing and Gene Expression 435
18.3.1.1 Processing 435
18.3.1.2 Gene Expression 436
18.3.2 Regulation of Glucagon Secretion 437
18.3.2.1 Ion Channels and Electrical Activity 437
18.3.2.2 Glucose and Other Nutrients 437
18.3.2.3 Nervous System and Neurotransmitters 439
18.3.2.4 Intraislet Regulation and Other Hormones 440
18.4 Growth of a-Cells 443
18.4.1 Development 443
18.4.2 Alterations in a-Cell Distribution in Human Type 1 and Type 2 Diabetes 444
18.4.3 Animal Models Exhibiting a-Cell Hypertrophy 444
18.5 Strategies for Restoring Glucagon Secretion 445
18.5.1 Potential Limitations 446
18.6 Perspective 447
References 447
19 Mechanisms of Pancreatic ß-Cell Apoptosis in Diabetes and Its Therapies 456
19.1 Introduction to ß-Cell Apoptosis 457
19.2 Increased ß-Cell Apoptosis as a Trigger and Mediator of Type 1 Diabetes 457
19.3 Pancreatic ß-Cell Apoptosis as a Complication of Diabetes: Glucose Toxicity 459
19.4 Apoptosis as a Contributing Factor in Type 2 Diabetes 460
19.5 Mechanisms of ß-Cell Apoptosis in Type 2 Diabetes: ER-Stress 461
19.6 Mechanisms of ß-Cell Apoptosis in Type 2 Diabetes: Lipotoxicity 461
19.7 Mechanisms of ß-Cell Apoptosis in Type 2 Diabetes: Pro-inflammatory Cytokines 462
19.8 Genetic Factors Affecting ß-Cell Apoptosis in Type 2 Diabetes 463
19.9 The Role of ß-Cell Apoptosis in Rare Forms of Diabetes 463
19.10 Islet Engraftment and ß-Cell Death in Islet Transplantation 464
19.11 Survival Factors that Prevent ß-Cell Apoptosis 465
19.12 ß-Cell Apoptosis as a Therapeutic Target in Diabetes: Future Directions 466
References 467
20 ß-Cell Function in Obese-Hyperglycemic Mice [ob/ob Mice] 472
20.1 The ob/ob Mouse 472
20.2 Discovery of Leptin 473
20.3 Insulin Resistance and Absence of Leptin 474
20.4 Pancreatic Islets 475
20.5 Oscillatory Insulin Release 476
20.6 ß-Cell Mass 477
20.7 Glucotoxicity and Lipotoxicity 478
20.8 Incretins 479
20.9 Conclusions 479
References 479
21 Islet Structure and Function in the GK Rat 487
21.1 The GotoKakizaki Wistar (GK) Rat as Model of Spontaneous T2D 488
21.2 A Perturbed Islet Architecture, with Signs of Progressive Fibrosis, Inflammatory Microenvironment, Microangiopathy and Increased Oxidative Stress 489
21.3 Less ß-Cells Within the Pancreas with Less Replicative Activity but Intact Survival Capacity 491
21.4 Which Aetiology for the ß-Cell Mass Abnormalities? 492
21.5 Multiple ß-Cell Functional Defects Mostly Targeting Insulin Release 493
21.5.1 Insulin Biosynthesis Is Grossly Preserved 493
21.5.2 Glucose-Induced Activation of Insulin Release Is Lost 494
21.5.3 Insulin Secretion Amplifying Mechanisms Are Altered 495
21.5.4 Insulin Exocytotic Machinery Is Abnormal 497
21.5.5 Secretory Response to Non-glucose Stimuli Is Partly Preserved 498
21.5.6 Islet ROS Scavenging Capacity Is Increased 500
21.6 Which Aetiology for the Islet Functional Abnormalities? 500
References 502
22 The ß-Cell in Human Type 2 Diabetes 509
22.1 Introduction 510
22.2 ß-Cell Mass Defects 510
22.3 ß-Cell Functional Defects 512
22.4 Molecular Changes 514
22.5 The Role of Genetic and Acquired Factors 515
22.6 Reversal of -Cell Damage in Type 2 Diabetes 517
22.7 Conclusions 518
References 519
23 Clinical Approaches to Preserve ß-Cell Function in Diabetes 523
23.1 Clinical Impact of Therapies Aimed at ß-Cell Preservation 525
23.1.1 Short-Term Improvement of ß-Cell Insulin Secretion 525
23.1.2 Long-Term Improvement of ß-Cell Insulin Secretion 526
23.2 Short-Term Intensive Insulin Therapy of Newly Diagnosed DM2 526
23.3 Glitazones 528
23.3.1 Indirect Effects by Amelioration of Insulin Sensitivity 528
23.3.2 Direct Effects via PPAR Activation in Pancreatic Islands 529
23.4 Incretin Mimetics 530
23.4.1 Exenatide 532
23.4.2 Liraglutide 533
23.5 Incretin Enhancers (DPP 4 Inhibitors) 535
23.5.1 Sitagliptin 536
23.5.2 Vildagliptin 537
References 539
24 Immunology of ß-Cell Destruction 544
24.1 Background and Historical Perspectives 546
24.2 Autoimmune ß-Cell Destruction 550
24.2.1 Genetic Etiology 550
24.2.2 Immune Cells in Tolerance 553
24.2.2.1 APC 553
24.2.2.2 T Cells 556
24.2.2.3 B Cells 557
24.2.3 What Happens in the Islet? 557
24.2.3.1 Virus-Induced ß-Cell Killing 559
24.2.3.2 Cytotoxin-Induced ß-Cell Killing 560
24.2.4 Antigen Presentation in Pancreatic Lymph Nodes 561
24.2.5 Homing of T Cells to Islets 561
24.2.6 Insulitis and ß-Cell Destruction 563
24.2.7 Is ß-Cell Destruction Reflected in the Blood? 565
24.2.7.1 APC 565
24.2.7.2 T Cells 566
24.2.7.3 B Cells and Autoantibodies 568
24.3 Prediction of ß-Cell Destruction 569
24.4 Concluding Remarks 570
References 570
25 Toll-Like Receptors and Type 1 Diabetes 591
25.1 Introduction 591
25.2 Toll-Like Receptors 592
25.3 The Natural History of T1D 593
25.4 Viruses and T1D 594
25.5 The Innate Immune System and Human T1D 595
25.6 TLR Pathways and T1D in the Rat 596
25.6.1 The BB and LEW1.WR1 Rat Models 596
25.6.2 Kilham Rat Virus 597
25.6.3 TLRs and T1D 600
25.6.4 Inflammation and T1D 601
25.7 TLR Pathways and T1D in the Mouse 602
25.7.1 Transgenic Mouse Models 602
25.7.2 The NOD Mouse 602
25.7.3 Streptozotocin-Induced Diabetes 605
25.8 Type I IFNs and T1D 605
25.9 Summary 607
References 607
26 Prevention of ß-Cell Destruction in Autoimmune Diabetes: Current Approaches and Future Prospects 617
26.1 Antigen-Based Therapy 619
26.1.1 GAD65 619
26.1.2 Oral Tolerance 619
26.1.3 Insulin and Cholera Toxin 620
26.1.4 Insulin 620
26.1.5 DiaPeP277 621
26.2 Antibody-Based Therapy 621
26.2.1 CD3 Antibodies 621
26.2.2 Improving the Existing CD3 Antibody Therapy 622
26.2.3 CD20 Antibodies 623
26.3 Other Forms of Therapy 623
26.3.1 DNA Vaccination 623
26.3.1.1 DNA Vaccination with GAD65 624
26.3.1.2 Microsphere-Based Vaccine 624
26.3.2 Use of Anti-inflammatory Agents 624
26.3.3 Vitamin D 625
26.4 Past Trials 625
26.4.1 Cyclosporin 625
26.4.2 Nicotinamide 625
26.4.3 BCG 625
26.5 Ongoing Prediction Studies 626
26.6 Future Directions 626
26.6.1 Strategies on Islet Expansion 627
26.6.2 Probiotic Approach 627
References 628
27 In Vivo Regeneration of Insulin-Producing ß-Cells 633
27.1 Introduction 633
27.2 Regeneration by Growth Factor Treatment 635
27.2.1 Background 635
27.2.2 Betacellulin 635
27.2.3 Glucagon-Like Peptide-1 636
27.2.4 Growth Factors in Combination with Gastrin 637
27.2.5 Other Factors 637
27.3 Regeneration by Transcription Factor Expression 638
27.3.1 Background 638
27.3.2 Pancreatic Transduction 639
27.3.3 Extra-Pancreatic Transduction 640
27.4 Regeneration by Injection of Stem/Progenitor Cells 641
27.5 Conclusions 641
References 642
28 Customized Cell-Based Treatment Options to Combat Autoimmunity and Restore ß-Cell Function in Type 1 Diabetes Mellitus: Current Protocols and Future Perspectives 647
28.1 Introduction 649
28.2 Autoimmune Diseases: Role of T Cells 650
28.3 Type 1 Diabetes Mellitus: Evidence for an Autoimmune-Based Origin 653
28.4 Diabetes-Specific Antigens and Associated Effector Cells 654
28.4.1 T Cells 654
28.4.2 Antigen-Presenting Cells 655
28.5 Surrogate Markers Preceding Autoimmunity in T1D 656
28.6 Treatment Options to Prevent and Cure T1D 657
28.6.1 Targeted Immunotherapies 657
28.6.2 Alternative Treatment Strategies 658
28.6.3 Stem Cell-Based Strategies for the Induction of Tolerance to Autoantigens 659
28.7 Own Work 662
References 666
29 The Programmable Cell of Monocytic Origin (PCMO): A Potential Adult Stem/Progenitor Cell Source for the Generation of Islet Cells 672
29.1 Introduction 673
29.2 The Programmable Cell of Monocytic Origin (PCMO): A Partially Dedifferentiated Monocyte with Stem Cell Characteristics 675
29.3 In Vitro Differentiation of PCMOs to Insulin-Expressing Cells (NeoIslet Cells) 677
29.3.1 General Protocol 677
29.3.2 Profiling of ß-Cell Markers in NeoIslet Cells 678
29.3.3 In Vitro and In Vivo Functions of NeoIslet Cells 679
29.3.4 Strategies to Improve NeoIslet Cell Phenotype and Function 679
29.4 Perspectives and Future Directions 683
References 684
30 Islet Isolation for Clinical Transplantation 688
30.1 Introduction 689
30.2 Donor Selection 690
30.3 Pancreas Preservation Prior to Islet Isolation 691
30.4 Pancreas Dissociation and Enzyme 693
30.5 Islet Purification 695
30.6 Islet Culture 698
30.7 Assessment of Islet Preparations 700
30.8 Cytoprotective Strategies During Islet Isolation 702
30.9 Conclusions 704
References 705
31 Human Islet Autotransplantation: The Trail Thus Far and the Highway Ahead 716
31.1 Introduction 716
31.2 Total Pancreatectomy in Combination with Islet Autotransplantation 717
31.3 What Can/Did We Learn from Islet Autotransplantations? 719
31.4 Still Open Issues in Islet Autotransplantation 721
31.4.1 Islet Mass 721
31.4.2 Islet Shipment 722
31.4.3 Cell Death 723
31.5 Which Are the Best Islets Does Size Matter? 724
31.6 The Role of the Surrounding Tissue: Site Matters 724
31.7 Conclusion 725
References 726
32 Modulation of Early Inflammatory Reactions to Promote Engraftment and Function of Transplanted Pancreatic Islets in Autoimmune Diabetes 730
32.1 Introduction 730
32.2 Defining the Site for Islet Transplantation 731
32.3 Main Biological Events Triggering Early Graft Failure of Transplanted Pancreatic Islets 734
32.4 Strategies to Prevent the Instant Blood-Mediated Inflammatory Reaction 736
32.5 Strategies for Cytoprotection and Revascularization 738
32.6 Modification of Transplant Site and Biomaterial-Based Strategies to Improve Engraftment 739
32.7 Concluding Remarks 743
References 743
33 Successes and Disappointments with Clinical Islet Transplantation 753
33.1 Introduction 753
33.2 The Burden of Type 1 Diabetes Mellitus 754
33.3 Pathophysiology of Type 1 Diabetes Mellitus 754
33.4 Who May Benefit from Islet Transplantation? 755
33.5 Islet Transplantation: A Historical Perspective 756
33.6 Clinical Outcomes of Islet Transplantation 756
33.6.1 Insulin Independence and Improved Glycaemic Control 756
33.6.2 Long-Term Diabetic Complications 759
33.6.3 Adverse Events in Islet Transplantation 760
33.7 Immunosuppressive Regimens for Islet Transplantation 761
33.8 Cost-Efficacy of Islet Transplantation 763
33.9 Future Developments 763
33.9.1 Novel Therapeutic Perspectives for Type 1 Diabetes Mellitus 766
33.10 Conclusion 767
References 767
34 Islet Cell Tumours 774
34.1 Introduction 775
34.2 Tumour Type 775
34.3 Hereditary Syndromes 777
34.4 Tumourigenesis 778
34.5 Radiology 779
34.6 Survival 780
34.7 Prognosis 780
34.8 Treatment 783
34.8.1 Management of Hormonal Symptoms 783
34.8.2 Surgery 784
34.8.3 Treatment of Metastatic Disease 784
References 788
Index 793