BetaSys (eBook)

Preface 5
Acknowledgements 8
Contents 9
Contributors 12
Systems Biology Approach to ß-Cells 16
Systems Biology of the ß-Cell – Revisited 17
1.1 Introduction 17
1.2 The ß-cell and Diabetes 18
1.3 Genetics of Diabetes – From GWA to NWA Studies 21
The History of Diabetes 22
1.4 Why Systems Biology? 23
1.5 Systems Biology – How? 24
Ludwig von Bertalanffy (1901–1972) 25
1.6 Challenges of Methodological Advances 28
1.7 Summary 28
1.8 Understanding Pancreatic ß-cell Death in Type 1 Diabetes – A Systems Biology Approach 29
1.9 Conclusions 33
References 34
Established Facts and Open Questions of Regulated Exocytosis in ß- Cells – A Background for a Focused Systems Analysis Approach 38
2.1 Introduction 40
2.2 The Basic Organization and Characteristics of the Exocytotic System in Pancreatic ß- Cells 41
Typical Length Scales (Rough Estimates of Diameters) in ß- Cell Research 43
Observation Means and Scales – From Light Microscopy to Electron Microscopy 48
2.3 The Role of the Pancreatic ß-Cell in Type 2 Diabetes and Future Challenges for ß- Cell Research 56
References 58
Mitochondria and Metabolic Signals in ß-Cells 66
3.1 Introduction 66
3.2 Overview of Metabolism-Secretion Coupling 67
3.3 Mitochondrial NADH Shuttles as Metabolic Sensors 68
3.4 Getting In and Out of the Tricarboxylic Acid Cycle 69
3.5 Mitochondrial Control of the Glutamate Dehydrogenase 70
3.6 Mitochondrial Activation 71
3.7 The Amplifying Pathway of the Secretory Response 72
3.8 Mitochondria-Derived Nucleotides as Coupling Factors 72
3.9 Fatty Acid Pathways and the Secretory Response 73
3.10 Mitochondria-Derived Metabolites as Coupling Factors 74
Panorama of ß-Cell Organelles 76
3.11 Reactive Oxygen Species Participate to ß-Cell Function 77
3.12 Conclusion 77
References 78
ß-Cell Ontogenesis and the Insulin Production Apparatus 85
4.1 Early Pancreatic Organogenesis 85
4.2 Expansion of Progenitors 87
4.3 Early Differentiation 87
4.4 The Choice to Become a ß-Cell 88
4.5 Young ß-Cells 88
4.6 Mature ß-Cells 89
References 90
The Role of the Cytoskeleton in Transport and Release of Insulin- Containing Granules by Pancreatic ß- Cells 94
5.1 Introduction 94
5.2 Models to Study Insulin Secretion 96
5.3 Metabolic Effects of Glucose in ß-Cells 96
5.4 The Response of the ß-Cell 97
5.5 The Intracellular Cytoskeleton 98
5.6 Some Basic Properties of Microtubules 98
5.7 Conventional Kinesin Transports Insulin Granules During Second- Phase Secretion 99
5.8 Some Basic Properties of F-Actin Filaments 100
5.9 The Role of the Actin Cytoskeleton During Exocytosis 101
5.10 Myosin Va and F-Actin Are Necessary for the Final Delivery of Insulin Granules to the Plasma Membrane 102
5.11 Control of Granule Docking 102
Scaffolds 103
5.12 Control of Granule and Plasma Membrane Fusion by F- Actin 104
5.13 Summary 104
References 105
The Mathematical Microscope – Making the Inaccessible Accessible 107
6.1 Introduction 107
6.2 The Mathematical Microscope Harvey’s Mathematical Microscope 109
6.3 Models Are Crucial in Measurements and Experiments 111
Theory–Model–Experiment: Towards a Classification 112
6.4 What Insights Can Modelling Provide? 113
6.5 Example 1: Cardiovascular Diseases 115
6.6 Example 2: Type 1 Diabetes 117
6.7 Example 3: Type 2 Diabetes 119
6.8 Example 4: Depression 119
6.9 Example 5: The Grey Triangle in the Metabolic Syndrome 121
6.10 Discussion and Conclusions 124
References 125
Imaging and Sensors 129
Magnetic Resonance Imaging of Pancreatic ß- Cells 130
7.1 Introduction 130
7.2 The Physics of MRI 131
7.3 ß-Cell MRI 145
Quantum Mechanics Playing into Macro-space 146
7.4 Conclusions 153
References 153
Mapping the ß-Cell in 3D at the Nanoscale Using Novel Cellular Electron Tomography and Computational Approaches 156
8.1 General Introduction 158
8.2 Background to Methods and Rationale 159
8.3 “Holistic” Insights from 3D Image Reconstruction of the ß- Cell at Nanometre Resolution 173
Tomography – Translating Maps into Images 177
8.4 Conclusions and Future Directions 182
References 183
In Vivo Applications of Inorganic Nanoparticles 193
9.1 Introduction 194
9.2 Bioconjugation 196
9.3 Imaging 199
Inorganic Nanoparticles 201
9.4 Therapy 209
9.5 Toxicity 213
References 218
Cell Cultivation and Sensor-Based Assays for Dynamic Measurements of Cell Vitality 229
10.1 Introduction 230
10.2 Prerequisites for Assessing Cell Vitality and Function In Vitro 233
10.3 Biochemical Assays and Their Information 235
10.4 Dynamic Measurements Via Multiparametric Sensor-Based Assays 237
MEMS – A New Generation of Miniaturized Integrated Devices 239
10.5 What Can Sensor-Based Method Contribute to Systems Biology of Islets and ß- Cells? 245
References 246
Bioimpedance Spectroscopy 249
11.1 Introduction 250
11.2 Theoretical Background of Bioimpedance Spectroscopy 250
11.3 Experimental Set-up 259
11.4 Applications 262
Complex Numbers 270
11.5 Phenomenological Relaxation Regions in Biomaterial 271
11.6 Conclusion 272
References 274
Genetics and Proteomics 280
DNA Variations, Impaired Insulin Secretion and Type 2 Diabetes 281
12.1 Introduction 281
Genetic Epidemiology 283
Genotyping Arrays 285
Pattern Recognition in Gene Analysis and the Hidden Markov Model ( HMM) 291
12.2 Clinical Implications and Future Directions 296
References 297
Genetically Programmed Defects in ß-Cell Function 304
13.1 Introduction 304
13.2 The Pancreatic ß-Cell, Insulin Secretion and the Main Targets of Genetically Programmed Defects 308
13.3 Glucose Transporter 2 (GLUT 2) and Fanconi–Bickel Syndrome 309
13.4 Glucokinase and Defects in Glucose Homeostasis 310
13.5 Mitochondrial Mutations Impairing ß-Cell Function and Mitochondrial Diabetes and Deafness ( MIDD) 312
13.6 The KATP Channel and Defects in Glucose Homeostasis 313
13.7 Defects in Glucose Homeostasis due to Mutations in Genes Encoding ß- Cell Transcription Factors 315
13.8 Mutations in Carboxy Ester Lipase (CEL) Cause Maturity-Onset Diabetes of the Young Subtype CEL (CEL-MODY) 318
13.9 Endoplasmic Reticulum (ER) Stress as a Cause of ß-Cell Death and Defects in Glucose Homeostasis 319
13.10 Common Genetic Variants Associated with T2D in Genes Implicated in Monogenic Forms of ß- Cell Dysfunction 320
13.11 Summary 320
References 321
Proteomic Analysis of the Pancreatic Islet ß-Cell Secretory Granule: Current Understanding and Future Opportunities 332
14.1 Introduction: Proteomics and the ß-Cell Secretory Granule 333
Proteomic Analysis 334
14.2 ß-Cell Secretory Granules: Structural Regions and Functional Specialization 339
14.3 Evolution of a Question That Might be Addressed by Proteomics: ’ How Might Amylin Misfolding Cause T2DM?’ 341
14.4 The ß-Cell Secretory Granule Proteome 345
14.5 Next Steps 359
References 360
Physiological and Pathophysiological Role of Islet Amyloid Polypeptide ( IAPP, Amylin) 368
15.1 Islet Amyloid Polypeptide 368
15.2 Regulation of the IAPP Gene 370
15.3 Receptor for IAPP 370
15.4 IAPP in Other Species 371
15.5 Physiology of IAPP 371
15.6 Amyloid 374
Amyloid 374
15.7 Conclusion 382
References 382
Physiological, Pharmaceutical and Clinical Applications and Perspectives 392
Present State of Islet Transplantation for Type 1 Diabetes Patients 393
16.1 The Prospects of ß-Cell Replacement Therapy in Type 1 Diabetes 393
16.2 The History of ß-Cell Replacement Therapy 394
16.3 Immunosuppression 395
16.4 Indications for Clinical Islet Transplantation 397
16.5 Results Obtained in Clinical Islet Transplantation Trials 2000– 2009 398
16.6 Practical Issues in Clinical Islet Transplantation Today 400
The History of Transplantation 403
16.7 The Liver as the “Gold Standard” for Clinical Islet Transplantation and Alternative Sites 403
16.8 Monitoring the Islet Graft 404
References 406
Predictive Protein Networks and Identification of Druggable Targets in the ß- Cell 410
17.1 The Need for NewWays of Identifying Druggable Targets 410
Drug Development 411
17.2 How Can Drug Target Identification Be Optimized? 411
The History of Insulin 413
Clinical Trials 420
References 421
Nanotoxicity 422
18.1 Nanotoxicology and Nanoparticles 422
18.2 Potential Routes of Exposure 424
18.3 Historical Perspective 427
18.4 Nanoparticle Toxicity 428
18.5 Nanomedicines for Pancreatic Disease 431
Classical Toxicity Studies 433
18.6 Summary 434
References 434
Mathematical Modelling and Numerical Simulation 438
From Silicon Cell to Silicon Human 439
19.1 Introduction 440
19.2 How Systems Biology? 441
Information and Complexity 447
19.3 Towards the Silicon Human 455
References 458
Probing Cellular Dynamics with Mesoscopic Simulations 461
20.1 Introduction 461
20.2 Particle-Based Computer Simulations in Biophysics 463
Buffon’s Needle Problem – An Early Forerunner of Monte Carlo Simulation 466
20.3 Dissipative Particle Dynamics Simulations of Vesicle Fusion 466
20.4 Conclusions and Outlook 471
References 473
What Drives Calcium Oscillations in ß-Cells? New Tasks for Cyclic Analysis 476
21.1 Introduction 477
Fourier Analysis 478
21.2 Schematic Model 479
21.3 [Ca2+]c as the Pacemaker Component 480
21.4 Role of [ATP]/[ADP] Ratio as Pacemaker 481
21.5 ER Ca2+ as a Pacemaker Component 483
21.6 Intracellular [Na+] as a Slow Component in a Pacemaker Mechanism 485
21.7 Mechanistic Interactions and Compound Patterns of Bursting and [Ca2+]c Oscillations 487
21.8 Summary 487
References 488
Whole-Body and Cellular Models of Glucose- Stimulated Insulin Secretion 490
22.1 Introduction 490
22.2 Modelling Issues in Assessing ß-Cell Function 491
22.3 Minimal Models of Insulin Secretion 494
Compartment Models 497
22.4 Minimal Models of Insulin Action and Hepatic Insulin Extraction 497
22.5 Cellular Model of Insulin Secretion 498
22.6 Cellular Modelling: Insight into Minimal Models 500
22.7 Conclusions 501
References 501
Geometric and Electromagnetic Aspects of Fusion Pore Making 505
23.1 Introduction 506
23.2 Synopsis of Established Facts 508
The Four Maxwell’s Equations at a Glance 516
23.3 The Model 521
High-Voltage Devices: Quantitative Comparison of Electric Field Strengths in Electrical Power Plants and Animal Cells 527
23.4 Apposite Results on Parabolic Obstacle Problems 529
Experiment and Discovery 533
23.5 Conclusions 534
References 536
Index 539