BetaSys : Systems Biology of Regulated Exocytosis in Pancreatic ß-Cells

Preface Acknowledgements Contents Contributors Part I Systems Biology Approach to β--Cells 1 Systems Biology of the β-Cell -- Revisited 1.1 Introduction 1.2 The β-cell and Diabetes 1.3 Genetics of Diabetes From GWA to NWA Studies The History of Diabetes 1.4 Why Systems Biology 1.5 Systems Biology How Ludwig von Bertalanffy (1901--1972) 1.6 Challenges of Methodological Advances 1.7 Summary 1.8 Understanding Pancreatic β-cell Death in Type 1 Diabetes -- A Systems Biology Approach 1.9 Conclusions References 2 Established Facts and Open Questions of Regulated Exocytosis in β-Cells -- A Background for a Focused Systems Analysis Approach 2.1 Introduction 2.2 The Basic Organization and Characteristics of the Exocytotic System in Pancreatic β-Cells 2.2.1 Synthesis of Insulin and Formation of Insulin Granules 2.2.2 Insulin Granule Transport to Release Sites Typical Length Scales (Rough Estimates of Diameters) in β-Cell Research 2.2.2.1 Directed and Random Granule Movement 2.2.2.2 Cytoskeleton and Motor Proteins in the β-Cell 2.2.3 Functional Insulin Granule Pools and the Relation to Phasic Insulin Secretion Observation Means and Scales -- From Light Microscopy to Electron Microscopy 2.2.3.1 Role of Cytoskeleton in Phasic Insulin Release 2.2.3.2 Exocytosis-Regulating Proteins of the β-Cell 2.2.3.3 Voltage-Gated Calcium Ion Channels (CaV) in the β-Cell 2.2.3.4 Hormonal Modulation of Glucose-Evoked Insulin Secretion 2.3 The Role of the Pancreatic β-Cell in Type 2 Diabetes and Future Challenges for β-Cell Research References 3 Mitochondria and Metabolic Signals in β-Cells 3.1 Introduction 3.2 Overview of Metabolism-Secretion Coupling 3.3 Mitochondrial NADH Shuttles as Metabolic Sensors 3.4 Getting In and Out of the Tricarboxylic Acid Cycle 3.5 Mitochondrial Control of the Glutamate Dehydrogenase 3.6 Mitochondrial Activation 3.7 The Amplifying Pathway of the Secretory Response 3.8 Mitochondria-Derived Nucleotides as Coupling Factors 3.9 Fatty Acid Pathways and the Secretory Response 3.10 Mitochondria-Derived Metabolites as Coupling Factors Panorama of β-Cell Organelles 3.11 Reactive Oxygen Species Participate to β-Cell Function 3.12 Conclusion References 4 β-Cell Ontogenesis and the Insulin Production Apparatus 4.1 Early Pancreatic Organogenesis 4.2 Expansion of Progenitors 4.3 Early Differentiation 4.4 The Choice to Become a β-Cell 4.5 Young β-Cells 4.6 Mature β-Cells References 5 The Role of the Cytoskeleton in Transport and Release of Insulin-Containing Granules by Pancreatic β-Cells 5.1 Introduction 5.2 Models to Study Insulin Secretion 5.3 Metabolic Effects of Glucose in β-Cells 5.4 The Response of the β-Cell 5.5 The Intracellular Cytoskeleton 5.6 Some Basic Properties of Microtubules 5.7 Conventional Kinesin Transports Insulin Granules During Second-Phase Secretion 5.8 Some Basic Properties of F-Actin Filaments 5.9 The Role of the Actin Cytoskeleton During Exocytosis 5.10 Myosin Va and F-Actin Are Necessary for the Final Delivery of Insulin Granules to the Plasma Membrane 5.11 Control of Granule Docking Scaffolds 5.12 Control of Granule and Plasma Membrane Fusion by F-Actin 5.13 Summary References 6 The Mathematical Microscope -- Making the Inaccessible Accessible 6.1 Introduction 6.2 The Mathematical Microscope Harveys Mathematical Microscope 6.3 Models Are Crucial in Measurements and Experiments Theory--Model--Experiment: Towards a Classification 6.4 What Insights Can Modelling Provide? 6.5 Example 1: Cardiovascular Diseases 6.6 Example 2: Type 1 Diabetes 6.7 Example 3: Type 2 Diabetes 6.8 Example 4: Depression 6.9 Example 5: The Grey Triangle in the Metabolic Syndrome 6.10 Discussion and Conclusions References Part II Imaging and Sensors 7 Magnetic Resonance Imaging of Pancreatic β-Cells 7.1 Introduction 7.2 The Physics of MRI 7.2.1 Nuclear Spin 7.2.2 The Larmor Frequency 7.2.3 Radiofrequency Excitation and the Free Induction Decay 7.2.4 T1 Relaxation 7.2.5 T2 Relaxation 7.2.6 Contrast Agents 7.2.6.1 T1-Shortening Contrast Agents 7.2.6.2 T2-Shortening Contrast Agents 7.2.6.3 Contrast Agent Compartmentalization and the Effects of Water Exchange 7.2.7 Pulse Sequences 7.2.7.1 Gradient Echo Pulse Sequence 7.2.7.2 Spin Echo Pulse Sequence 7.2.7.3 Inversion Recovery Gradient Echo Pulse Sequence 7.3 β-Cell MRI 7.3.1 Introduction 7.3.2 MRI of Islet Transplantation Quantum Mechanics Playing into Macro-space 7.3.3 Manganese-Enhanced MRI of β-Cells 7.4 Conclusions References 8 Mapping the β-Cell in 3D at the Nanoscale Using Novel Cellular Electron Tomography and Computational Approaches 8.1 General Introduction 8.2 Background to Methods and Rationale 8.2.1 Introduction -- Same Dog, New Tricks 8.2.2 Initial Method Development for Improved Ultrastructural Preservation -- Making β-Cells Even Cooler 8.2.3 Tomographic Reconstruction of β-Cell -- 3D Snapshots of the Insulin Pathway Literally ''Frozen in Time'' 8.2.4 Seeing Is Believing -- But Only If You Can Make Sense of It All 8.2.5 Reconstructing the Insulin Pathway in 3D -- ET Studies Using Transformed β-Cell Lines Versus Islet β--Cells 8.2.6 Whole Cell Tomography for Mapping Islet β-Cell Biology In Toto in 3D at The EM Level -- Getting The ''Bigger Picture'' 8.3 ``Holistic" Insights from 3D Image Reconstruction of the β--Cell at Nanometre Resolution 8.3.1 Developing a More Integrated Understanding of Cellular Organization and Membrane Transport in Insulin-Secreting Cells 8.3.2 New Lessons Learned from 3D Studies of Whole Cells -- Mapping Mitochondrial Structure to β-Cell Function Tomography Translating Maps into Images 8.3.3 Mapping Interactions Between the Microtubule Cytoskeleton and Key Organelles of the Insulin Pathway at the Cellular and Nanometre Scales 8.3.4 "Virtual TIRF" -- New Computational Tools for Complex Quantitative Analysis of Structure--Function Variation Among Insulin Granules in Different Exocytic Pools 8.4 Conclusions and Future Directions Supplementary Online Material References 9 In Vivo Applications of Inorganic Nanoparticles 9.1 Introduction 9.2 Bioconjugation 9.3 Imaging 9.3.1 Magnetic Resonance Imaging Inorganic Nanoparticles Labelling Properties in Structures 9.3.2 Optical Imaging 9.3.2.1 Gold Nanoparticles 9.3.2.2 Quantum Dots 9.3.2.3 Rare-earth Doped Particles and Upconverting Nanocrystals 9.4 Therapy 9.4.1 Hyperthermia 9.4.2 Photodynamic Therapy 9.4.3 Magnetic Targeting 9.5 Toxicity 9.5.1 A Complex Task 9.5.1.1 Practical Considerations 9.5.1.2 Experimental Set-up 9.5.2 Towards Measuring Toxicity: Chemical and Nanoscopic Risks 9.5.2.1 A Chemical Risk 9.5.2.2 A Nanoscopic Risk 9.5.3 Conclusion References 10 Cell Cultivation and Sensor-Based Assays for Dynamic Measurements of Cell Vitality 10.1 Introduction 10.1.1 Cell Cultivation in Biomedicine 10.1.2 Biochemical Processes Describing Cell Vitality 10.2 Prerequisites for Assessing Cell Vitality and Function In Vitro 10.2.1 Cell Culture Conditions 10.2.2 Culture Conditions for Islets and β-Cells 10.3 Biochemical Assays and Their Information 10.3.1 Testing Cell Vitality 10.3.2 Testing Cell Functions 10.3.3 Stimulating Insulin Secretion in Islets and β-Cells 10.3.4 Defining the Time of Measurements 10.4 Dynamic Measurements Via Multiparametric Sensor-Based Assays 10.4.1 Basic Properties 10.4.2 Electric Sensors MEMS -- A New Generation of Miniaturized Integrated Devices 10.4.3 Opto-chemical Sensors 10.4.4 Evaluation of Measurements and Possible Interpretations 10.4.5 Some Applications 10.5 What Can Sensor-Based Method Contribute to Systems Biology of Islets and β-Cells References 11 Bioimpedance Spectroscopy 11.1 Introduction 11.2 Theoretical Background of Bioimpedance Spectroscopy 11.2.1 General Considerations 11.2.2 Dipoles and Polarization 11.2.3 Electric Dipole Layers 11.2.4 Effect of External Fields 11.2.4.1 Motion in External Fields 11.2.4.2 Polarization in Electric Fields 11.2.4.3 Oscillating (AC) Fields 11.2.5 Dielectric Spectrum 11.2.5.1 Properties of the Dipole Relaxation Spectrum 11.3 Experimental Set-up 11.4 Applications 11.4.1 Application to Colloidal Model Systems -- Lipid Vesicles 11.4.2 Application to Living Biomaterial 11.4.2.1 Lab-on-a-chip Systems in General 11.4.2.2 Impedance Spectroscopy with IDES in Lab-on-a-Chip Devices Complex Numbers 11.5 Phenomenological Relaxation Regions in Biomaterial 11.6 Conclusion References Part III Genetics and Proteomics 12 DNA Variations, Impaired Insulin Secretion and Type 2 Diabetes 12.1 Introduction 12.1.1 Evidence That Type 2 Diabetes Is Inherited 12.1.2 Risk Factors Predicting Future T2D Genetic Epidemiology 12.1.3 Genetic Variability Genotyping Arrays 12.1.4 Mapping Genetic Variability 12.1.5 Linkage 12.1.5.1 Candidate Genes from Linkage Studies 12.1.6 Association Studies -- Candidate Genes Pattern Recognition in Gene Analysis and the Hidden Markov Model (HMM) 12.1.7 Genome-Wide Association Studies 12.1.8 Common Variants in MODY Genes 12.1.9 Personalized Prediction of T2D Risk? 12.1.10 Pharmacogenetics 12.2 Clinical Implications and Future Directions References 13 Genetically Programmed Defects in β-Cell Function 13.1 Introduction Monogenic Forms of Diabetes (www.monogenicdiabetes.org and www.diabetesgenes.org) 13.2 The Pancreatic β-Cell, Insulin Secretion and the Main Targets of Genetically Programmed Defects 13.3 Glucose Transporter 2 (GLUT 2) and FanconiBickel Syndrome 13.4 Glucokinase and Defects in Glucose Homeostasis 13.4.1 Mutations in Glucokinase (GCK) Cause Maturity-Onset Diabetes of the Young Subtype GCK (GCK-MODY) (Formerly Known as MODY 2) 13.4.2 Permanent Neonatal Diabetes Mellitus due to GCK Mutations (GCK-PNDM) 13.4.3 Hyperinsulinaemic Hypoglycaemia due to GCK Mutations (GCK-HH) 13.5 Mitochondrial Mutations Impairing β-Cell Function and Mitochondrial Diabetes and Deafness (MIDD) 13.6 The KATP Channel and Defects in Glucose Homeostasis 13.6.1 Neonatal Diabetes Mellitus Caused by KCNJ11 Mutations 13.6.2 Hyperinsulinaemic Hypoglycaemia Caused by KCNJ11 Mutations 13.6.3 Neonatal Diabetes Mellitus Caused by ABCC8 Mutations 13.6.4 Hyperinsulinaemic Hypoglycaemia Caused by ABCC8 Mutations 13.6.5 The Underlying Molecular Diagnosis in NDM and HH Has Implications for Treatment 13.7 Defects in Glucose Homeostasis due to Mutations in Genes Encoding β-Cell Transcription Factors 13.7.1 Mutations in Hepatocyte Nuclear Factor 1 Alpha (HNF1 Alpha) Cause Maturity-Onset Diabetes of the Young Subtype HNF1A (HNF1A-MODY) (Formerly Known as MODY 3) 13.7.2 Mutations in Hepatocyte Nuclear Factor 1 Beta (HNF1 Beta) Cause Maturity-Onset Diabetes of the Young Subtype HNF1B ( HNF1B-MODY ) (Formerly Known as MODY 5) 13.7.3 Mutations in Hepatocyte Nuclear Factor 4 Alpha (HNF4 Alpha) Cause Maturity-Onset Diabetes of the Young Subtype HNF4A (HNF4A-MODY) (Formerly Known as MODY 1) 13.7.4 Mutations in Insulin Promoter Factor 1 (IPF1) Cause Maturity-Onset Diabetes of the Young Subtype IPF1 (IPF1-MODY) (Formerly Known as MODY 4) 13.7.5 Mutations in Neurogenic Differentiation 1 (NeuroD1) Cause Maturity-Onset Diabetes of the Young Subtype NEUROD1 (NEUROD1-MODY) (Formerly Known as MODY 6) 13.7.6 RFX6 Encodes β-Cell Transcription Factor Which When Mutated Causes Diabetes 13.8 Mutations in Carboxy Ester Lipase (CEL) Cause Maturity-Onset Diabetes of the Young Subtype CEL (CEL-MODY) 13.9 Endoplasmic Reticulum (ER) Stress as a Cause of β-Cell Death and Defects in Glucose Homeostasis 13.9.1 Mutations in the Insulin (INS) Gene as a Cause of Neonatal Diabetes and Maturity-Onset Diabetes of the Young 13.9.2 Wolfram and Wolcott--Rallison Syndromes 13.10 Common Genetic Variants Associated with T2D in Genes Implicated in Monogenic Forms of β-Cell Dysfunction 13.11 Summary References 14 Proteomic Analysis of the Pancreatic Islet β-Cell Secretory Granule: Current Understanding and Future Opportunities 14.1 Introduction: Proteomics and the proteomics β--Cell Secretory Granule 14.1.1 Proteomes and Proteomics: Definitions Proteomic Analysis Lipidomics 14.1.2 Proteomic Methods: A Very Brief Overview 14.1.3 The Islet β-Cell and Its Secretory Granule: Targets for Proteomics 14.1.4 Granule-Associated Pathogenic Processes and the Origins of Diabetes diabetes 14.1.5 Granule Proteins as Putative Autoantigens in T1DM 14.1.6 Granule Proteins and Hormone Secretion 14.1.7 Potential Future Contributions by Proteomics 14.2 β-Cell Secretory Granules: Structural Regions and Functional Specialization 14.2.1 Before Proteomics: Major Protein Components of the β-Cell Secretory Granule 14.3 Evolution of a Question That Might be Addressed by Proteomics: `How Might Amylin amylin Misfolding Cause T2DM?' 14.4 The β-Cell Secretory Granule Proteome 14.4.1 Proteomic Approach to the β-Cell Secretory Granule 14.4.2 Method Comparisons 14.4.3 How to Account for Contrasting Conclusions? 14.4.4 Possible Explanations for Between-Study Divergence 14.4.5 Calreticulin Calreticulin: Putative Assignment as an Insulin-Granule Protein or Indicator of ER-Protein Contamination? 14.4.6 How Might the Appearance of `Mitochondrial Proteins' in `Insulin-Granule-Specific' Preparations Be Interpreted? 14.4.7 Chaperones in the β-Cell Secretory Granule: Possible Implications 14.5 Next Steps References 15 Physiological and Pathophysiological Role of Islet Amyloid Polypeptide (IAPP, Amylin) 15.1 Islet Amyloid Polypeptide 15.2 Regulation of the IAPP Gene 15.3 Receptor for IAPP 15.4 IAPP in Other Species 15.5 Physiology of IAPP 15.5.1 Glucose Regulation 15.5.2 Peripheral Effects of IAPP 15.5.3 Gastric Emptying 15.5.4 Regulation of Food Intake 15.5.5 Calcium Metabolism 15.5.6 IAPP as a Drug in Obesity and Diabetes Treatment 15.6 Amyloid 15.6.1 Amyloid in General Amyloid 15.6.2 Islet Amyloid 15.6.3 Amyloid in Transgenic Animal Models 15.6.4 Oligomers and Cell Toxicity 15.6.5 IAPP in the Secretory Granules 15.6.6 Mutations in the IAPP Gene and Amyloid 15.6.7 Importance of Amyloid in Transplanted Islets 15.7 Conclusion References Part IV Physiological, Pharmaceutical and Clinical Applications and Perspectives 16 Present State of Islet Transplantation for Type 1 Diabetes Patients 16.1 The Prospects of β-Cell Replacement Therapy in Type 1 Diabetes 16.2 The History of β-Cell Replacement Therapy 16.3 Immunosuppression 16.4 Indications for Clinical Islet Transplantation 16.5 Results Obtained in Clinical Islet Transplantation Trials 2000--2009 16.6 Practical Issues in Clinical Islet Transplantation Today The History of Transplantation 16.7 The Liver as the ``Gold Standard" for Clinical Islet Transplantation and Alternative Sites 16.8 Monitoring the Islet Graft References 17 Predictive Protein Networks and Identification of Druggable Targets in the β-Cell 17.1 The Need for New Ways of Identifying Druggable Targets Drug Development 17.2 How Can Drug Target Identification Be Optimized The History of Insulin 17.2.1 GWAS and Systems Biology 17.2.2 Moving from Genomes to Networks 17.2.3 Moving from Networks to Phenotypes 17.2.4 Future Directions Clinical Trials References 18 Nanotoxicity 18.1 Nanotoxicology and Nanoparticles 18.2 Potential Routes of Exposure 18.2.1 Portals of Entry 18.3 Historical Perspective 18.4 Nanoparticle Toxicity 18.4.1 Mechanisms of Nanoparticle Toxicity 18.4.1.1 Oxidative Stress 18.4.1.2 Calcium Flux 18.4.1.3 Inflammatory Response 18.5 Nanomedicines for Pancreatic Disease Classical Toxicity Studies 18.6 Summary References Part V Mathematical Modelling and Numerical Simulation 19 From Silicon Cell to Silicon Human 19.1 Introduction 19.1.1 Where Systems Biology Is Different 19.1.2 What Systems Biology? 19.2 How Systems Biology? 19.2.1 Top-Down Systems Biology 19.2.2 The Silicon Cell 19.2.3 Silicon Cell Models: Advantages and Disadvantages Information and Complexity 19.2.4 Blueprint Modelling 19.2.5 The Wisdom of MOSES: Domino Systems Biology 19.2.6 Metabolic Control Analysis Models 19.2.7 The Silicon Cell Strategy in Yeast 19.2.8 Silicon Cell and Differential Network-Based Drug Design 19.2.9 The True Silicon Cell 19.2.10 Crossing the Scales 19.2.11 Different Types of Modelling 19.3 Towards the Silicon Human References 20 Probing Cellular Dynamics with Mesoscopic Simulations 20.1 Introduction 20.2 Particle-Based Computer Simulations in Biophysics Buffon's Needle Problem -- An Early Forerunner of Monte Carlo Simulation 20.3 Dissipative Particle Dynamics Simulations of Vesicle Fusion 20.4 Conclusions and Outlook References 21 What Drives Calcium Oscillations in β-Cells? New Tasks for Cyclic Analysis 21.1 Introduction Fourier Analysis 21.2 Schematic Model 21.3 [Ca2+]c as the Pacemaker Component 21.4 Role of [ATP]/[ADP] Ratio as Pacemaker 21.5 ER Ca2+ as a Pacemaker Component 21.6 Intracellular [Na+] as a Slow Component in a Pacemaker Mechanism 21.7 Mechanistic Interactions and Compound Patterns of Bursting and [Ca2+]c Oscillations 21.8 Summary References 22 Whole-Body and Cellular Models of Glucose-Stimulated Insulin Secretion 22.1 Introduction 22.2 Modelling Issues in Assessing β-Cell Function 22.2.1 Glucose--Insulin Feedback Loop 22.2.2 Hepatic Extraction 22.2.3 Whole-Body Kinetics 22.2.4 Intravenous and Oral Glucose Tests 22.3 Minimal Models of Insulin Secretion 22.3.1 Intravenous Glucose Tolerance Test 22.3.2 Oral Glucose Tests Compartment Models 22.4 Minimal Models of Insulin Action and Hepatic Insulin Extraction 22.5 Cellular Model of Insulin Secretion 22.6 Cellular Modelling: Insight into Minimal Models 22.7 Conclusions References 23 Geometric and Electromagnetic Aspects of Fusion Pore Making 23.1 Introduction 23.1.1 On Our Heuristic (Suggestive) Use of Mathematical Modelling 23.1.2 Electromagnetic Free Boundary Route to Fusion Pore Making 23.1.3 Plan of the Chapter 23.2 Synopsis of Established Facts 23.2.1 Membrane Fusion and the Fusion Pore Challenge 23.2.2 Competing Mathematical Approaches to Space--Time Processes 23.2.3 Oscillatory Intracellular Release and Binding of Ca2+ Ions 23.2.3.1 Basic Observations of Ca2+ oscillations 23.2.3.2 Postulated Electrodynamic Field Character 23.2.4 The Magnetic Character of the Induced Field Wave The Four Maxwells Equations at a Glance 23.2.5 Dimple Formation Prior to the Fusion Event 23.2.6 The Flickering of Regulated Exocytosis 23.3 The Model 23.3.1 The Force Balance Equation 23.3.2 The 1D Case 23.3.3 The 2D Case 23.3.4 Further Approximations 23.3.5 Lorentz Force 23.3.5.1 Peculiarity of the Lorentz Force High-Voltage Devices: Quantitative Comparison of Electric Field Strengths in Electrical Power Plants and Animal Cells 23.3.5.2 Energy Estimates 23.3.5.3 Model Quantities 23.3.5.4 Model Equations 23.3.5.5 The Lorentz Force 23.3.5.6 Work Equation 23.4 Apposite Results on Parabolic Obstacle Problems 23.4.1 Review of Free Boundary Problems 23.4.2 Qualitative Properties of Solutions 23.4.3 Classification of Blow-Up Limits in Rn+1 23.4.4 Classification of the Free Boundary Points Experiment and Discovery 23.5 Conclusions 23.5.1 Summary of (Partly Speculative) Working Hypotheses 23.5.2 The Findings 23.5.3 Suggested Experiments and Measurements References Index