Insulin

ISBN-13: 9783642741005 / Angielski / Miękka / 2011 / 474 str.

Pedro Cuatrecasas; Steven Jacobs; J. Avruch

Opis

It is fourteen years since insulin was last reviewed in The Handbook of Ex- perimental Pharmacology, in volume 32. The present endeavor is more modest in scope. Volume 32 appeared in two separate parts, each having its own subeditors, and together the two parts covered nearly all areas of insulin pharmacology. Such comprehensiveness seemed impractical in a new volume. The amount of in- formation related to insulin that is now available simply would not fit in a reasonable amount of space. Furthermore, for better or worse, scientists have be- come so specialized that a volume providing such broad coverage seemed likely in its totality to be of interest or value to very few individuals. We therefore decided to limit the present volume to the following areas: insulin chemistry and structure, insulin biosynthesis and secretion, insulin receptor, and insulin action at the cellular level. We felt these areas formed a coherent unit. We also felt, perhaps as much because of our own interests and perspectives as any objective reality, that these were the areas in which recent progress has been most dramatic, and yet, paradoxically and tantalizingly, these were the areas in which most has yet to be learned. Even with this limited scope, there are some major gaps in coverage. Regrettably, two important areas, the beta cell ATP-sensitive potassium channel and the glucose transporter, were among these. Nevertheless, the authors who con- tributed have done an excellent job, and we would like to thank them for their diligence.

Spis treści

I. Insulin.- 1 Insulin Chemistry.- A. Introduction.- B. Analysis, Purification.- I. HPLC.- II. Isolation.- III. Degradation.- IV. Stability.- C. Chemical and Enzymatic Modification, Semisynthesis.- I. Modification of Amino Groups and NH2 Terminal Semisyntheses.- II. Hydroxy Amino Acids.- III. COOH Terminal Shortening and Semisynthesis.- IV. Other Semisyntheses.- V. Labeling.- VI. Photoreactive Insulins.- VII. Cross-linking.- D. Chemical Synthesis of Insulin Analogs.- I. Synthesis of A Chains.- II. Synthesis of B Chains.- III. Chain Combination.- IV. Syntheses of Related Molecules.- E. Biosynthesis by Recombinant DNA Techniques.- I. Human Insulin.- II. Analogs.- F. Conclusions.- References.- 2 Insulin Structure.- A. Introduction.- B. The Three-Dimensional Structure of the Insulin Molecule.- I. The Insulin Monomer.- II. The Insulin Dimer.- III. The Insulin Hexamer.- C. Structural Variation in the Insulin Molecule.- D. Conclusions.- References.- 3 Mutant Human Insulins and Insulin Structure-Function Relationships.- A. Introduction.- B. Structural Relationships Within the Human Insulin Gene and its Expressed Products.- C. Abnormal Insulin Gene Products.- I. Mutant Human Proinsulins and Processing Intermediates.- II. Mutant Human Insulins.- D. Insulin Structure-Function Relationships and Mutant Insulins.- I. Substitutions at Position A3 (Insulin Wakayama).- II. Substitutions at Position B24 (Insulin Los Angeles).- III. Substitutions at Position B25 (Insulin Chicago).- E. Physiology, Genetics, and Clinical Aspects.- F. Concluding Remarks.- References.- II. Biosynthesis, Secretion, and Degradation.- 4 The Biosynthesis of Insulin.- A. Introduction.- B. Insulin Precursors.- I. Preproinsulin: Its Role in Insulin Biosynthesis.- II. Structure and Properties of Proinsulin.- III. Proinsulin is the Immediate Precursor of Insulin.- C. Cell Biology of Insulin Biosynthesis.- D. Mechanism of Conversion of Proinsulin to Insulin.- E. Formation of Insulin Secretory Granules.- F. The C-Peptide as a Product of Proinsulin Transformation.- G. The Regulation of Insulin Production.- H. The Insulin Gene Family.- J. Defects in the Insulin Gene: The Insulinopathies.- K. Summary.- References.- 5 Insulin Gene Regulation.- A. Overview.- B. Introduction.- C. Insulin Gene Structure.- D. Experimental Approaches.- I. Transient Assay.- II. Stable Assay.- III. Transgenic Animals.- E. Identification of Control Sequences.- I. Role of 5’ Flanking DNA.- II. Cell-Specific Enhancer and Promoter.- III. Positive and Negative Control.- IV. Regulation by Glucose.- V. Systematic Mutagenesis.- VI. Role of Other Sequences in Cell Specificity.- VII. Biochemical Approaches.- F. Expression During Development.- G. Prospects.- I. Biochemical.- II. Genetic.- III. Expression Library Screening.- IV. Gene Therapy.- References.- 6 Regulation of Insulin Release by the Intracellular Mediators Cyclic AMP, Ca2+, Inositol 1, 4, 5-Trisphosphate, and Diacylglycerol.- A. Introduction.- B. Cyclic AMP.- I. Cyclic AMP Synthesis and Breakdown.- II. Mode of Action of Cyclic AMP.- III. Physiological Role of Cyclic AMP.- C. Calcium.- I. Regulation of Ca2+Fluxes in Islet Cells.- II. Target Systems for Cytosolic Ca2+.- D. Inositol 1, 4, 5-Trisphosphate.- E. Diacylglycerol.- I. Generation of Diacylglycerol.- II. Activation of Protein Kinase C.- III. Functional Implications.- F. Concluding Remarks.- References.- 7 The Role of Cholecystokinin and Other Gut Peptides on Regulation of Postprandial Glucose and Insulin Levels.- A. Summary.- B. Background.- C. Incretin Criteria.- D. Candidate Incretins.- I. Glucose Insulinotropic Peptide.- II. Secretin.- III. Gastrin.- IV. Vasoactive Inhibitory Peptide.- V. Peptide Histidine Isoleucine and Peptide YY.- VI. Enteroglucagon.- E. An Established Incretin: Cholecystokinin.- F. Conclusion.- References.- 8 Insulin-Degrading Enzyme.- A. Introduction.- B. Substrate Specificity.- C. Inhibition Studies.- D. Subcellular Location.- E. Tissue Distribution.- F. Insulin Degradation Assays.- G. Enzyme Products.- H. Physiological Role of Insulin Protease.- J. Other Insulin-Degrading Enzymes.- I. Glutathione Insulin Transhydrogenase.- II. High Molecular Weight Insulin-Degrading Enzyme.- K. Future Studies.- References.- III. Insulin Receptor.- 9 Insulin Receptor Structure.- A. Background.- B. Early Glimpses of the Structure of the Insulin Receptor.- C. Sequence of the Insulin Receptor.- I. The ? Subunit.- II. Theß Subunit.- III. Domain Structure of the Insulin Receptor.- D. Insulin Receptors in Different Tissues and Species.- E. Concluding Remarks.- References.- 10 Insulin Receptor-Mediated Transmembrane Signalling.- A. Introduction.- B. Mechanisms of Transmembrane Signalling.- I. Signal Generation.- II. Signal Amplification.- III. Role of G Proteins.- IV. Messengers.- V. Receptor Dynamics and Transmembrane Signalling.- VI. Feedback Regulation.- C. Insulin-Mediated Transmembrane Signalling.- I. Insulin Receptor Tyrosine Kinase Activity, Insulin Action, and Receptor Internalization.- II. Receptor-Triggered Phosphorylation and Signalling.- III. G Proteins and Insulin Action.- IV. Interactions with Other Membrane Proteins.- V. Low Molecular Weight Mediators of Insulin Action.- VI. Receptor Internalization and Insulin Action.- VII. Feedback Regulation and Insulin Action.- D. Summary and Conclusions.- References.- 11 The Insulin Receptor Tyrosine Kinase.- A. Introduction.- B. Background.- I. Purification of the Insulin Receptor Kinase.- II. Role of Autophosphorylation in Insulin Receptor Kinase Function.- III. Autophosphorylation.- IV. Sites of ß Subunit Autophosphorylation.- V. Structural Requirements for Receptor Autophosphorylation.- C. Substrates of the Receptor Kinase.- I. In Vitro Substrates.- II. In Vivo Substrates.- D. Regulation of the Insulin Receptor Kinase.- I. Possible Role of cAMP-Dependent Kinase.- II. Role of Protein Kinase C.- III. Role of Phospholipids.- IV. Role of Interactions with Other Proteins.- V. Physiological Aspects.- References.- 12 Receptor-Mediated Internalization and Turnover.- A. Introduction.- B. The Insulin Receptor Itinerary.- C. Insulin Processing and Dissociation.- D. Insulin Degradation.- E. Retroendocytosis.- F. Insulin Receptor Processing.- References.- 13 Insulin-like Growth Factor I Receptors.- A. Introduction.- B. Hormonal Determinants of Binding and Specificity.- I. D Peptide.- II. C Peptide.- III. B Peptide.- IV. A Peptide.- C. The Receptor Binding Site.- D. Biological Responses.- E. Tyrosine Kinase Activity.- F. Receptor Heterogeneity.- G. A Hybrid IGF-I Receptor.- References.- IV. Effect of Insulin on Cellular Metabolism.- 14 Second Messengers of Insulin Action.- A. Overview.- B. Introduction.- C. Biological Characterization of the Putative Insulin Second Messengers.- I. Purification.- II. Biological Activities.- D. Chemical Characterization of the Enzyme Modulator as an Inositol Glycan.- I. Similarity with the Glycosyl-PI Protein Anchor.- II. Metabolic Labeling of the Inositol Glycan.- E. Structure and Biosynthesis of Glycosyl-PI.- I. Structural Studies.- II. Relationship to the Glycosyl-PI Protein Anchor.- F. Glycosyl-PI Hydrolysis is Catalyzed by an Insulin-Sensitive Glycosyl-PI-Specific Phospholipase C.- I. Characterization of a Specific PLC.- II. Coupling of the Insulin Receptor to the Glycosyl-PI-Specific PLC..- III. Release of Glycosyl-PI-Anchored Proteins.- G. The Role of Diacylglycerol in Insulin Action.- H. Inositol Glycans as Second Messengers of Insulin Action.- References.- 15 Insulin Regulation of Protein Phosphorylation.- A. Introduction.- B. Insulin-Stimulated Tyrosine Phosphorylation.- I. Insulin Receptor ß Subunit.- II. Is Tyr Phosphorylation of Other Proteins the Next Step?.- III. Strategies for the Detection of Physiologically Relevant Receptor Kinase Substrates.- IV. Candidate Substrates for the Insulin Receptor Kinase.- C. Insulin-Stimulated Ser/Thr Protein Phosphorylation.- I. Insulin-Stimulated Ser/Thr Kinases.- D. Insulin-Induced Dephosphorylation.- I. Inhibition of Protein Kinase Activity.- II. Activation of Protein Phosphatase.- E. Conclusion.- References.- 16 Effects of Insulin on Glycogen Metabolism.- A. Introduction.- I. Historical.- II. Research Approach.- B. Experimental.- I. Phosphorylation Sites of Glycogen Synthase.- II. Decreased Phosphorylation of Glycogen Synthase with Insulin Action.- III. Integration of Co valent and Allosteric Controls of Phosphorylase and Glycogen Synthase.- IV. Emerging Significance of Multiple Phosphorylation.- V. Insulin and Tissue cAMP Concentrations.- VI. Insulin and cAMP-Dependent Protein Kinase: A Marker for Mediator.- VII. Effects of Insulin on Other Kinases: A Potential Phosphorylation Cascade.- VIII. Effects of Insulin on Phosphoprotein Phosphatases: A Mechanism for Dephosphorylation.- IX. Purification and Action of Two Mediators: A Mechanism for Control of Dephosphorylation.- X. Formation of Insulin Mediators.- XI. Insulin Receptor Activation and Mediator Formation.- C. Summary.- References.- 17 Insulin-Sensitive cAMP Phosphodiesterase.- A. Introduction.- B. Localization of Insulin-Sensitive Phosphodiesterase.- C. Solubilization, Purification, and Characterization.- D. Hormonal Stimulation and its Physiological Significance.- E. Cell-Free Activation and Deactivation.- I. Effects of Salts.- II. Effects ofDithiothreitol at 37 °C.- III. Effects of SH Blocking Agents.- IV. Effects of a Mild Proteolysis.- V. Effects of cGMP and cAMP.- VI. Effects of GTP and ATP.- VII. Effects of Phosphodiesterase-Specific Inhibitors.- VIII. Effects ofTPA (a Phorbol Ester).- IX. Effects of Phosphorylation.- F. Possible Mechanisms of Insulin Action.- I. Phosphorylation Theory.- II. Mediator Theory.- III. G Protein Theory.- References.- 18 Regulation of Gene Expression by Insulin.- A. Introduction.- B. Genes Inhibited by Insulin.- I. Phosphoenolpyruvate Carboxykinase.- II. Other Genes Inhibited by Insulin.- C. Genes Induced by Insulin.- I. p33.- II. c-fos and c-myc.- III. Glyceraldehyde-3-Phosphate Dehydrogenase.- IV. Fatty Acid Synthase and Malic Enzyme.- V. Pyruvate Kinase.- VI. Ornithine Decarboxylase.- VII. Other Hepatic Genes Induced by Insulin.- VIII. Other Nonhepatic Genes Induced by Insulin.- D. Genes Inhibited or Induced by Insulin.- I. Albumin.- II. Tyrosine Aminotransferase.- E. Protein Kinase C and Insulin’s Regulation of Gene Expression.- F. Summary and Conclusions.- References.- 19 Insulin, Membrane Polarization, and Ionic Currents.- A. Insulin Effect on Membrane Potential.- I. Some Pertinent Electrophysiology.- II. Insulin Hyperpolarizes Skeletal Muscle.- III. Insulin Hyperpolarizes Adipocytes.- IV. Insulin Hyperpolarizes Myocardium.- V. Insulin and Liver Membrane Potential.- VI. Insulin and Vm of Other Cells.- VII. A Tentative Conclusion About Insulin-Induced Hyperpolarization.- B. Some Other Electrical Effects, Not on Striated Muscle.- C. Insulin’s Effect on Vm of Striated Muscle when K + Distribution Has Been Altered.- D. The Immediate Mechanism by which Insulin Hyperpolarizes Skeletal Muscle.- I. List of Candidates.- II. The Pump as Candidate.- III. Changes in Electrolyte Concentration.- IV. Changes in Permeability Coefficients.- E. Is Hyperpolarization a Step in the Transduction Chain Leading to Stimulated Glucose Uptake?.- I. Criteria.- IL Evidence that IIH is a Transduction Step Leading to Glucose Uptake.- III. Evidence That IIH is Not a Transduction Step Leading to Glucose Uptake.- IV. What May Be the Roles of IIH?.- F. Insulin Effects on Some Voltage-Sensitive Currents.- I. Voltage-Sensitive vs Resting Currents.- II. Insulin Increases an Na+ Current-Dependent K+ Current.- III. Insulin Decreases Both Ca2+ Currents in Rat Myoballs.- IV. Functions of Insulin Effects on Voltage-Sensitive Channels.- G. Electrical Steps in the Insulin Transduction Scheme.- References.- 20 Insulin Regulation of Metabolism Relevant to Gluconeogenesis.- A. Introduction.- B. Overview of Blood Glucose Regulation.- C. Biochemical Pathways of Glycolysis and Gluconeogenesis.- I. Enzymes of Glycolysis and Gluconeogenesis.- II. Futile Cycles, Regulation by Enzyme Pairs.- III. Hepatic Gluconeogenesis.- D. Hormonal Regulation.- I. Glucagon.- II. Insulin Effects on Gluconeogenesis.- III. Hepatic Gene Expression and Metabolic Zonation.- References.