Glucagon I by T.T. AokiGlucagon I by T.T. Aoki

Glucagon I

byT.T. Aoki

Paperback | November 19, 2011

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The Editorial Board of the Handbook of Experimental Pharmacology apparently did not hurry in suggesting production of a volume on glucagon since the present opus is number sixty-six in the series. This fact is even more striking if we consider that 34 volumes published over about eight years will separate the books on glucagon from those on insulin on library shelves, whereas only a few microns separate the cells manufacturing these two polypeptides within the islets of Langerhans in the pancreas! Numerous factors have probably caused this dicrimination; four of them are: First, insulin deficiency or resistance is the cause of one of the most serious and distressing diseases, diabetes mellitus, which affects millions of people, whereas glucagon deficiency is apparently an extremely rare disorder, for which detailed reports are published of individual cases whenever they occur. Second, since its discovery in 1921 by BANTING and BEST, insulin has been irreplaceable for the treatment of the most severe forms of diabetes, whereas, in contrast, glucagon was until recently considered a relatively minor therapeutic agent. Third, whereas insulin is a compound which has been well characterized since the pioneering work of SANGER and its biosynthesis clearly identified by STEINER and his co-workers, glucagon, also well characterized chemically, has suffered from its parenthood with the so-called "glucagon-like immunoreactive substances", an incompletely defined series of immunologically related polypeptides present in the gut, the pancreas and some other parts of the body.
Title:Glucagon IFormat:PaperbackDimensions:536 pages, 24.4 × 17 × 0.17 inPublished:November 19, 2011Publisher:Springer-Verlag/Sci-Tech/TradeLanguage:English

The following ISBNs are associated with this title:

ISBN - 10:3642688683

ISBN - 13:9783642688683

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Table of Contents

Chemistry and Physicochemistry of Glucagon.- 1 Chemical Characteristics of Glucagon.- A. Introduction.- B. Isolation and Purification.- C. Properties.- D. Amino Acid Sequence.- E. Covalent Chemical Modification and Biologic Function.- I. Limitations of the Approach.- II. General Considerations.- III. The Question of Several Active Sites.- IV. Amino Terminal and Diamino Modifications.- V. Inhibitors of Glucagon.- VI. Modifications of Glutamyl, Lysyl, Arginyl, and Tryptophyl Residues.- VII. Modifications of Tyrosyl Residues.- VIII. Methionyl Residue and Carboxyl Terminal Modifications.- IX. Summary of Covalent Modifications and Function.- References.- 2 The Chemical Synthesis of Glucagon.- A. Introduction.- B. Early Synthetic Efforts.- C. The First Total Synthesis.- D. Further Syntheses by Fragment Condensation in Solution.- E. Solid Phase Fragment Synthesis.- F. Stepwise Solid Phase Synthesis.- G. Conclusions.- References.- 3 The Conformation of Glucagon.- A. Introduction.- B. The Crystal Structure.- I. Crystals.- II. Protomer Conformation.- III. Trimer Conformation.- C. The Solution Structure.- I. Monomer.- II. Trimers.- III. Fibrils.- D. Conformation of Micelle-Bound Glucagon.- E. Conformation and Storage Granules.- F. Conformation and Receptor Binding.- References.- Morphology of the A-cell of Islets of Langerhans, Biosynthesis of Glucagon and Related Peptides.- 4 Glucagon- and Glicentin-Producing Cells.- A. Introduction.- B. Pancreas.- I. Morphological Features.- II. Distribution of A-cells.- III. Intracellular Distribution of Secretory Polypeptides.- C. Digestive Tract.- D. Pathology of A- and L-cells.- E. Conclusions.- F. Appendix.- I. Sampling of the Pancreas.- II. Immunofluorescence Technique.- III. Quantitative Evaluation.- References.- 5 Ontogeny and Phylogeny of the Glucagon Cell.- A. Introduction.- B. Material, Methods, Nomenclature.- C. Prokaryotes, Eukaryote Protozoa, Coelenterates.- D. Protostomian Invertebrates.- I. Molluscs.- II. Arthropods.- 1. Crustaceans.- 2. Insects.- E. Deuterostomian Invertebrates.- I. Echinoderms, Hemichordates.- II. Protochordates (Tunicates, Amphioxus).- F. Vertebrates.- I. Agnatha (Cyclostomes; Jawless Fish).- II. Gnathostomata.- 1. Cartilaginous Fish.- 2. Bony Fish.- 3. Tetrapods.- G. Discussion and Summarising Conclusions.- References.- 6 The Biosynthesis of Glucagon.- A. Introduction.- B. General Aspects of the Formation, Intracellular Conversion, and Storage of Peptide Hormones.- C. Biosynthesis of Glucagon.- I. Formation of Preproglucagon.- II. Formation and Conversion of Proglucagon.- III. Structure and Storage of Proglucagon and Glucagon.- D. Concluding Remarks.- References.- 7 Glucagon, Glicentin, and Related Peptides.- A. Introduction.- B. The Immunochemistry of Gut GLIs.- C. The Chemistry of Crude Gut GLIs.- I. Distribution.- II. Size.- III. Charge.- D. The Chemistry of Glicentin, GRPP, and Oxyntomodulin.- I. Isolation of Glicentin.- II. Sequence of Glicentin.- III. Relationship of Glicentin to Other Peptides.- IV. Structural Analysis of Glicentin.- V. Isolation of GRPP.- VI. Chemistry of GRPP.- VII. Relationship of GRPP to other Peptides.- VIII. Chemistry of Oxyntomodulin.- E. The Immunochemistry of Glicentin.- I. Reaction of Glicentin with Anti-Glucagon Sera.- II. Anti-Glicentin Sera.- III. Radioimmunoassay for Glicentin.- IV. Distribution of Immunoreactive Glicentin.- F. Glicentin Cells.- I. Intestinal Gut GLI Cells.- II. The Glicentin Cell.- 1. Animal Tissue.- 2. Normal Human Tissue.- 3. Pathologic Human Tissue.- III. Fine Structure of the A- and L-cell Secretory Granules.- G. Glicentin and Glucagon Biosynthesis.- H. Circulating Gut GLIs.- I. Radioimmunoassay of Gut GLI.- II. Factors Controlling Gut GLI Release.- III. Circulating Forms of Gut GLI.- IV. Circulating Gut GLI Levels in Adult Humans.- V. Circulating Gut GLI Levels in the Perinatal Period.- J. Effects of Gut GLIs.- I. Postulated Effects.- II. Effects of Partially Purified Gut GLIs.- III. Effects of Pure Gut GLIs.- 1. Synthetic Peptides.- 2. Oxyntomodulin.- 3. Glicentin.- K. Discussion.- I. Clinical Significance of Circulating Gut GLIs.- II. Structure-Function Relationships of Gut GLIs.- III. Role of Gut GLIs.- References.- Production and Assay of Glucagon.- 8 Glucagon Preparations.- A. Introduction.- B. Production.- C. Pharmaceutical Preparations.- D. Assays.- I. Physicochemical Methods.- 1. Ultraviolet Absorption.- 2. Electrophoretic Methods.- 3. Chromatographic Methods.- 4. High Pressure Liquid Chromatography.- II. Bioassay Methods.- B. Stability.- C. Timing of Action.- References.- 9 The Immunogenicity of Glucagon.- A. Introduction.- B. Immunogenicity of Glucagon and Glucagon Fragments.- I. Species Used for Immunization.- II. Immunogen.- 1. Glucagon.- 2. Glucagon Fragments.- 3. Coupling Procedures.- 4. Mode of Administration, Dose, Frequency, Adjuvant.- C. Characterization of the Glucagon Antibodies.- I. Affinity and Capacity.- II. Specificity.- 1. Reactivity with Glicentin, Gut GLIs, and Glucagon Analogs.- 2. Reactivity with Glucagon Fragments.- D. Purification of Mixtures of Glucagon Antibodies.- E. Summary.- I. Production of COOH-Terminal Specific Antibodies.- II. Production of NH2-Terminal Specific Antibodies Giving Linear Dilution Curves with Gut GLI.- References.- 10 Immunoassays for Glucagon.- A. Introduction.- B. Method of Radioimmunoassay.- I. Sources of Peptides.- II. Preparation and Purification of Radiolabeled Ligand.- III. Preparation of Standard.- IV. Production and Characterization of Antisera.- 1. Antigenic Determinants and Coupling Procedures.- 2. Immunization Procedure.- 3. Characterization of Antisera.- V. Assay Procedure.- C. Measurement of Glucagon-Related Peptides.- I. Collection and Processing of Plasma.- II. Contribution of Different Species to Plasma Levels.- D. Summary.- References.- 11 Heterogeneity of Circulating Glucagon and Glucagon-Like Immunoreactivity.- A. Introduction.- B. Types of Glucagon Antibodies.- I. COOH Terminal-Specific..- II. NH2 Terminal-Specific.- C. Plasma COOH Terminal-Specific Antibody-Reacting Components...- I. Plasma IRG Components in the Normal Adult.- 1. Basal State.- 2. After Intravenous Arginine Administration.- 3. After Glucose Administration.- II. Plasma IRG Components in the Neonatal Period.- III.Plasma IRG in Pathologic States.- 1. Glucagonoma.- 2. Diabetes.- 3. Pancreatectomy.- 4. Chronic Hypoglycemia.- 5. Renal Failure.- 6. Cirrhosis of the Liver.- 7. Other Conditions.- IV. Origin of Plasma IRG Components.- D. Plasma GLI Components.- I. Basal State and During Glucose Absorption.- 1. Normal Humans.- 2. Normal Dogs.- 3. Nephrectomized Dogs.- II. Origin of Plasma GLI Components.- E. Concluding Remarks.- References.- 12 Radioreceptorassays for Glucagon.- A. Introduction.- B. Glucagon Radioreceptorassay Methodology.- I. Receptor Preparations.- 1. Isolated Cells.- 2. Isolated Membranes.- II. Radioactive Glucagon.- III. Incubation Conditions.- 1. Temperature and Incubation Time.- 2. Reagent Volumes.- 3. Assay Buffer.- 4. Degradation.- 5. Plasma Effects.- 6. Separation.- C. Performance and Applications of the Glucagon Radioreceptorassay.- I. Requirements for Ligand-Receptor Interaction.- 1. Coupling of Binding to Biologic Activity.- 2. Specificity of the Receptor.- II. Applications.- 1. Assay of Gut Peptides.- 2. Assay of Pancreatic Peptides.- 3. Glucagonomas.- References.- Actions of Glucagon.- 13 The Actions of Glucagon at Its Receptor: Regulation of Adenylate Cyclase.- A. Introduction.- B. Characteristics of Hormone-Sensitive Adenylate Cyclase Systems.- I. Role of GTP in Hormone Action.- II. Specificity for Guanine Nucleotides.- III. Effects of Adenosine.- IV. Role of GTPase.- V. Actions of Cholera Toxin.- VI. Actions of Guanine Nucleotides on Hormone Receptors.....- VII. Effects of GTP on Hormone Binding Versus Action.- VIII. Multiple Sites of GTP Action.- IX. Characteristics of the N Unit.- X. Independent Complexes of N with R and C.- XI. Characteristics of the Catalytic Unit.- XII. Regulation by Divalent Cations.- XIII. The Role of Sulfhydryl Groups in Transduction.- XIV. The Role of Membrane Lipids.- XV. Desensitization of Glucagon Action.- XVI. Relationship Between Glucagon Binding and Action.- C. The Glucagon Receptor.- D. Target Analysis of the Glucagon-Sensitive Adenylate Cyclase System.- E. A Model for Glucagon Action.- F. The Glucagon "Message".- G. Summary and Conclusions.- References.- 14 Glucagon and Liver Glycogen Metabolism.- A. Glucagon, Glycogenolysis, and Glucose Output.- B. The Enzymes Involved in Hepatic Glycogen Metabolism.- I. The General Pathways.- II. The Regulated Enzymes.- 1. Protein Kinases.- 2. Protein Phosphatases.- B. The Enzymic Mechanism of Glucagon Action.- I. Glucagon Causes Glycogenolysis via Phosphorylase a.- 1. Facts.- 2. Questions.- II. Glycogenolysis Mediated by cAMP.- 1. Activation of the Glycogenolytic Cascade.- 2. An Effect of cAMP on Phosphorylase Phosphatase.- III. Can Glucagon Act in a cAMP-Independent Way?.- IV. Glucagon also Causes Inactivation of Glycogen Synthase.- D. Expression and Modulation of Glucagon Action.- I. Regulation of Hepatic Glycogen Metabolism by Glucagon.- II. Modulation of the Response to Glucagon.- 1. Effects of Insulin and Glucose.- 2. Glucocorticoid Hormones.- References.- 15 Glucagon and Gluconeogenesis.- A. Introduction.- B. Sites of Action of Glucagon on Hepatic Gluconeogenesis.- I. Action on Mitochondrial Sites.- 1. Pyruvate Carboxylase.- 2. Pyruvate Dehydrogenase.- II. Action on Extramitochondrial Sites.- 1. Phosphoenolpyruvate-Pyruvate Substrate Cycle.- 2. Fructose-6-phosphate-Fructose-l,6-bisphosphate Substrate Cycle 333 III. Other Possible Sites of Glucagon Action.- C.Summary and Overview.- References.- 16 Glucagon and Liver Glucose Output In Vivo.- A. Introduction.- B. Effects of Glucagon on Hepatic Glucose Production.- I. Glycogenolysis.- II. Gluconeogenesis.- C. Glucagon-Insulin Interaction in the Regulation of Hepatic Glucose Production.- I. Glycogenolysis.- II. Gluconeogenesis.- D. Role of Glucagon in the Regulation of Glucose Homeostasis.- I. Feasting.- II. Fasting.- III. Exercise.- IV. Diabetes Mellitus.- References.- 17 Glucagon and Ketogenesis.- A. Introduction.- B. Intrahepatic Factors in the Regulation of Ketogenesis.- C. Emergence of a Ketogenic Role for Glucagon.- I. Studies in Animals.- II. Studies in Humans.- D. Interactions of Insulin and Glucagon on Hepatic Metabolism....- I. The "Fed to Fasted" Transition.- II. The "Fasted to Fed" Transition.- E. Overview.- References.- 18 Glucagon and Amino Acid Metabolism.- A. Introduction.- B. Effects of Glucagon on Amino Acid Levels.- C. Glucagon and Liver Amino Acid Metabolism.- D. Glucagon and Muscle Amino Acid Metabolism.- E. Physiologic and Pathologic States in Which Glucagon Affects Amino Acid Metabolism.- I. Glucagon Deficiency.- II. Glucagon Excess.- 1. Diabetes Mellitus.- 2. Glucagonoma.- 3. Trauma and Sepsis.- F. Summary.- References.- 19 Glucagon and Adipose Tissue Lipolysis.- A. Introduction.- B. Glucagon and Adipose Tissue.- I. Species Variations in Glucagon-Induced Lipolysis.- II. Mechanisms Involved in the Lipolytic Action of Glucagon....- II. Glucagon-Induced Lipolysis and Glucose Metabolism in the Adipocyte.- III. Factors Affecting Glucagon-Induced Adipose Tissue Lipolysis...- 1. Size of the Adipocytes, Age and Nutritional Status of the Animals.- 2. Innervation of the Adipose Tissue.- 3. Hypophysectomy, Adrenalectomy, Hypothyroidism.- 4. Insulin.- 5. Prostaglandins and Prostaglandin Synthesis Inhibitors.....- 6. Other Factors.- V. Glucagon-Like Peptides and Adipose Tissue Lipolysis.- VI. Brown Adipose Tissue and Nonshivering Thermogenesis.....- VII. Adipose Tissue Lipoprotein Lipase Activity.- C. Glucagon and Circulating Free Fatty Acids.- I. Intravenous, Subcutaneous, or Intramuscular Injection of High Doses of Glucagon in Mammals.- 1. The Early Rise in Plasma FFA.- 2. The Secondary Drop in Plasma FFA.- 3. The Late Increase in Plasma FFA.- II. Intraarterial, Intravenous, or Intraportal Infusion of Low Doses of Glucagon in Mammals.- III. Intravenous Injection or Infusion of Glucagon in Birds.- D. Physiologic Importance of Glucagon-Induced Lipolysis.- I. Fasting.- II. Muscular Exercise.- III. Adaptation to Extrauterine Life.- References.- 20 Glucagon and Lipoprotein Metabolism.- A. Introduction.- B. Glucagon Effects on Liver Lipid Metabolism.- C. Metabolic Effects of Glucagon In Vivo.- References.- 21 Glucagon and Liver Regeneration.- A. Nature of Liver Regeneration.- I. Phenomenology.- 1. Key Questions.- 2. Background.- 3. Kinetic Aspects.- II. The Endocrine Hypothesis.- 1. Concerted Control by Peptide Hormones.- 2. Interactions with Nutrients.- 3. Two Sequential Rate-Limiting Events.- B. Regulatory Evidence.- I. Direct.- II. Indirect.- C. Physiology.- I. Extrahepatic.- 1. Bloodstream.- 2. Responsive Tissues.- II. Hepatic.- 1. Hepatocytes.- 2. Nonparenchymal Cells.- III. Specificity.- 1. Mimetics.- 2. Nonhepatocyte Targets.- D. Mechanisms of Action.- I. Potentiation of Signal 2.- 1. Kinetic Evidence.- 2. Synergisms with Other Peptide Hormones.- 3. Nonrequirement of Glucocorticoids.- II. Molecular.- 1. cAMP-Dependent.- 2. cAMP-Independent.- III. Functional Linkages.- 1. Na+ Gradient-Dependent Amino Acid Cotransport.- 2. Altered Hepatocyte Lipid Metabolism.- 3. Deoxyribonucleoside Triphosphate Production.- IV. Inhibitory Aspects.- 1. Hepatocyte Loci.- 2. Desynchronization of Diurnal Rhythms.- E. Future Goals.- I. Role of Other Factors.- 1. High Molecular Weight Glucagon.- 2. Intrahepatic Loci.- II. Additional Problems.- 1. Complexity of Animal Cell Regulatory Processes.- 2. Limitations of Current Experimental Models.- III. Reasons for Optimism.- F. Summary.- References.- 22 Glucagon and Insulin Secretion.- A. Introduction and Historical Overview.- B. Experimental Stimulation of Insulin Secretion by Glucagon in Vivo and In Vitro.- I. Effect of Food and Fasting.- II. Adrenergic Effects.- III. Insulinotropic Effect of Glucagon in Disease.- IV. Insulinotropic Effect of Glucagon in the Child, Neonate, and Fetus.- V. Mechanism of Insulinotropic Effect of Glucagon.- C. Consideration of the Evidence for the Endogenous Insulinotropic Effect of Glucagon.- I. Inherent Difficulties in Testing the Hypothesis.- II. Anatomy of the Islets of Langerhans.- III. Dynamic and Magnitudinal Changes in Glucagon and Insulin After Secretagogue Administration.- IV. Augmentation of Insulin Secretion by Protein and/or Fat Meals. 497 V. Active and Passive Immunization.- VI. Diabetes Mellitus.- VII. Glucagonoma-Induced Hyperglucagonemia and Hyperinsulinemia 498 VIII. Evidence Against an Insulinotropic Effect of Endogenous Glucagon.- D. Potential Physiologic and Pathologic Significance of the Insulinotropic Effect of Glucagon.- E. Effect of Insulin on Glucagon Secretion.- I. Effect of Exogenous Insulin on Glucagon Release in Vivo.- II.Effect of endogenous Insulin on Glucagon Release in Vivo.- III. Effect of Exogenous Insulin on Glucagon Secretion in Vitro.- IV. Mechanism of the Glucagonsuppressive Effect of Insulin.- F. Evidence For and Against an Intraislet Negative Insulin-Glucagon Feedback.- G. New Hypotheses and Concepts in Local Intraislet Regulation of A- and B-cells.- I. Compartmentalization: Systemic Versus Local Intraislet Effects.- II. The Principle of Uncertainty in Studies of Local Islet Interactions.- III. Possible Paracrine Effects on Growth and Differentiation.- H. Synopsis and Conclusions.- References.