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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.