Glucagon

著者

• Lefèbvre, P. J. (Pierre J.)

書誌事項

Glucagon

editor, P.J. Lefèbvre

（Handbook of experimental pharmacology, v. 66, 123）

Springer-Verlag, 1983-

• part 1 : us
• part 2 : us
• part 1 : gw
• part 2 : gw
• 3

注記

Includes bibliographies and index

内容説明・目次

巻冊次

part 1 : gw ISBN 9783540120681

内容説明

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.

目次

• 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.

巻冊次

part 2 : gw ISBN 9783540122722

目次

• Control of Glucagon Secretion.- 23 Glucose in the Control of Glucagon Secretion.- A. Introduction.- B. Effect of Changes in Extracellular Glucose Concentration on Glucagon Secretion.- I. Increases in Extracellular Glucose Concentration.- 1. In Vivo Studies.- 2. In Vitro Studies.- II. Decreases in Extracellular Glucose Concentration.- 1. In Vivo Studies.- 2. In Vitro Studies.- C. Mechanism of Glucose Action on A-cell Function.- I. A-cell Glucose Metabolism.- II. Effects of Glucose Metabolites and Inhibitors of Glucose Metabolism.- III. Evidence for a Glucoreceptor Mechanism not Involving Metabolism.- IV. Calcium-Potassium and Glucose Action.- V. Mechanism for A-cell Response to Hypoglycemia.- 1. General Considerations.- 2. Sympathetic and Parasympathetic Modulation.- D. Modulatory Effects of Glucose on A-cell Function.- I. Acute Effects.- II. Prolonged and Chronic Effects.- References.- 24 The Amino Acid-Induced Secretion of Glucagon.- A. Introduction.- B. Phenomenology.- I. In Vitro.- 1. Isolated Perfused Pancreas.- 2. Pancreatic Fragments, Islets and Islet Cells.- 3. Gastric A-cells In Vitro.- 4. Other Tissues.- II. In Vivo.- 1. Human Studies.- 2. Studies in Normal Dogs.- 3. Other Studies.- C. Mechanism of Amino Acid-Induced Glucagon Release.- I. Contribution of the Microtubular-Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Potassium and Glucose Action.- V. Mechanism for A-cell Response to Hypoglycemia.- 1. General Considerations.- 2. Sympathetic and Parasympathetic Modulation.- D. Modulatory Effects of Glucose on A-cell Function.- I. Acute Effects.- II. Prolonged and Chronic Effects.- References.- 24 The Amino Acid-Induced Secretion of Glucagon.- A. Introduction.- B. Phenomenology.- I. In Vitro.- 1. Isolated Perfused Pancreas.- 2. Pancreatic Fragments, Islets and Islet Cells.- 3. Gastric A-cells In Vitro.- 4. Other Tissues.- II. In Vivo.- 1. Human Studies.- 2. Studies in Normal Dogs.- 3. Other Studies.- C. Mechanism of Amino Acid-Induced Glucagon Release.- I. Contribution of the Microtubular-Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Potassium Pump.- IV. Ammonium.- E. Anions.- F. Conclusions.- References.- 27 Cyclic Nucleotides in the Control of Glucagon Secretion.- A. Introduction.- B. Effects of Exogenous Cyclic AMP.- C. Effects of Phosphodiesterase Inhibitors.- D. Effects of Agents Thought to Act via Endogenous Cyclic AMP.- E. Conclusions..- References.- 28 Prostaglandins and Glucagon Secretion.- A. Introduction.- I. Origin and Metabolism of Prostaglandins.- II. Prostaglandins as Local or Intracellular Messengers.- III. Methodological Considerations.- B. Studies In Vitro on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- II. Role of Endogenous Prostaglandins.- 1. Prostaglandin Biosynthesis by Islet Tissue.- 2. Endogenous Prostaglandins and Glucagon Secretion In Vitro.- C. Studies In Vivo on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- 1. Rats.- 2. Dogs.- 3. Humans.- II. Role of Endogenous Prostaglandins.- D. Summary and Conclusions.- References.- 29 Hormones in the Control of Glucagon Secretion.- A. Introduction.- B. Thyroid Hormones.- C. Calcium-Regulating Hormones.- I. Parathyroid Hormone.- II. Calcitonin.- III. Vitamin D.- D. Steroid Hormones.- I. Glucocorticoids.- II. Mineralocorticoids.- III. Sex Steroids.- E. Placental Hormones.- F. Gastrointestinal Hormones.- I. Gastric Inhibitory Polypeptide.- II. Vasoactive Intestinal Peptide.- III. Secretin.- IV. Porcine Intestinal Heptacosapeptide.- V. Bombesin.- VI. Cholecystokinin.- VII. Gastrin.- VIII. Cerulein.- IX. Motilin.- G. Pituitary Hormones.- I. Growth Hormone.- II. Adrenocorticotropic Hormone.- III. Endorphins and Enkephalins.- H. Hypothalamic Hormones.- I. Hypothalamic Lesions.- II. Substance P and Neurotensin.- III. Unidentified Polypeptides.- J. Conclusions.- References.- 30 Neural Control of Glucagon Secretion.- A. Introduction.- B. Anatomic Observations.- I. Neural Pathways.- II. Species Variations.- C. Experimental Observations.- I. Central Nervous System Studies.- II. Nerve Stimulation and Sectioning Studies.- III. Infusion Studies.- D. Physiologic and Pathophysiologic Observations.- E. Neural Control of Gastric Glucagon.- F. Conclusions.- References.- 31 Intraislet Insulin-Glucagon-Somatostatin Relationships.- A. Introduction.- B. Overview of Islet Anatomy.- C. General Mechanisms of Communication Between Cells.- D. Potential Interactions Within Islets.- I. Potential Interactions Between Cells.- 1. Basic Scheme.- 2. Effect of Glucagon Upon B- and D-cells.- 3. Effect of Somatostatin Upon A- und B-cells.- 4. Effect of Insulin Upon A- and D-cells.- 5. Pancreatic Polypeptide as an Ignored Entity and Why.- 6. Other Potential Islet Mediators.- II. Neural Control.- 1. Cholinergic Agonism.- 2. Adrenergic Agonism.- 3. Local Presynaptic Autonomic Regulation.- 4. Peptidergic and Purinergic Regulation.- III. Potential Role of Gap Junctions as Determinants of Coordination Between Islet Cells.- E. Anatomic Determinants of Islet Regulation.- F. Indirect Experimental Evidence for Interaction Between Islet Cells.- G. Efforts to Demonstrate Local Interactions Directly with Immune Neutralization.- H. Arguments Against Islet Interactions.- J. Oscillation of Secretion Suggesting Coordination Between Islets.- K. Consideration of an Islet-Acinar Portal System.- L. Islet Interrelationships in Diabetes.- M. Overview and Conclusions.- References.- 32 Pharmacologic Compounds Affecting Glucagon Secretion.- A. Introduction.- B. Drugs Used in the Treatment of Diabetes.- I. Insulin.- II. Sulfonylureas.- III. Biguanides.- C. Drugs Related to the Cholinergic System.- D. Drugs Related to the Sympathetic Nervous System.- I. Reserpine.- II. Beta-Adrenergic Blocking Agents.- III. Alpha-Adrenergic Blocking Agents.- IV. Clonidine.- V. L-Dopa, Dopamine, and Bromocriptine.- VI. Diazoxide and Tolmesoxide.- E. Serotonin and Serotonin Antagonists.- F. Drugs Affecting Ionic Concentrations and/or Fluxes.- I. Calcium, Calcitonin, and Vitamin D.- II. Verapamil and Procaine.- III. Veratridine, Ouabain, and Hydroquinidine.- G. Drugs Affecting Lipid Metabolism.- H. Drugs Acting on the Central Nervous System.- I. Diphenylhydantoin, Diazepam, and Haloperidol.- II. Morphine, Endorphins, and Enkephalins.- J. Hormonal Steroids.- I. Glucocorticoids.- II. Contraceptive Steroids.- K. Drugs Affecting the Mitotic Spindle.- L. Somatostatin and Somatostatin Analogs.- References.- Extrapancreatic Glucagon.- 33 Extrapancreatic Glucagon and Its Regulation.- A. Introduction.- B. Extrapancreatic Glucagon in the Canine Stomach.- I. Presence of A-cells.- II. Presence of Glucagon.- III. Control of Gastric Glucagon Release In Vitro.- 1. Role of Glucose and Insulin.- 2. Stimulation by Arginine.- 3. Role of the Autonomic Nervous System.- 4. Possible Role of Prostaglandins.- IV. Secretion of Gastric Glucagon In Vivo.- V. Physiologic and Pathophysiologic Relevance of Extrapancreatic Glucagon.- C. Gastrointestinal Glucagon in Other Animal Species.- D. Glucagon and the Salivary Glands.- E. Other Extrapancreatic Localizations of Glucagon.- F. In Vivo Generation of Glucagon from Glucagon-Like Immunoreactive Peptides.- G. Extrapancreatic Glucagon in Humans.- H. Conclusions.- References.- Glucagon in Various Physiological Conditions.- 34 Glucagon and Starvation.- A. Introduction.- B. The Postabsorptive State.- C. Glucoregulatory Hormones in Starvation.- D. Metabolic Alterations in Starvation.- I. The Early Phase.- II. Prolonged Starvation.- E. Summary and Conclusions.- References.- 35 Glucagon and Pregnancy.- A. Introduction.- I. Impaired Glucose Tolerance in Pregnancy.- II. Metabolic Adaptations to Pregnancy.- B. Plasma Glucagon in the Fasted State.- I. Changes After Overnight Fasting.- II. Changes After Prolonged Fasting and Insulin-Induced Hypoglycemia.- III. Placental Transfer of Glucagon and Morphology of A-cells in Pregnancy.- C. Plasma Glucagon in the Fed State.- I. Response to Glucose Administration.- II. Response to Amino Acids.- III. Response to Mixed Meals.- D. Summary and Conclusions.- References.- 36 Glucagon in the Fetus and the Newborn.- A. Introduction.- B. Ontogenesis of Glucagon in Pancreas and Plasma.- I. Rat.- II. Rabbit.- III. Sheep.- IV. Human.- C. Glucagon Secretion in the Fetus.- I. Impermeability of the Placenta to Glucagon.- II. Control of Glucagon Secretion in the Fetus.- 1. Changes in Glucose Concentration.- 2. Effects of Amino Acids.- 3. Effects of Neurotransmitters.- 4. Effects of Hypoxia.- 5. Prolonged Pregnancy.- D. Glucagon Secretion in the Newborn.- I. Evidence for a Role of the Sympathetic Nervous System in the Neonatal Surge of Glucagon.- II. Glucagon Secretion in Newborn Infants of Diabetic Mothers.- III. Glucagon Secretion During the Suckling Period.- IV. Glucagon Secretion During the Weaning Period.- E. Metabolic Effects of Glucagon.- I. In the Fetus.- II. In the Neonate.- III. During the Suckling Period.- IV. During the Weaning Period.- F. Glucagon Receptors in the Perinatal Period.- References.- 37 Glucagon as a Counterregulatory Hormone.- A. Glucose Counterregulation, an Overview.- B. Glucagon in the Prevention of Hypoglycemia.- I. The Postabsorptive State.- II. The Intraprandial State.- C. Glucagon in the Restoration of Normoglycemia.- D. Glucagon and the Somoygi Phenomenon.- E. Summary.- References.- 38 Glucagon and Its Relationship to Other Glucoregulatory Hormones in Exercise and Stress in Normal and Diabetic Subjects.- A. Introduction.- B. Exercise.- I. Metabolic Events During Exercise.- II. Fuel Sources During Exercise.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Changes During Exercise.- IV. Hormonal Interactions in the Control of Glucoregulation During Exercise.- 1. Role of Insulin.- 2. Role of Catecholamines.- 3. Role of Glucagon.- V. The Response to Exercise in Diabetic Subjects.- 1. Exercise in Insulin-Dependent Diabetics.- 2. Exercise in Noninsulin-Dependent Diabetics.- C. Stress.- I. Hormonal Response to Stress.- II. Major Changes in Fuels or Energy Substrate During Stress.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Interactions in Glucoregulation During Stress.- 1. Pathologic Stress States.- 2. Experimental Stress Models.- 3. Glucagon-Insulin Interactions in Glucoregulation and the Diabetogenic Role of Glucagon.- 4. Glucagon-Insulin-Epinephrine Interactions in Glucoregulation.- 5. Hormonal Regulation of "Futile Cycling"Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Potassium Pump.- IV. Ammonium.- E. Anions.- F. Conclusions.- References.- 27 Cyclic Nucleotides in the Control of Glucagon Secretion.- A. Introduction.- B. Effects of Exogenous Cyclic AMP.- C. Effects of Phosphodiesterase Inhibitors.- D. Effects of Agents Thought to Act via Endogenous Cyclic AMP.- E. Conclusions..- References.- 28 Prostaglandins and Glucagon Secretion.- A. Introduction.- I. Origin and Metabolism of Prostaglandins.- II. Prostaglandins as Local or Intracellular Messengers.- III. Methodological Considerations.- B. Studies In Vitro on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- II. Role of Endogenous Prostaglandins.- 1. Prostaglandin Biosynthesis by Islet Tissue.- 2. Endogenous Prostaglandins and Glucagon Secretion In Vitro.- C. Studies In Vivo on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- 1. Rats.- 2. Dogs.- 3. Humans.- II. Role of Endogenous Prostaglandins.- D. Summary and Conclusions.- References.- 29 Hormones in the Control of Glucagon Secretion.- A. Introduction.- B. Thyroid Hormones.- C. Calcium-Regulating Hormones.- I. Parathyroid Hormone.- II. Calcitonin.- III. Vitamin D.- D. Steroid Hormones.- I. Glucocorticoids.- II. Mineralocorticoids.- III. Sex Steroids.- E. Placental Hormones.- F. Gastrointestinal Hormones.- I. Gastric Inhibitory Polypeptide.- II. Vasoactive Intestinal Peptide.- III. Secretin.- IV. Porcine Intestinal Heptacosapeptide.- V. Bombesin.- VI. Cholecystokinin.- VII. Gastrin.- VIII. Cerulein.- IX. Motilin.- G. Pituitary Hormones.- I. Growth Hormone.- II. Adrenocorticotropic Hormone.- III. Endorphins and Enkephalins.- H. Hypothalamic Hormones.- I. Hypothalamic Lesions.- II. Substance P and Neurotensin.- III. Unidentified Polypeptides.- J. Conclusions.- References.- 30 Neural Control of Glucagon Secretion.- A. Introduction.- B. Anatomic Observations.- I. Neural Pathways.- II. Species Variations.- C. Experimental Observations.- I. Central Nervous System Studies.- II. Nerve Stimulation and Sectioning Studies.- III. Infusion Studies.- D. Physiologic and Pathophysiologic Observations.- E. Neural Control of Gastric Glucagon.- F. Conclusions.- References.- 31 Intraislet Insulin-Glucagon-Somatostatin Relationships.- A. Introduction.- B. Overview of Islet Anatomy.- C. General Mechanisms of Communication Between Cells.- D. Potential Interactions Within Islets.- I. Potential Interactions Between Cells.- 1. Basic Scheme.- 2. Effect of Glucagon Upon B- and D-cells.- 3. Effect of Somatostatin Upon A- und B-cells.- 4. Effect of Insulin Upon A- and D-cells.- 5. Pancreatic Polypeptide as an Ignored Entity and Why.- 6. Other Potential Islet Mediators.- II. Neural Control.- 1. Cholinergic Agonism.- 2. Adrenergic Agonism.- 3. Local Presynaptic Autonomic Regulation.- 4. Peptidergic and Purinergic Regulation.- III. Potential Role of Gap Junctions as Determinants of Coordination Between Islet Cells.- E. Anatomic Determinants of Islet Regulation.- F. Indirect Experimental Evidence for Interaction Between Islet Cells.- G. Efforts to Demonstrate Local Interactions Directly with Immune Neutralization.- H. Arguments Against Islet Interactions.- J. Oscillation of Secretion Suggesting Coordination Between Islets.- K. Consideration of an Islet-Acinar Portal System.- L. Islet Interrelationships in Diabetes.- M. Overview and Conclusions.- References.- 32 Pharmacologic Compounds Affecting Glucagon Secretion.- A. Introduction.- B. Drugs Used in the Treatment of Diabetes.- I. Insulin.- II. Sulfonylureas.- III. Biguanides.- C. Drugs Related to the Cholinergic System.- D. Drugs Related to the Sympathetic Nervous System.- I. Reserpine.- II. Beta-Adrenergic Blocking Agents.- III. Alpha-Adrenergic Blocking Agents.- IV. Clonidine.- V. L-Dopa, Dopamine, and Bromocriptine.- VI. Diazoxide and Tolmesoxide.- E. Serotonin and Serotonin Antagonists.- F. Drugs Affecting Ionic Concentrations and/or Fluxes.- I. Calcium, Calcitonin, and Vitamin D.- II. Verapamil and Procaine.- III. Veratridine, Ouabain, and Hydroquinidine.- G. Drugs Affecting Lipid Metabolism.- H. Drugs Acting on the Central Nervous System.- I. Diphenylhydantoin, Diazepam, and Haloperidol.- II. Morphine, Endorphins, and Enkephalins.- J. Hormonal Steroids.- I. Glucocorticoids.- II. Contraceptive Steroids.- K. Drugs Affecting the Mitotic Spindle.- L. Somatostatin and Somatostatin Analogs.- References.- Extrapancreatic Glucagon.- 33 Extrapancreatic Glucagon and Its Regulation.- A. Introduction.- B. Extrapancreatic Glucagon in the Canine Stomach.- I. Presence of A-cells.- II. Presence of Glucagon.- III. Control of Gastric Glucagon Release In Vitro.- 1. Role of Glucose and Insulin.- 2. Stimulation by Arginine.- 3. Role of the Autonomic Nervous System.- 4. Possible Role of Prostaglandins.- IV. Secretion of Gastric Glucagon In Vivo.- V. Physiologic and Pathophysiologic Relevance of Extrapancreatic Glucagon.- C. Gastrointestinal Glucagon in Other Animal Species.- D. Glucagon and the Salivary Glands.- E. Other Extrapancreatic Localizations of Glucagon.- F. In Vivo Generation of Glucagon from Glucagon-Like Immunoreactive Peptides.- G. Extrapancreatic Glucagon in Humans.- H. Conclusions.- References.- Glucagon in Various Physiological Conditions.- 34 Glucagon and Starvation.- A. Introduction.- B. The Postabsorptive State.- C. Glucoregulatory Hormones in Starvation.- D. Metabolic Alterations in Starvation.- I. The Early Phase.- II. Prolonged Starvation.- E. Summary and Conclusions.- References.- 35 Glucagon and Pregnancy.- A. Introduction.- I. Impaired Glucose Tolerance in Pregnancy.- II. Metabolic Adaptations to Pregnancy.- B. Plasma Glucagon in the Fasted State.- I. Changes After Overnight Fasting.- II. Changes After Prolonged Fasting and Insulin-Induced Hypoglycemia.- III. Placental Transfer of Glucagon and Morphology of A-cells in Pregnancy.- C. Plasma Glucagon in the Fed State.- I. Response to Glucose Administration.- II. Response to Amino Acids.- III. Response to Mixed Meals.- D. Summary and Conclusions.- References.- 36 Glucagon in the Fetus and the Newborn.- A. Introduction.- B. Ontogenesis of Glucagon in Pancreas and Plasma.- I. Rat.- II. Rabbit.- III. Sheep.- IV. Human.- C. Glucagon Secretion in the Fetus.- I. Impermeability of the Placenta to Glucagon.- II. Control of Glucagon Secretion in the Fetus.- 1. Changes in Glucose Concentration.- 2. Effects of Amino Acids.- 3. Effects of Neurotransmitters.- 4. Effects of Hypoxia.- 5. Prolonged Pregnancy.- D. Glucagon Secretion in the Newborn.- I. Evidence for a Role of the Sympathetic Nervous System in the Neonatal Surge of Glucagon.- II. Glucagon Secretion in Newborn Infants of Diabetic Mothers.- III. Glucagon Secretion During the Suckling Period.- IV. Glucagon Secretion During the Weaning Period.- E. Metabolic Effects of Glucagon.- I. In the Fetus.- II. In the Neonate.- III. During the Suckling Period.- IV. During the Weaning Period.- F. Glucagon Receptors in the Perinatal Period.- References.- 37 Glucagon as a Counterregulatory Hormone.- A. Glucose Counterregulation, an Overview.- B. Glucagon in the Prevention of Hypoglycemia.- I. The Postabsorptive State.- II. The Intraprandial State.- C. Glucagon in the Restoration of Normoglycemia.- D. Glucagon and the Somoygi Phenomenon.- E. Summary.- References.- 38 Glucagon and Its Relationship to Other Glucoregulatory Hormones in Exercise and Stress in Normal and Diabetic Subjects.- A. Introduction.- B. Exercise.- I. Metabolic Events During Exercise.- II. Fuel Sources During Exercise.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Changes During Exercise.- IV. Hormonal Interactions in the Control of Glucoregulation During Exercise.- 1. Role of Insulin.- 2. Role of Catecholamines.- 3. Role of Glucagon.- V. The Response to Exercise in Diabetic Subjects.- 1. Exercise in Insulin-Dependent Diabetics.- 2. Exercise in Noninsulin-Dependent Diabetics.- C. Stress.- I. Hormonal Response to Stress.- II. Major Changes in Fuels or Energy Substrate During Stress.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Interactions in Glucoregulation During Stress.- 1. Pathologic Stress States.- 2. Experimental Stress Models.- 3. Glucagon-Insulin Interactions in Glucoregulation and the Diabetogenic Role of Glucagon.- 4. Glucagon-Insulin-Epinephrine Interactions in Glucoregulation.- 5. Hormonal Regulation of "Futile Cycling" in the Liver.- D. Summary.- References.- Catabolism of Glucagon.- 39 The Metabolic Clearance Rate of Glucagon.- A. Introduction.- B. Principles of Measurement.- C. Glucagon Metabolic Clearance Rate in Laboratory Animals.- D. Glucagon Metabolic Clearance Rate in Humans.- E. Organ Contribution to Overall Glucagon Metabolic Clearance Rate.- F. Plasma Half-Life.- G. Summary and Conclusions.- References.- 40 Hepatic Handling of Glucagon.- A. Introduction.- B. Evidence for Glucagon Extraction by the Liver.- I. In Vitro Studies.- II. Relationship Between Portal and Peripheral Vein Glucagon Levels.- III. Studies in Subjects with Portacaval Shunts.- IV. Direct Measurement of Basal Hepatic Extraction of Glucagon.- V. Effect of Glucagon Heterogeneity on Hepatic Glucagon Extraction Rate.- VI. Relationship Between Hepatic Extraction of Glucagon and Insulin.- C. Factors Regulating Hepatic Extraction of Glucagon.- I. Changes in Splanchnic Blood Flow.- II. Anesthesia and Laparotomy.- III. Changes in Portal Vein Glucagon Concentration.- 1. Increased Amount of Glucagon Presented to the Liver.- 2. Decreased Amount of Glucagon Presented to the Liver.- IV. Partial Hepatectomy.- D. Relationship Between Net Hepatic Glucose Output and Glucagon and Insulin.- I. Peripheral Vein Insulin: Glucagon Molar Ratio.- II. Portal Vein Insulin: Glucagon Molar Ratio.- III. Molar Ratio of Insulin and Glucagon Extracted by the Liver.- E. Fate of Glucagon Extracted by the Liver.- F. Conclusions.- References.- 41 The Renal Handling of Glucagon.- A. Introduction.- B. Kidney Glucagon Uptake and Urinary Excretion.- C. Heterogeneity of Plasma Glucagon and Renal Uptake.- D. The Fate of the Glucagon Taken up by the Kidney.- E. Conclusions.- References.- Glucagon in Pathology.- 42 Glucagon Deficiency.- A. Introduction.- B. Chronic Glucagon Deficiency.- I. After Surgical Resection of A-cells.- 1. In Humans.- 2. In Dogs.- 3. In Other Experimental Animals.- II. Idiopathic Chronic Glucagon Deficiency in Neonates.- C. Acute Glucagon Deficiency.- I. After Administration of Anti-Glucagon Sera.- II. After Infusion of Somatostatin.- D. Metabolic Effects of Glucagon Deficiency.- I. On Protein and Amino Acid Metabolism.- II. On Hepatic Glucose Production.- E. Summary and Conclusions.- References.- 43 The Glucagonoma Syndrome.- A. Introduction.- B. Incidence.- I. Age.- II. Sex.- C. Clinical Features.- I. Skin Lesions.- 1. Pathogenesis.- 2. Distribution and Appearance.- 3. Histology.- 4. Differential Diagnosis of Necrolytic Migratory Erythema.- II. Diabetes Mellitus.- III. Anaemia.- IV. Other Features.- D. Biochemical Findings.- I. Plasma Glucagon.- 1. Hyperglucagonaemia: Its Differential Diagnosis.- 2. Glucagon Secretory Patterns.- II. Plasma Insulin.- III. Glucose Tolerance.- IV. Other Peptides Secreted by Glucagonomas.- V. Plasma Amino Acids.- E. Tumour Characteristics.- I. Tumours Associated with the Glucagonoma Syndrome.- 1. Site and Spread.- 2. Light Microscopy.- 3. Immunofluorescence.- 4. Neuron Specific Enolase.- 5. Electron Microscopy.- II. Tumours not Associated with the Glucagonoma Syndrome.- F. Localisation of Tumours.- I. Arteriography.- II. Percutaneous Transhepatic Portal Venous Sampling.- III. Other Techniques.- G. Diagnosis and Treatment.- I. Surgery.- II. Chemotherapy.- III. Antisecretory Therapy.- IV. Hepatic Artery Embolisation.- V. Symptomatic Treatment.- H. Prognosis.- References.- 44 Glucagon in Diabetes Mellitus.- A. A-cell Function in Human Diabetes.- B. Relationships of A-cell Malfunction to Insulin.- C. The Islets in Diabetes: A-cell Relationships Within the Islets.- D. The Effects of Insulin on the A-cell Abnormalities of Type I Diabetics.- E. The Effects of Insulin on A-cell Abnormalities of Type II Diabetics.- F. The Bihormonal Abnormality Hypothesis.- G. The "Glucagon Controversy".- H. Glucagon Suppression as a Therapeutic Adjunct in Diabetes.- References.- 45 Glucagon in Human Endocrine and Exocrine Disorders.- A. Introduction.- B. Human Endocrine Metabolic Disorders.- I. Hypoglycemia.- 1. Hypoglycemia in Infancy and Childhood.- 2. Reactive Hypoglycemia.- 3. Hypoglycemia in Diabetes and in Chronic Pancreatitis.- 4. Glucagon Antibodies.- 5. Beta-Adrenergic Blockade.- II. Hyperglucagonemia.- 1. Glucagonoma.- 2. Nonislet Glucagon-Secreting Tumors.- 3. The Multiple Endocrine Neoplasia.- III. Pheochromocytoma.- IV. Pituitary Interrelationships.- 1. Acromegaly.- 2. Hypopituitarism.- V. Glucagon and the Parathyroid Glands.- 1. Hyperparathyroidism.- 2. Hypoparathyroidism.- VI. Glucagon and Other Endocrine Diseases.- 1. Cushing's Syndrome.- 2. Hyperthyroidism.- 3. Hypothyroidism.- 4. Addison's Disease.- VII. Comment.- C. Glucagon and the Exocrine Pancreas.- I. Interplay with the Islets of Langerhans.- II. Insulin and Glucagon in Pancreatic Exocrine Fluid.- III. Pancreatitis.- References.- 46 Glucagon and Hyperlipoproteinemias.- A. Introduction.- B. The Glucagon-Insulin Environment.- C. Studies in the Zucker Genetic Hyperlipemic Rat.- I. Glucagon Secretion.- II. Glucagon Regulation.- III. Effect of Reduced Glucagon.- IV. Effect of Elevated Insulin.- D. Studies in Human Hyperlipemia.- I. Immunoassayable Glucagon.- II. Hypolipemic Response to Glucagon.- III. Glucagon Structure-Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Potassium Pump.- IV. Ammonium.- E. Anions.- F. Conclusions.- References.- 27 Cyclic Nucleotides in the Control of Glucagon Secretion.- A. Introduction.- B. Effects of Exogenous Cyclic AMP.- C. Effects of Phosphodiesterase Inhibitors.- D. Effects of Agents Thought to Act via Endogenous Cyclic AMP.- E. Conclusions..- References.- 28 Prostaglandins and Glucagon Secretion.- A. Introduction.- I. Origin and Metabolism of Prostaglandins.- II. Prostaglandins as Local or Intracellular Messengers.- III. Methodological Considerations.- B. Studies In Vitro on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- II. Role of Endogenous Prostaglandins.- 1. Prostaglandin Biosynthesis by Islet Tissue.- 2. Endogenous Prostaglandins and Glucagon Secretion In Vitro.- C. Studies In Vivo on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- 1. Rats.- 2. Dogs.- 3. Humans.- II. Role of Endogenous Prostaglandins.- D. Summary and Conclusions.- References.- 29 Hormones in the Control of Glucagon Secretion.- A. Introduction.- B. Thyroid Hormones.- C. Calcium-Regulating Hormones.- I. Parathyroid Hormone.- II. Calcitonin.- III. Vitamin D.- D. Steroid Hormones.- I. Glucocorticoids.- II. Mineralocorticoids.- III. Sex Steroids.- E. Placental Hormones.- F. Gastrointestinal Hormones.- I. Gastric Inhibitory Polypeptide.- II. Vasoactive Intestinal Peptide.- III. Secretin.- IV. Porcine Intestinal Heptacosapeptide.- V. Bombesin.- VI. Cholecystokinin.- VII. Gastrin.- VIII. Cerulein.- IX. Motilin.- G. Pituitary Hormones.- I. Growth Hormone.- II. Adrenocorticotropic Hormone.- III. Endorphins and Enkephalins.- H. Hypothalamic Hormones.- I. Hypothalamic Lesions.- II. Substance P and Neurotensin.- III. Unidentified Polypeptides.- J. Conclusions.- References.- 30 Neural Control of Glucagon Secretion.- A. Introduction.- B. Anatomic Observations.- I. Neural Pathways.- II. Species Variations.- C. Experimental Observations.- I. Central Nervous System Studies.- II. Nerve Stimulation and Sectioning Studies.- III. Infusion Studies.- D. Physiologic and Pathophysiologic Observations.- E. Neural Control of Gastric Glucagon.- F. Conclusions.- References.- 31 Intraislet Insulin-Glucagon-Somatostatin Relationships.- A. Introduction.- B. Overview of Islet Anatomy.- C. General Mechanisms of Communication Between Cells.- D. Potential Interactions Within Islets.- I. Potential Interactions Between Cells.- 1. Basic Scheme.- 2. Effect of Glucagon Upon B- and D-cells.- 3. Effect of Somatostatin Upon A- und B-cells.- 4. Effect of Insulin Upon A- and D-cells.- 5. Pancreatic Polypeptide as an Ignored Entity and Why.- 6. Other Potential Islet Mediators.- II. Neural Control.- 1. Cholinergic Agonism.- 2. Adrenergic Agonism.- 3. Local Presynaptic Autonomic Regulation.- 4. Peptidergic and Purinergic Regulation.- III. Potential Role of Gap Junctions as Determinants of Coordination Between Islet Cells.- E. Anatomic Determinants of Islet Regulation.- F. Indirect Experimental Evidence for Interaction Between Islet Cells.- G. Efforts to Demonstrate Local Interactions Directly with Immune Neutralization.- H. Arguments Against Islet Interactions.- J. Oscillation of Secretion Suggesting Coordination Between Islets.- K. Consideration of an Islet-Acinar Portal System.- L. Islet Interrelationships in Diabetes.- M. Overview and Conclusions.- References.- 32 Pharmacologic Compounds Affecting Glucagon Secretion.- A. Introduction.- B. Drugs Used in the Treatment of Diabetes.- I. Insulin.- II. Sulfonylureas.- III. Biguanides.- C. Drugs Related to the Cholinergic System.- D. Drugs Related to the Sympathetic Nervous System.- I. Reserpine.- II. Beta-Adrenergic Blocking Agents.- III. Alpha-Adrenergic Blocking Agents.- IV. Clonidine.- V. L-Dopa, Dopamine, and Bromocriptine.- VI. Diazoxide and Tolmesoxide.- E. Serotonin and Serotonin Antagonists.- F. Drugs Affecting Ionic Concentrations and/or Fluxes.- I. Calcium, Calcitonin, and Vitamin D.- II. Verapamil and Procaine.- III. Veratridine, Ouabain, and Hydroquinidine.- G. Drugs Affecting Lipid Metabolism.- H. Drugs Acting on the Central Nervous System.- I. Diphenylhydantoin, Diazepam, and Haloperidol.- II. Morphine, Endorphins, and Enkephalins.- J. Hormonal Steroids.- I. Glucocorticoids.- II. Contraceptive Steroids.- K. Drugs Affecting the Mitotic Spindle.- L. Somatostatin and Somatostatin Analogs.- References.- Extrapancreatic Glucagon.- 33 Extrapancreatic Glucagon and Its Regulation.- A. Introduction.- B. Extrapancreatic Glucagon in the Canine Stomach.- I. Presence of A-cells.- II. Presence of Glucagon.- III. Control of Gastric Glucagon Release In Vitro.- 1. Role of Glucose and Insulin.- 2. Stimulation by Arginine.- 3. Role of the Autonomic Nervous System.- 4. Possible Role of Prostaglandins.- IV. Secretion of Gastric Glucagon In Vivo.- V. Physiologic and Pathophysiologic Relevance of Extrapancreatic Glucagon.- C. Gastrointestinal Glucagon in Other Animal Species.- D. Glucagon and the Salivary Glands.- E. Other Extrapancreatic Localizations of Glucagon.- F. In Vivo Generation of Glucagon from Glucagon-Like Immunoreactive Peptides.- G. Extrapancreatic Glucagon in Humans.- H. Conclusions.- References.- Glucagon in Various Physiological Conditions.- 34 Glucagon and Starvation.- A. Introduction.- B. The Postabsorptive State.- C. Glucoregulatory Hormones in Starvation.- D. Metabolic Alterations in Starvation.- I. The Early Phase.- II. Prolonged Starvation.- E. Summary and Conclusions.- References.- 35 Glucagon and Pregnancy.- A. Introduction.- I. Impaired Glucose Tolerance in Pregnancy.- II. Metabolic Adaptations to Pregnancy.- B. Plasma Glucagon in the Fasted State.- I. Changes After Overnight Fasting.- II. Changes After Prolonged Fasting and Insulin-Induced Hypoglycemia.- III. Placental Transfer of Glucagon and Morphology of A-cells in Pregnancy.- C. Plasma Glucagon in the Fed State.- I. Response to Glucose Administration.- II. Response to Amino Acids.- III. Response to Mixed Meals.- D. Summary and Conclusions.- References.- 36 Glucagon in the Fetus and the Newborn.- A. Introduction.- B. Ontogenesis of Glucagon in Pancreas and Plasma.- I. Rat.- II. Rabbit.- III. Sheep.- IV. Human.- C. Glucagon Secretion in the Fetus.- I. Impermeability of the Placenta to Glucagon.- II. Control of Glucagon Secretion in the Fetus.- 1. Changes in Glucose Concentration.- 2. Effects of Amino Acids.- 3. Effects of Neurotransmitters.- 4. Effects of Hypoxia.- 5. Prolonged Pregnancy.- D. Glucagon Secretion in the Newborn.- I. Evidence for a Role of the Sympathetic Nervous System in the Neonatal Surge of Glucagon.- II. Glucagon Secretion in Newborn Infants of Diabetic Mothers.- III. Glucagon Secretion During the Suckling Period.- IV. Glucagon Secretion During the Weaning Period.- E. Metabolic Effects of Glucagon.- I. In the Fetus.- II. In the Neonate.- III. During the Suckling Period.- IV. During the Weaning Period.- F. Glucagon Receptors in the Perinatal Period.- References.- 37 Glucagon as a Counterregulatory Hormone.- A. Glucose Counterregulation, an Overview.- B. Glucagon in the Prevention of Hypoglycemia.- I. The Postabsorptive State.- II. The Intraprandial State.- C. Glucagon in the Restoration of Normoglycemia.- D. Glucagon and the Somoygi Phenomenon.- E. Summary.- References.- 38 Glucagon and Its Relationship to Other Glucoregulatory Hormones in Exercise and Stress in Normal and Diabetic Subjects.- A. Introduction.- B. Exercise.- I. Metabolic Events During Exercise.- II. Fuel Sources During Exercise.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Changes During Exercise.- IV. Hormonal Interactions in the Control of Glucoregulation During Exercise.- 1. Role of Insulin.- 2. Role of Catecholamines.- 3. Role of Glucagon.- V. The Response to Exercise in Diabetic Subjects.- 1. Exercise in Insulin-Dependent Diabetics.- 2. Exercise in Noninsulin-Dependent Diabetics.- C. Stress.- I. Hormonal Response to Stress.- II. Major Changes in Fuels or Energy Substrate During Stress.- 1. Carbohydrate-Derived Fuels.- 2. Fat-Derived Fuels.- 3. Protein-Derived Fuels.- III. Hormonal Interactions in Glucoregulation During Stress.- 1. Pathologic Stress States.- 2. Experimental Stress Models.- 3. Glucagon-Insulin Interactions in Glucoregulation and the Diabetogenic Role of Glucagon.- 4. Glucagon-Insulin-Epinephrine Interactions in Glucoregulation.- 5. Hormonal Regulation of "Futile Cycling" in the Liver.- D. Summary.- References.- Catabolism of Glucagon.- 39 The Metabolic Clearance Rate of Glucagon.- A. Introduction.- B. Principles of Measurement.- C. Glucagon Metabolic Clearance Rate in Laboratory Animals.- D. Glucagon Metabolic Clearance Rate in Humans.- E. Organ Contribution to Overall Glucagon Metabolic Clearance Rate.- F. Plasma Half-Life.- G. Summary and Conclusions.- References.- 40 Hepatic Handling of Glucagon.- A. Introduction.- B. Evidence for Glucagon Extraction by the Liver.- I. In Vitro Studies.- II. Relationship Between Portal and Peripheral Vein Glucagon Levels.- III. Studies in Subjects with Portacaval Shunts.- IV. Direct Measurement of Basal Hepatic Extraction of Glucagon.- V. Effect of Glucagon Heterogeneity on Hepatic Glucagon Extraction Rate.- VI. Relationship Between Hepatic Extraction of Glucagon and Insulin.- C. Factors Regulating Hepatic Extraction of Glucagon.- I. Changes in Splanchnic Blood Flow.- II. Anesthesia and Laparotomy.- III. Changes in Portal Vein Glucagon Concentration.- 1. Increased Amount of Glucagon Presented to the Liver.- 2. Decreased Amount of Glucagon Presented to the Liver.- IV. Partial Hepatectomy.- D. Relationship Between Net Hepatic Glucose Output and Glucagon and Insulin.- I. Peripheral Vein Insulin: Glucagon Molar Ratio.- II. Portal Vein Insulin: Glucagon Molar Ratio.- III. Molar Ratio of Insulin and Glucagon Extracted by the Liver.- E. Fate of Glucagon Extracted by the Liver.- F. Conclusions.- References.- 41 The Renal Handling of Glucagon.- A. Introduction.- B. Kidney Glucagon Uptake and Urinary Excretion.- C. Heterogeneity of Plasma Glucagon and Renal Uptake.- D. The Fate of the Glucagon Taken up by the Kidney.- E. Conclusions.- References.- Glucagon in Pathology.- 42 Glucagon Deficiency.- A. Introduction.- B. Chronic Glucagon Deficiency.- I. After Surgical Resection of A-cells.- 1. In Humans.- 2. In Dogs.- 3. In Other Experimental Animals.- II. Idiopathic Chronic Glucagon Deficiency in Neonates.- C. Acute Glucagon Deficiency.- I. After Administration of Anti-Glucagon Sera.- II. After Infusion of Somatostatin.- D. Metabolic Effects of Glucagon Deficiency.- I. On Protein and Amino Acid Metabolism.- II. On Hepatic Glucose Production.- E. Summary and Conclusions.- References.- 43 The Glucagonoma Syndrome.- A. Introduction.- B. Incidence.- I. Age.- II. Sex.- C. Clinical Features.- I. Skin Lesions.- 1. Pathogenesis.- 2. Distribution and Appearance.- 3. Histology.- 4. Differential Diagnosis of Necrolytic Migratory Erythema.- II. Diabetes Mellitus.- III. Anaemia.- IV. Other Features.- D. Biochemical Findings.- I. Plasma Glucagon.- 1. Hyperglucagonaemia: Its Differential Diagnosis.- 2. Glucagon Secretory Patterns.- II. Plasma Insulin.- III. Glucose Tolerance.- IV. Other Peptides Secreted by Glucagonomas.- V. Plasma Amino Acids.- E. Tumour Characteristics.- I. Tumours Associated with the Glucagonoma Syndrome.- 1. Site and Spread.- 2. Light Microscopy.- 3. Immunofluorescence.- 4. Neuron Specific Enolase.- 5. Electron Microscopy.- II. Tumours not Associated with the Glucagonoma Syndrome.- F. Localisation of Tumours.- I. Arteriography.- II. Percutaneous Transhepatic Portal Venous Sampling.- III. Other Techniques.- G. Diagnosis and Treatment.- I. Surgery.- II. Chemotherapy.- III. Antisecretory Therapy.- IV. Hepatic Artery Embolisation.- V. Symptomatic Treatment.- H. Prognosis.- References.- 44 Glucagon in Diabetes Mellitus.- A. A-cell Function in Human Diabetes.- B. Relationships of A-cell Malfunction to Insulin.- C. The Islets in Diabetes: A-cell Relationships Within the Islets.- D. The Effects of Insulin on the A-cell Abnormalities of Type I Diabetics.- E. The Effects of Insulin on A-cell Abnormalities of Type II Diabetics.- F. The Bihormonal Abnormality Hypothesis.- G. The "Glucagon Controversy".- H. Glucagon Suppression as a Therapeutic Adjunct in Diabetes.- References.- 45 Glucagon in Human Endocrine and Exocrine Disorders.- A. Introduction.- B. Human Endocrine Metabolic Disorders.- I. Hypoglycemia.- 1. Hypoglycemia in Infancy and Childhood.- 2. Reactive Hypoglycemia.- 3. Hypoglycemia in Diabetes and in Chronic Pancreatitis.- 4. Glucagon Antibodies.- 5. Beta-Adrenergic Blockade.- II. Hyperglucagonemia.- 1. Glucagonoma.- 2. Nonislet Glucagon-Secreting Tumors.- 3. The Multiple Endocrine Neoplasia.- III. Pheochromocytoma.- IV. Pituitary Interrelationships.- 1. Acromegaly.- 2. Hypopituitarism.- V. Glucagon and the Parathyroid Glands.- 1. Hyperparathyroidism.- 2. Hypoparathyroidism.- VI. Glucagon and Other Endocrine Diseases.- 1. Cushing's Syndrome.- 2. Hyperthyroidism.- 3. Hypothyroidism.- 4. Addison's Disease.- VII. Comment.- C. Glucagon and the Exocrine Pancreas.- I. Interplay with the Islets of Langerhans.- II. Insulin and Glucagon in Pancreatic Exocrine Fluid.- III. Pancreatitis.- References.- 46 Glucagon and Hyperlipoproteinemias.- A. Introduction.- B. The Glucagon-Insulin Environment.- C. Studies in the Zucker Genetic Hyperlipemic Rat.- I. Glucagon Secretion.- II. Glucagon Regulation.- III. Effect of Reduced Glucagon.- IV. Effect of Elevated Insulin.- D. Studies in Human Hyperlipemia.- I. Immunoassayable Glucagon.- II. Hypolipemic Response to Glucagon.- III. Glucagon Structure-Function Relationships.- IV. Response to Therapy.- E. The Mechanism of the Hypolipemic Response to Glucagon.- References.- 47 Glucagon and Renal Insufficiency.- A. Introduction.- B. The Effects of Renal Failure on Circulating Glucagon Levels and Molecular Profiles.- C. The Effects of Renal Failure on Glucagon Secretion, Biologic Action, and Receptor Binding.- I. Glucagon Secretion.- II. Biologic Activity.- III. Receptor Binding.- D. The Role of Abnormalities in Glucagon Levels and Action in the Metabolic Disturbances of Uremia.- I. Glucose Intolerance.- 1. Hyperglucagonemia and Hepatic Glucose Production.- 2. Increased Tissue Sensitivity to Glucagon.- II. Hypoglycemia.- E. Summary and Conclusions.- References.- 48 Glucagon in Cirrhosis of the Liver.- A. Introduction.- B. Plasma Glucagon Levels in Cirrhotic Patients.- I. In the Basal State.- II. After A-cell Stimulation.- III. After A-cell Inhibition.- C. The Cause of Hyperglucagonism in Cirrhotic Patients.- I. The Role of Portasystemic Shunting.- II. The Role of Hepatocellular Damage.- III. Other Factors.- D. Plasma Glucagon-Like Immunoreactivity Levels in Cirrhotic Patients.- E. The Nature of Circulating Immunoreactive Glucagon in Cirrhotic Patients.- F. Pathogenic Implications of Hyperglucagonemia in Cirrhosis of the Liver.- G. Summary.- References.- 49 Glucagon in Obesity.- A. Introduction.- B. Glucagon in Human Obesity.- I. Plasma Concentrations of Glucagon.- 1. Basal State.- 2. Tests of A-cell Function.- II. Effect of Glucagon in Human Obesity.- C. Experimental Obesity.- I. The Obese Mouse.- II. The Zucker Rat.- III. Rats with Dietary Obesity.- IV. VMH Rats.- D. Extrapancreatic Glucagon in Obesity.- References.- Pharmacological Effects of Glucagon and the Use of Glucagon for Diagnosis and in Therapeutics.- 50 Influence of Glucagon on Water and Electrolyte Metabolism.- A. Introduction.- B. The Kidney as a Target Site for Glucagon Action on Water and Mineral Metabolism.- I. Renal Extraction, Handling, and Metabolism of Glucagon.- II. Direct Effect of Glucagon on Renal Function.- 1. Glucagon-Induced Increase in the Glomerular Filtration Rate.- 2. Influence of Glucagon on Renal Hemodynamics.- 3. Postulated Direct Effect of Glucagon on Tubular Function.- C. The Influence of Glucagon on Natriuresis of Starvation.- D. The Effect of Glucagon on Plasma Electrolyte Levels.- I. Hypocalcemic Effect of Glucagon.- II. Glucagon-Induced Decrease in Plasma Phosphate Levels.- III. Influence of Glucagon on Plasma Potassium Levels.- E. Summary and Conclusions.- References.- 51 Glucagon and Catecholamines.- A. Introduction.- B. Glucagon and Catecholamine Release In Vitro.- C. Glucagon and Catecholamine Release In Vivo.- I. Rats.- II. Guinea Pigs.- III. Dogs.- IV. Cats.- V. Humans.- 1. Plasma Catecholamines.- 2. Urinary Catecholamines and Metabolites.- D. Glucagon and Pheochromocytoma.- I. Glucagon as a Provocative Test in Pheochromocytoma.- II. Mode of Action of Glucagon in Pheochromocytoma.- E. Conclusions.- References.- 52 Glucagon and Growth Hormone.- A. Introduction.- B. Acute and Chronic Effects of Growth Hormone on Glucagon Secretion.- C. Effect of Glucagon on Growth Hormone Secretion.- D. Summary.- References.- 53 Glucagon and the Heart.- A. Introduction.- B. Effects of Glucagon on Mechanical and Electrophysiologic Properties.- I. Cardiac Contractility and Rate.- II. Atrioventricular Conduction and Idioventricular Rhythms.- III. Cardiac Action Potentials.- IV. Coronary Blood Flow and Cardiac Oxygen Consumption.- C. Factors Which Influence Inotropic and Chronotropic Effects.- I. Species Differences.- II. Temperature Effects.- III. Rate-Force Relationship.- IV. Heart Failure.- V. Hypertension.- VI. Age.- VII. Ionic Composition.- VIII. Adrenergic Blocking Agents.- IX. The Interaction of Glucagon with Phosphodiesterase Inhibitors.- X. Interaction of Glucagon with Cardiac Glycosides.- D. Glucagon and Cyclic AMP Formation in Cardiac Muscle.- E. Glucagon, Cyclic AMP, and Calcium Ion Fluxes.- F. Effects of Glucagon on Cardiac Carbohydrate Metabolism.- G. Effects of Glucagon on Cardiac Lipid Metabolism.- H. Relation of the Metabolic Effects of Glucagon to Cardiac Potassium Metabolism.- J. Glucagon-Receptor Interactions.- K. Desensitization.- L. Clinical Studies with Glucagon.- M. Conclusions.- References.- 54 Spasmolytic Action and Clinical Use of Glucagon.- A. Spasmolytic Effects of Glucagon in Various Species.- I. Mechanisms of Action.- II. Structure-Activity Relationships.- III. Conclusions.- B. Clinical Use of Glucagon as a Spasmolytic or Hypotonic Drug...#8212
• Function Relationships.- IV. Response to Therapy.- E. The Mechanism of the Hypolipemic Response to Glucagon.- References.- 47 Glucagon and Renal Insufficiency.- A. Introduction.- B. The Effects of Renal Failure on Circulating Glucagon Levels and Molecular Profiles.- C. The Effects of Renal Failure on Glucagon Secretion, Biologic Action, and Receptor Binding.- I. Glucagon Secretion.- II. Biologic Activity.- III. Receptor Binding.- D. The Role of Abnormalities in Glucagon Levels and Action in the Metabolic Disturbances of Uremia.- I. Glucose Intolerance.- 1. Hyperglucagonemia and Hepatic Glucose Production.- 2. Increased Tissue Sensitivity to Glucagon.- II. Hypoglycemia.- E. Summary and Conclusions.- References.- 48 Glucagon in Cirrhosis of the Liver.- A. Introduction.- B. Plasma Glucagon Levels in Cirrhotic Patients.- I. In the Basal State.- II. After A-cell Stimulation.- III. After A-cell Inhibition.- C. The Cause of Hyperglucagonism in Cirrhotic Patients.- I. The Role of Portasystemic Shunting.- II. The Role of Hepatocellular Damage.- III. Other Factors.- D. Plasma Glucagon-Like Immunoreactivity Levels in Cirrhotic Patients.- E. The Nature of Circulating Immunoreactive Glucagon in Cirrhotic Patients.- F. Pathogenic Implications of Hyperglucagonemia in Cirrhosis of the Liver.- G. Summary.- References.- 49 Glucagon in Obesity.- A. Introduction.- B. Glucagon in Human Obesity.- I. Plasma Concentrations of Glucagon.- 1. Basal State.- 2. Tests of A-cell Function.- II. Effect of Glucagon in Human Obesity.- C. Experimental Obesity.- I. The Obese Mouse.- II. The Zucker Rat.- III. Rats with Dietary Obesity.- IV. VMH Rats.- D. Extrapancreatic Glucagon in Obesity.- References.- Pharmacological Effects of Glucagon and the Use of Glucagon for Diagnosis and in Therapeutics.- 50 Influence of Glucagon on Water and Electrolyte Metabolism.- A. Introduction.- B. The Kidney as a Target Site for Glucagon Action on Water and Mineral Metabolism.- I. Renal Extraction, Handling, and Metabolism of Glucagon.- II. Direct Effect of Glucagon on Renal Function.- 1. Glucagon-Induced Increase in the Glomerular Filtration Rate.- 2. Influence of Glucagon on Renal Hemodynamics.- 3. Postulated Direct Effect of Glucagon on Tubular Function.- C. The Influence of Glucagon on Natriuresis of Starvation.- D. The Effect of Glucagon on Plasma Electrolyte Levels.- I. Hypocalcemic Effect of Glucagon.- II. Glucagon-Induced Decrease in Plasma Phosphate Levels.- III. Influence of Glucagon on Plasma Potassium Levels.- E. Summary and Conclusions.- References.- 51 Glucagon and Catecholamines.- A. Introduction.- B. Glucagon and Catecholamine Release In Vitro.- C. Glucagon and Catecholamine Release In Vivo.- I. Rats.- II. Guinea Pigs.- III. Dogs.- IV. Cats.- V. Humans.- 1. Plasma Catecholamines.- 2. Urinary Catecholamines and Metabolites.- D. Glucagon and Pheochromocytoma.- I. Glucagon as a Provocative Test in Pheochromocytoma.- II. Mode of Action of Glucagon in Pheochromocytoma.- E. Conclusions.- References.- 52 Glucagon and Growth Hormone.- A. Introduction.- B. Acute and Chronic Effects of Growth Hormone on Glucagon Secretion.- C. Effect of Glucagon on Growth Hormone Secretion.- D. Summary.- References.- 53 Glucagon and the Heart.- A. Introduction.- B. Effects of Glucagon on Mechanical and Electrophysiologic Properties.- I. Cardiac Contractility and Rate.- II. Atrioventricular Conduction and Idioventricular Rhythms.- III. Cardiac Action Potentials.- IV. Coronary Blood Flow and Cardiac Oxygen Consumption.- C. Factors Which Influence Inotropic and Chronotropic Effects.- I. Species Differences.- II. Temperature Effects.- III. Rate-Force Relationship.- IV. Heart Failure.- V. Hypertension.- VI. Age.- VII. Ionic Composition.- VIII. Adrenergic Blocking Agents.- IX. The Interaction of Glucagon with Phosphodiesterase Inhibitors.- X. Interaction of Glucagon with Cardiac Glycosides.- D. Glucagon and Cyclic AMP Formation in Cardiac Muscle.- E. Glucagon, Cyclic AMP, and Calcium Ion Fluxes.- F. Effects of Glucagon on Cardiac Carbohydrate Metabolism.- G. Effects of Glucagon on Cardiac Lipid Metabolism.- H. Relation of the Metabolic Effects of Glucagon to Cardiac Potassium Metabolism.- J. Glucagon-Receptor Interactions.- K. Desensitization.- L. Clinical Studies with Glucagon.- M. Conclusions.- References.- 54 Spasmolytic Action and Clinical Use of Glucagon.- A. Spasmolytic Effects of Glucagon in Various Species.- I. Mechanisms of Action.- II. Structure-Activity Relationships.- III. Conclusions.- B. Clinical Use of Glucagon as a Spasmolytic or Hypotonic Drug...Microfilamentous System.- II. How Do Amino Acids Trigger Glucagon Release?.- III. Contribution of the Adenylate Cyclase System and of Ca2+ and Other Ion Fluxes.- IV. Relative Resistance of A-cell Function to Hypothermia.- D. Modulation of Amino Acid-Induced Glucagon Release.- I. Major Role of Glucose and Insulin Concentrations.- 1. Role of Glucose in Nondiabetic Subjects.- 2. Role of Insulin.- 3. Studies in Diabetic Subjects.- II. Other Physiologic Modulations.- 1. Short-Term Modulations.- 2. Long-Term Modulations.- III. Other Pathophysiologic Modulations.- 1. Liver Cirrhosis.- 2. Kidney Failure.- 3. Thyroid Conditions.- 4. The Somatostatinoma Syndrome.- 5. The Glucagonoma Syndrome.- 6. Obese Nondiabetic Patients.- 7. Pheochromocytoma.- 8. Stress.- E. Amino Acid-Induced Glucagon Release and the Regulation of Substrate Distribution.- I. Physiologic Relevance of the Amino Acid and Glucagon Concentrations.- 1. Blood Amino Acid Concentration.- 2. Plasma Glucagon Concentration and Biologic Efficacy.- II. Clinical Correlations.- 1. Normal Subjects.- 2. Insulin-Dependent Patients.- References.- 25 Free Fatty Acids and Glucagon Secretion.- A. Introduction.- B. In Vitro Studies.- I. Isolated Islets.- II. Isolated Perfused Rat Pancreas.- C. Experiments in Animals.- I. Dogs.- II. Rats.- III. Ducks.- D. Studies in Humans.- I. Normal Subjects.- II. Pregnant Women.- III. Diabetes.- IV. Hypertriglyceridemia.- E. The Modulating Role of Circulating FFA on Glucagon Secretion.- I. Mechanism of Action of FFA on A-cells.- II. Possible Significance of the Role of FFA in the Regulation of A-cell Secretion.- References.- 26 Ions in the Control of Glucagon Release.- A. Introduction.- B. Calcium and Glucagon Release.- I. The Inhibitory Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- II. The Positive Modulating Role of Calcium.- 1. Experimental Data.- 2. Possible Mechanisms of Action.- III. The Recognition Role of Calcium.- IV. The In Vivo Effects of Calcium.- V. Conclusions.- C. Other Divalent Cations.- I. Magnesium.- II. Manganese.- III. Miscellaneous Cations.- D. Monovalent Cations.- I. Potassium.- II. Sodium.- III. The Sodium-Potassium Pump.- IV. Ammonium.- E. Anions.- F. Conclusions.- References.- 27 Cyclic Nucleotides in the Control of Glucagon Secretion.- A. Introduction.- B. Effects of Exogenous Cyclic AMP.- C. Effects of Phosphodiesterase Inhibitors.- D. Effects of Agents Thought to Act via Endogenous Cyclic AMP.- E. Conclusions..- References.- 28 Prostaglandins and Glucagon Secretion.- A. Introduction.- I. Origin and Metabolism of Prostaglandins.- II. Prostaglandins as Local or Intracellular Messengers.- III. Methodological Considerations.- B. Studies In Vitro on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- II. Role of Endogenous Prostaglandins.- 1. Prostaglandin Biosynthesis by Islet Tissue.- 2. Endogenous Prostaglandins and Glucagon Secretion In Vitro.- C. Studies In Vivo on the Influence of Prostaglandins on Glucagon Secretion.- I. Effect of Exogenous Prostaglandins.- 1. Rats.- 2. Dogs.- 3. Humans.- II. Role of Endogenous Prostaglandins.- D. Summary and Conclusions.- References.- 29 Hormones in the Control of Glucagon Secretion.- A. Introduction.- B. Thyroid Hormones.- C. Calcium-Regulating Hormones.- I. Parathyroid Hormone.- II. Calcitonin.- III. Vitamin D.- D. Steroid Hormones.- I. Glucocorticoids.- II. Mineralocorticoids.- III. Sex Steroids.- E. Placental Hormones.- F. Gastrointestinal Hormones.- I. Gastric Inhibitory Polypeptide.- II. Vasoactive Intestinal Peptide.- III. Secretin.- IV. Porcine Intestinal Heptacosapeptide.- V. Bombesin.- VI. Cholecystokinin.- VII. Gastrin.- VIII. Cerulein.- IX. Motilin.- G. Pituitary Hormones.- I. Growth Hormone.- II. Adrenocorticotropic Hormone.- III. Endorphins and Enkephalins.- H. Hypothalamic Hormones.- I. Hypothalamic Lesions.- II. Substance P and Neurotensin.- III. Unidentified Polypeptides.- J. Conclusions.- References.- 30 Neural Control of Glucagon Secretion.- A. Introduction.- B. Anatomic Observations.- I. Neural Pathways.- II. Species Variations.- C. Experimental Observations.- I. Central Nervous System Studies.- II. Nerve Stimulation and Sectioning Studies.- III. Infusion Studies.- D. Physiologic and Pathophysiologic Observations.- E. Neural Control of Gastric Glucagon.- F. Conclusions.- References.- 31 Intraislet Insulin-Glucagon-Somatostatin Relationships.- A. Introduction.- B. Overview of Islet Anatomy.- C. General Mechanisms of Communication Between Cells.- D. Potential Interactions Within Islets.- I. Potential Interactions Between Cells.- 1. Basic Scheme.- 2. Effect of Glucagon Upon B- and D-cells.- 3. Effect of Somatostatin Upon A- und B-cells.- 4. Effect of Insulin Upon A- and D-cells.- 5. Pancreatic Polypeptide as an Ignored Entity and Why.- 6. Other Potential Islet Mediators.- II. Neural Control.- 1. Cholinergic Agonism.- 2. Adrenergic Agonism.- 3. Local Presynaptic Autonomic Regulation.- 4. Peptidergic and Purinergic Regulation.- III. Potential Role of Gap Junctions as Determinants of Coordination Between Islet Cells.- E. Anatomic Determinants of Islet Regulation.- F. Indirect Experimental Evidence for Interaction Between Islet Cells.- G. Efforts to Demonstrate Local Interactions Directly with Immune Neutralization.- H. Arguments Against Islet Interactions.- J. Oscillation of Secretion Suggesting Coordination Between Islets.- K. Consideration of an Islet-Acinar Portal System.- L. Islet Interrelationships in Diabetes.- M. Overview and Conclusions.- References.- 32 Pharmacologic Compounds Affecting Glucagon Secretion.- A. Introduction.- B. Drugs Used in the Treatment of Diabetes.- I. Insulin.- II. Sulfonylureas.- III. Biguanides.- C. Drugs Related to the Cholinergic System.- D. Drugs Related to the Sympathetic Nervous System.- I. Reserpine.- II. Beta-Adrenergic Blocking Agents.- III. Alpha-Adrenergic Blocking Agents.- IV. Clonidine.- V. L-Dopa, Dopamine, and Bromocriptine.- VI. Diazoxide and Tolmesoxide.- E. Serotonin and Sero

巻冊次

3 ISBN 9783540609896

内容説明

This work is a part of a three volume series that comprises a glucagon encyclopedia. It looks at data on glucagon molecular biology, clinically relevant information on the role of glucagon in the pathophysiology of diabetes, the place of glucagon in medical imaging or in emergency medicine. Chapters are devoted to members of the glucagon family such as glucagon-like peptide-1 (GLP-1)) and oxyntomodulin.

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詳細情報

• NII書誌ID(NCID): BA10154230
• ISBN:
  • 0387120688
  • 0387122729
  • 3540120688
  • 3540122729
  • 354060989X
• LCCN: 83000583
• 出版国コード: gw
• タイトル言語コード: eng
• 本文言語コード: eng
• 出版地: Berlin ; Tokyo
• ページ数/冊数: v.
• 大きさ: 25 cm
• 分類:
  • LCC : QP905
  • LCC : QP572.G5
  • DC19 : 615/.1 s
  • DC19 : 612/.34
• 件名:
  • LCSH : Glucagon -- Addresses, essays, lectures
  • MESH : Glucagon
• 親書誌ID:
  • BA00516120