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.

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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…