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Handbook of Experimental Pharmacology Continuation of Handbuch der experimentellen Pharmakologie Vol. 66/1 Editorial Board G. V. R. Born, London· A. Farah, Rensselaer, New York H. Herken, Berlin· A. D. Welch, Memphis, Tennessee Advisory Board S. Ebashi· E. G. Erdos' V. Erspamer' U. S. von Euler' W S. Feldberg G. B. Koelle' M. Rocha e Silva' 1. R. Vane' P. G. Waser Glucagon I Contributors T. T. Aoki . T. L. Blundell . C. Bordi . 1. Brange . W W Bromer G. F. Cahill, lr.· A. D. Cherrington' 1.-L. Chiasson· T.H. Claus 1. W Ensinck . S. Falkmer . D. W Foster· L. G. Heding C. Hellerstrom . B. de Hemptinne . 1. 1. Holst . K. S. Koch P.l. Lad . P.l. Lefebvre' H. L. Leffert· 1. D. McGarry R.B. Merrifield· A.1. Moody· S. Mojsov . R. Nosadini L. Orci . C. R. Park . A. Perrelet . S.1. Pilkis . M. Pingel M. Rodbell . E. Samols . B. Skelbaek-Pedersen . H. Skelly R.1. Smith· W. Stalmans . L. Thim . A. Tiengo . R. H. Unger I. Valverde' S. Van Noorden Editor P.J. Lefebvre Springer-Verlag Berlin Heidelberg New York Tokyo 1983 Professor PIERRE 1. LEFEBVRE, M.D. Professor of Medicine, University of Liege Guest Professor, University of Brussels (V.U.B.) Corresponding Member, Royal Academy of Medicine of Belgium Chairman, Medical Policlinics, University of Liege Head, Division of Diabetes, University of Liege Institut de M6decine, Hopital de Baviere Boulevard de la Constitution, 66 4020 Liege, Belgium With 136 Figures ISBN -13: 978-3-642-68868-3 e-ISBN-13: 978-3-642-68866-9 DOl: 10.1007/978-3-642-68866-9 Library of Congress Cataloging in Publication Data. Main entry under title: Glucagon. (Handbook of experimental pharmacology; v. 66) Bibliography: p. Includes index. I. Glucagon -Addresses, essays, lectures. I. Lefebvre, Pierre J. II. Series. [DNLM: I. Glucagon. WI HA51L vol. 66 pt. 1-2/WK 801 G5656] QP905.H3 vol. 66 [QP572.G5], 615'.ls [612'.34] 83-583 This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machine or similar means, and storage in data banks. Under § 54 of the German Copyright Law where copies are made for other than private use, a fee is payable to "Verwertungsgesellschaft Wort", Munich. © by Springer-Verlag Berlin Heidelberg 1983. Softcover reprint of the hardcover 1st edition 1983 The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. Product Liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 2122/3130-543210 List of Contributors T. T. AOKI, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA T. L. BLUNDELL, Laboratory of Molecular Biology, Department of Crystallo graphy, Birkbeck College, University of London, Malet Street, London WCIE 7HX, Great Britain C. BORDI, Istituto di Anatomia ed Istologia Patologica, Universita di Parma, Parma, Italy J. BRANGE, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark W. W. BROMER, Research Advisor, Lilly Research Laboratories, Indianapolis, IN 46285, USA G. F. CAHILL, Jr., Director of Research, Howard Hughes Medical Institute, 398 Brookline Avenue, Suite 8, Boston, MA 02215, USA A. D. CHERRINGTON, Department of Physiology, Howard Hughes Medical Institute, Vanderbilt University, 702 Light Hall, Nashville, TN 37232, USA J.-L. CHIASSON, Director, Research Laboratory in Diabetes and Carbohydrates Metabolism, Clinical Research Institute of Montreal, 110 Avenue des Pins Ouest, Montreal, Que. H2W lR7, Canada T. H. CLAUS, American Cyanamid Company, Medical Research Division, Lederle Laboratories, Pearl River, NY 10965, USA J. W. ENSINCK, Department of Medicine, Program Director, Clinical Research Center, University Hospital, RC-14, University of Washington, Seattle, WA 98195, USA S. FALKMER, Department of Pathology, Malmo General Hospital, 21401 Malmo, Sweden D. W. FOSTER, Department of Internal Medicine, University of Texas Health Science Center at Dallas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA L. G. HEDING, Medical Department, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark C. HELLERSTROM, University of Uppsala, Department of Medical Cell Biology, Biomedicum, Box 571, 75123 Uppsala, Sweden VI List of Contributors B. DE HEMPTINNE, Laboratory of experimental Surgery, Catholic University of Louvain, 1200 Brussels, Belgium J. J. HOLST, Institute of Medical Physiology C, University of Copenhagen, The Panum Institute, Blegdamsvej 3,2200 Copenhagen N, Denmark K. S. KOCH, Department of Medicine, M - 013 H, Division of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA P. J. LAD, Department of Medicine, M - 013 H, Division of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA P. J. LEFEBVRE, Head of the Division of Diabetes, Universite de Liege, Hopital Universitaire de Baviere, Institut de Medecine, Diabetologie, Boulevard de la Constitution, 66, 4020 Liege, Belgium H. L. LEFFERT, Department of Medicine, M-Ol3 H, Division of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA J. D. MCGARRY, Departments ofInternal Medicine and Biochemistry, University of Texas Health Science Center at Dallas, Southwestern Medical School, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA R. B. MERRIFIELD, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA A. J. MOODY, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark S. MOJsov, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA R. NOSADINI, Istituto di Medicina Clinica dell'Universita di Pad ova, Via Giustiniani, 2, 35100 Padova, Italy L. ORCI, Institute of Histology and Embryology, University of Geneva Medical School, 1211 Geneva 4, Switzerland C. R. PARK, Chairman, Department of Physiology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA A. PERRELET, Institute of Histology and Embryology, University of Geneva, Medical School, 1211 Geneva 4, Switzerland S. J. PILKIS, Department of Physiology, Vanderbilt University, School of Medicine, Nashville, TN 37232, USA M. PINGEL, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark M. RODBELL, Section on Membrane Regulation, National Institute of Arthritis, Diabetes, Digestive, and Kidney Diseases, Bethesda, MD 20205, USA List of Contributors VII E. SAMOLS, Division of Endocrinology, Metabolism and Radionuclide Studies, Department of Medicine, V A Medical Center, 800 Zorn Avenue, Louisville, KY 40202, USA B. SKELBAEK-PEDERSEN, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark H. SKELLY, Department of Medicine, M - 013 H, Division of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA R. J. SMITH, Howard Hughes Medical Institute, Laboratories at the Joslin Diabetes Center, One Joslin Place, Boston, MA 02215, USA W. STALMANS, Afdeling Biochemie, Faculteit Geneeskunde, Katholieke Universiteit Leuven, Herestraat 49, 3000 Leuven, Belgium L. TRIM, Novo Research Institute, Novo Allee, 2880 Bagsvaerd, Denmark A. TIENGO, Istituto di Medicina Clinica dell'Universita di Padova, Cattedra di Malattie del Ricambio, Via Giustiniani, 2, 35100 Padova, Italy R. H. UNGER, Senior Medical Investigator, Dallas VA Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235, USA I. VALVERDE, Fundaci6n Jimenez Diaz, U niversidad Aut6noma de Madrid, A vda. Reyes Cat6licos 2, Ciudad Universitaria, Madrid 3, Spain S. VAN NOORDEN, Department of Histopathology, Royal Postgraduate Medical School, Hammersmith Hospital, London, Great Britain Preface 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. Fourth, while the insulin-producing cell, the B-cell of the islets of Langerhans, has received a great amount of attention from morphologists for many years, the glucagon-producing cell or A-cell has long been considered as the "parent pauvre." The credentials of glucagon are numerous however. It was among the very first polypeptide hormones to be isolated, purified, sequenced, and synthetized. Thanks to the efforts of UNGER, it was the second polypeptidic hormone to become measurable by radioimmunoassay, a few months after insulin. It has served as a very valuable tool which permitted SUTHERLAND and his co-workers to discover cyclic AMP and RODBELL and his associates to investigate cell membrane receptors. Our knowledge of physiology of glucagon is based on the work of STAHL, FOA, SUTHERLAND, and DE DuVE, to mention only few of the pioneers, and on work performed since the late fifties in Dallas by UNGER and his co-workers. In the seventies UNGER and ORCI, combining their physiological and morphological x Preface expertises, renewed the study of the pathopysiology of diabetes; they considered the microanatomy of the islets of Langerhans and demonstrated both the interaction and the partition of the various cell types involved. When asked to serve as editor for a volume on glucagon in the present series, I immediately decided to accept since there was a great need for a comprehensive book on this subject. As a matter of fact, my task of selecting and contacting contributors has been easy: all are personal friends, all are undisputed experts in their field, and all accepted my invitation. The only major problem arose when all the contributions had been collected, namely the total amount of pages exceeded by far that which could be reasonably gathered in a single volume. Analysis of the content showed that shortening the individual contributions was definitely unacceptable. Another possibility was to renounce the comprehensive character of the book by leaving out several topics, a position which was acceptable neither to the authors, who had already written the chapters, nor to the editor, who had indicated to the contributors that comprehensiveness was a major characteristic of the whole project. The help came from the publisher, who accepted a third possible solution, that of producing Glucagon in two volumes. The first volume gathers the more "basic" contributions on the chemistry and physicochemistry of glucagon, the morphology of the A-cells, the biosynthesis of the hormone, its production, its immunogenicity, and its assay procedures. It also contains ten chapers describing the actions of the hormone at the molecular level. The second volume deals with the various factors controlling glucagon secretion, the question of extrapancreatic glucagon, the place of glucagon in physiology and in pathology, the catabolism of the hormone, the pharmacological effects of glucagon, and its use in diagnosis and in therapy. Two critiques often made on a work like this are redundancy and not being up to date. We have done our best to eliminate both. About redundancy, great efforts have been made to delineate the topics to be treated by the various contributors, and direct contacts have been encouraged between contributors having to deal with closely related topics. At the editorial level, redundant paragraphs or figures have been deleted. Yet, it has been our deliberate policy to preserve homogeneity of each chapter and, as a consequence, some topics have been considered in two chapters on a different scope. For instance, glicentin, the newly recognized precursor of glucagon, has been considered both in the chapter on the biosynthesis of glucagon and in the one dealing with the various glucagon-related peptides. Similarly, the chapter on "glucagon and liver output in vivo" is a physiological review of mechanisms dealt with in a more biochemical manner in the contributions on "liver glycogen metabolism" and on "gluconeo genesis." With such an approach, we think that the reader will find both detailed analyses of the mechanisms involved and comprehensive and integregated views on the phenomena as they occur in the organism as a whole. About up-dating, producing a multiauthored book like this takes time; this is not, however, an excuse for it to be out of date when in print. Every effort has been made by the contributors and by the editor to cover the literature completely up to the very last possible moment. Newly published data have been introduced, when Preface XI necessary, at the various steps of scientific editing, copy editing, and galley-proof correcting. We hope that this effort will be appreciated by the readers. I wish to thank all those who participated in this enterprise: the authors for their comprehensive contributions and their willingness to abide by the rules of the game, my secretary Mrs. V AESSEN-PETIT in Liege who helped me in the editorial process, Mr. EMERSON, in Great Britain, whose copy editing was outstanding and the publisher, in Heidelberg, from whom I have received help from Mr. BERGSTEDT, Mrs. WALKER, and Mr. BISCHOFF. Our readers will be the judge of our joint efforts; let us hope that they will not be disappointed. PIERRE J. LEFEBVRE Contents Chemistry and Physicochemistry of Glucagon CHAPTER 1 Chemical Characteristics of Glucagon. W. W. BROMER. With 2 Figures A. Introduction. . . . . . 1 B. Isolation and Purification 1 C. Properties. . . . . . . 2 D. Amino Acid Sequence 3 E. Covalent Chemical Modification and Biologic Function 5 I. Limitations of the Approach . . . . 5 II. General Considerations . . . . . . . . . . 7 III. The Question of Several Active Sites. . . . . 7 IV. Amino Terminal and Diamino Modifications. 12 V. Inhibitors of Glucagon . . . . . . . . . . 13 VI. Modifications of Glutamyl, Lysyl, Arginyl, and Tryptophyl Residues. . . . . . . . . . . . . . . . . . . . . . 14 VII. Modifications of Tyrosyl Residues . . . . . . . . . . 15 VIII. Methionyl Residue and Carboxyl Terminal Modifications 16 IX. Summary of Covalent Modifications and Function 18 References . . . . . . . . . . . . . . . . . . . . . . . . . 19 CHAPTER 2 The Chemical Synthesis of Glucagon. R. B. MERRIFIELD and S. MOJsov With 8 Figures A. Introduction. . . . . . 23 B. Early Synthetic Efforts . 24 C. The First Total Synthesis 24 D. Further Syntheses by Fragment Condensation in Solution 26 E. Solid Phase Fragment Synthesis 28 F. Stepwise Solid Phase Synthesis. 30 G. Conclusions 33 References . . . . . . . . . . . 34
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