Table Of ContentHandbook of
Experimental Pharmacology
Volume 123
Editorial Board
G.V.R.Born,London
P. Cuatrecasas, Ann Arbor, MI
D. Ganten, Berlin
H. Herken, Berlin
K.L. Melmon, Stanford, CA
Springer
Berlin
Heidelberg
New York
Barcelona
Budapest
Hong Kong
London
Milan
Paris
Santa Clara
Singapore
Tokyo
Glucagon I I I
Contributors
J.M. Amatruda, D. Bataille, D. Bennis, H.-P. Bode
P.E. Cryer, C.F. Deacon, H.-C. Fehmann, N. Geary
B. Goke, R. Goke, J.J. Holst, V. Iwanij, M.M. Johnson
T. Kornfelt, P.J. Lefebvre, J.N. Livingston, I. Mollerup
M.A. Nauck, P. Oreskov, C. 0rskov, G. Paolisso, C. Pavoine
F. Peeker, J. Philippe, A.J. Scheen, J. Skucas, G. Slama
B. Thorens, H.V. Tszjttrup, C. Widmann, G.P. Zaloga
P. Zirinis
Editor
Pierre J. Lefebvre
Springer
Professor PIERRE J. LEFEBVRE, M.D., Ph.D., FRCP
Centre Hospitalier Universitaire de Liege
Department of Medicine
Division of Diabetes, Nutrition, and Metabolic Disorders
C.H.U. Sart Tilman
B-4000 Liege 1
Belgium
With 69 Figures and 7 Tables
ISBN -13:978-3-642-64718-5
Library of Congress Cataloging in Publication Data. Main entry under title: Glucagon. (Handbook of experi
mental pharmacology: v. 123 Bibliography: p. Includes index. I. Glucagon-Adresses, essays, lectures. I.
Lefebvre, Pierre J. II. Series. [DNLM: I. Glucagon. WI HA5IL vol. 66 pt. 1-2IWK 801G5656) QP905:H3 vol.
123 [QP572.G5) 615'ls [612'.34) 83-583
ISBN -13:978-3-642-64718-5 e-ISBN-13 :978-3-642-61150-6
DOl: 10.1007/978-3-642-61150-6
This work is subject to copyright. All rights are reserved, whether the whole or part of the material is
concerned, specifically the rights of translation, reprinting, reuse of illustrations,recitation, broadcasting,
reproduction on microfilm or in any other ways, and storage in data banks. Duplication of this publication or
parts thereof is permitted only under the provisions of the German Copyright Law of September 9, 1965, in
its current version, and permission for use must always be obtained from Springer-Verlag. Violations are
liable for prosecution under the German Copyright Law.
© Springer-Verlag Berlin Heidelberg 1996
Softcover reprint of the hardcover 1st edition 1996
The use of general descriptive names, 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 cannot guarantee the accuracy of any information about dosage and
application contained in this book. In every individual case the user must check such information by
consulting the relevant literature.
Cover design: Design & Production, Heidelberg
Typesetting: Best-set Typesetter Ltd., Hong Kong
SPIN: 10497518 27/3136/SPS-5 4 3 2 1 ~Printed on acid-free paper
Preface
Glucagon III supplements Glucagon I and II, also published in the Handbook
of Experimental Pharmacology (vols. 66 I, II), updating the encyclopedic
information compiled on glucagon, the hyperglycemic hormone produced by
the A-cells in the islets of Langerhans of the pancreas. Since 1983, the year of
publication of Glucagon I and II, the increase in our knowledge on glucagon
has been immense: the glucagon gene and the glucagon receptor gene have
been identified, the biosynthesis of glucagon has been elucidated, and our
understanding of the mode of action of the hormone has been revised. The
role of glucagon in diabetes is now recognized, and the search for glucagon
antagonists is active. Furthermore, glucagon is used not only to treat
hypoglycemia but also as a useful agent in emergency medicine, an interesting
drug to improve imaging of the gut, and a useful tool to evaluate residual
insulin secretion. Recent data also indicate that glucagon might be involved in
the regulation of appetite. Another member of the glucagon family, glucagon
like peptide 1 or GLP-1, has now been clearly identified. It is recognized as a
major "incretin," stimulating the release of insulin in response to food inges
tion. GLP-1 appears to have a great future in the management of diabetes
while another glucagon-related peptide, oxyntomodulin, seems to playa major
role in the control of gastric acid secretion.
These various topics are covered in the 19 chapters of the present volume,
all of which have been written by recognized world experts.
Individuals working on glucagon will find Glucagon III to be an
unrivaled source of information, joining volumes I and II as the standard
references on this subject. Hospital physicians are likely to be interested in the
chapters on the role of glucagon in diabetes, the modes of glucagon adminis
tration, the place of glucagon in emergency medicine and in medical imaging,
the glucagon test for evaluating insulin secretion, and glucagonoma and its
management.
I wish to thank the authors for their comprehensive contributions
and - almost all of them - for having sent their chapters on the agreed
deadline. This permits us to present a perfectly updated volume. Thanks go
also to my secretary, Mrs. E. Vaessen-Petit, who, once again, helped me
in the editorial process, to Mrs. D. Walker who has been a most efficient
contact with the publisher, and to Mr. W. Shufflebotham, an excellent copy
editor.
VI Preface
Glucagon I and II received an enthusiastic welcome when they were
published in 1983. I wish the same fate to the third volume of the trilogy some
13 years later.
Liege
July 1996 PIERRE J. LEFEBVRE
List of Contributors
AMATRUDA, 1.M., Bayer Corporation, Pharmaceutical Division, Metabolic
Disorders Research, Building B-24, 400 Morgan Lane, West Haven, CT
06516-4175, USA
BATAILLE, D., INSERM U376, CHU Arnaud-de-Villeneuve, 34295
Montpellier Cedex OS, France
BENNIS, D., Service de Diabetologie, Hotel-Dieu, 1, place du Parvis Notre
Dame, 75181 Paris Cedex 04, France
BODE, H.-P., Clinical Research Unit for Gastrointestinal Endocrinology, De
partment of Internal Medicine, Philipps-University Marburg, Baldinger
strasse, 35033 Marburg, Germany
CRYER, P.E., Division of Endocrinology, Diabetes and Metabolism, Washing
ton University School of Medicine, Campus Box 8127, 660 S. Euclid
Avenue, St. Louis, MO 63110, USA
DEACON, C.F., Institute of Medical Physiology C, The Panum Instituttet,
University of Copenhagen, Blegdamsvej 3,2200 Copenhagen N, Denmark
FEHMANN, H.-C., Clinical Research Unit for Gastrointestinal Endocrino
logy, Department of Internal Medicine, Philipps-University Marburg,
Baldingerstrasse, 35033 Marburg, Germany
GEARY, N., E.W. Bourne Behavioral Research Laboratory, New York
Hospital, Cornell Medical Center, 21 Bloomingdale Road, White Plains,
NY 10605, USA
GOKE, B., Clinical Research Unit for Gastrointestinal Endocrinology, Depart
ment of Internal Medicine, Philipps-University Marburg, Baldingerstrasse,
35033 Marburg, Germany
GOKE, R., Clinical Research Unit for Gastrointestinal Endocrinology, Depart
ment of Internal Medicine, Philipps-University Marburg, Baldingerstrasse,
35033 Marburg, Germany
VIII List of Contributors
HOLST, J.J., Department of Medical Physiology, The Panum Instituttet,
University of Copenhagen, Blegdamsvej 3,2200 Copenhagen N, Denmark
IWANIJ, V., Department of Genetics and Cell Biology, University of Minne
sota, College of Biological Sciences, 250 Biological Sciences Center, 1445
Gortner Avenue, St. Paul, MN 55108-1095, USA
JOHNSON, M.M., Department of Medicine, Pulmonary Critical Care, Bowman
Gray School of Medicine, Wake Forest University, Winston-Salem, NC
27157-1009, USA
KORNFELT, T., Novo Nordisk, Hagedornsvej 1, 2820 Gentofte, Denmark
LEFEBVRE, P.J., Centre Hospitalier Universitaire de Liege, Department of
Medicine, Division of Diabetes, Nutrition and Metabolic Disorders,
C.H.U. Sart Tilman (B35), 4000 Liege 1, Belgium
LIVINGSTON, J.N., Bayer Corporation, Pharmaceutical Division, Metabolic
Disorders Research, Building B-24, 400 Morgan Lane, West Haven, CT
06516-4175, USA
MOLLERUP, 1., Novo Nordisk, Hagedornsvej 1,2820 Gentofte, Denmark
NAUCK, M.A., Department of Internal Medicine, Knappschaftskrankenhaus,
Ruhr-University, In der Schornau, 44892 Bochum-Langendreer, Germany
ORESKOV, P., Novo Nordisk, Novo AIle, 2880 Bagsvaerd, Denmark
0RSKOV, c., Institute of Medical Anatomy, The Panum Instituttet, University
of Copenhagen, Blegdamsvej 3,2200 Copenhagen N, Denmark
PAOLISSO, G., Department of Geriatric Medicine and Metabolic Diseases, II
University of Naples, 80138, Naples, Italy
PAVOINE, c., Unite de Recherches INSERM U99, Hopital Henri Mondor,
94010 Creteil, France
PECKER, F., Unite de Recherches INSERM U99, Hopital Henri Mondor, 94010
Creteil, France
PHILIPPE, J., Department de Medecine, Division d'Endrocrinolgie et
Diabetologie, Hopital Cantonal Universitaire, Unite de Diabetologie
Clinique, 1211 Geneva 14, Switzerland
List of Contributors IX
SCHEEN, A.J., Centre Hospitalier Universitaire de Liege, Department of Medi
cine, Division of Diabetes, Nutrition and Metabolic Disorders, C.H.U. Sart
Tilman (B35), 4000 Liege 1, Belgium
SKUCAS, J., Department of Diagnostic Radiology, University of Rochester
Medical Center, 601 Elmwood Avenue, Box 648, Rochester, NY 14642-
8648, USA
SLAMA, G., Service de Diabetologie, Hotel-Dieu, 1, place du Parvis Notre
Dame, 75004 Paris, France
THORENS, B., Institute of Pharmacology and Toxicology, University of
Lausanne, 27, Rue du Bugnon, 1005 Lausanne, Switzerland
Tl/.iTIRUP, H.V., Novo Nordisk, Hagedomsvej 1,2820 Gentofte, Denmark
WIDMANN, c., Institute of Pharmacology and Toxicology, University of
Lausanne, 27, Rue du Bugnon, 1005 Lausanne, Switzerland
ZALOGA, G.P., Section on Critical Care, Bowman Gray School of Medicine,
Wake Forest University, Winston-Salem, NC 27157-1009, USA
ZIRINIS, P., Service de Diabetologie, Hotel-Dieu, 1, place du Parvis Notre
Dame, 75181 Paris Cedex 04, France
Contents
CHAPTER 1
The Industrial Production of Glucagon
I. MOLLERup, T. KORNFELT, P. ORESKOV, and H.V. TjljTTRUP
With 7 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
A. Introduction............................................... 1
B. Production................................................ 1
I. Expression and Fermentation. . . . . . . . . . . . . .. . . . . . . . .. . . . 1
II. Recovery and Purification. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
1. Recovery.......................................... 1
2. Purification........................................ 2
3. Aggregation....................................... 3
III. Pharmaceutical Preparations. . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
C. Analysis of Recombinant Human Glucagon. . . . . . . . . . . . . . . . . . . . 3
I. Introduction.......................................... 3
II. Identification......................................... 3
III. Purity............................................... 4
1. Microbiological Impurities. . . . . . . . . . . . . . . . . . . . . . . . . . . 4
2. Water............................................. 5
3. Chemical Impurities... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
IV. Assay................................................ 9
D. Stability................................................... 9
References. . . . .. . .. . . .. . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . .. . .. 10
CHAPTER 2
The Glucagon Gene and Its Expression
J. PHILIPPE. With 8 Figures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
A. Introduction............................................... 11
B. Structure.................................................. 12
I. The Glucagon Gene. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
II. Genes Encoding Peptide Hormones of the Glucagon
Superfamily. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 14
C. Expression................................................. 17
