Diabetes Mellitus: Pathophysiology and Therapy978-3-642-74255-2/1.pdf · On the Pathogenesis of Insulin-Dependent Diabetes Mellitus A Discussion of Three Recently Proposed Models

Diabetes Mellitus: Pathophysiology and Therapy Bayer AG Centenary Symposium

Edinburgh, U. K., May 25-28, 1988

Editors: W. Creutzfeldt P. Lefebvre

Springer-Verlag Berlin Heidelberg New York London Paris Tokyo

Professor Dr. Werner Creutzfeldt Medizinische Klinik und Poliklinik Abteilung fUr Gastroenterologie und Endokrinologie Georg-August -U niversitat G6ttingen Robert-Koch-StraBe 40 3400 G6ttingen FRG

Professor Dr. Pierre J. Lefebvre Diabetes, Nutrition and Metabolic Disorders Unit CHU Sart Tilman (B 35) 4000 Liege Belgium

ISBN-13: 978-3-540-50506-8 DOl: 10.1007/978-3-642-74255-2

e-ISBN-13: 978-3-642-74255-2

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 microfilms or in other ways, and storage in data banks. Duplication of this publication or parts thereof is only permitted under the provisions of the German Copyright Law of September 9, 1965, in its version of June 24, 1985, and a copyright fee must always be paid. Violations fall under the prosecution act of the German Copyright Law.

© Springer-Verlag Berlin Heidelberg 1989

The use of general descriptive names, trade names, trade marks, etc. in this publication, even if the former are not especially identified, is not to be taken as a sign that such names, as understood by the Trade Marks and Merchandise Marks Act, may accordingly be used freely by anyone.

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.

2127/3140/543210 - Printed on acid-free paper

Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. XIX

History and Philosophy of Bayer Pharmaceutical Research W.-D. BussE. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. XXI

Pathophysiology

Etiology

Epidemiology -Its Contribution to Understanding of the Etiology, Pathogenesis, and Prevention of Diabetes Mellitus P. ZIMMET, G. DowsE, R. LA PORTE, C. FINCH, and C. Moy

Genetics of Diabetes Mellitus

5

J. KOBBERLING, andH. TILLIL ............................... 27

On the Pathogenesis of Insulin-Dependent Diabetes MellitusA Discussion of Three Recently Proposed Models J. NERUP, T. MANDRUP-POULSEN, J. M0LVIG, S. HELQVIST, andL. DALL WOGENSEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 39

Challenging Views on the Pathogenesis of Type I (Insulin-Dependent) Diabetes Mellitus G.F. BOTTAZZO, E. BONIFACIO, E. BOSI, R. MlRAKIAN, I. TODD, and R. PUJoL-BoRRELL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 51

Islet Amyloid and Type 2 Diabetes P. WESTERMARK . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 63

Physiology and Pathophysiology

Insulin Receptor: Role of Receptor Tyrosine Kinase in Insulin Signalling and Action E. VAN OBBERGHEN, S. GAMMELTOFT, Y. LE MARcHAND-BRUSTEL, and R. BALLOTTI. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 73

VI Contents

The Kinetics ofInsulin, C-Peptide, and Proinsulin in Normal and Diabetic Man K. S. POLONSKY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 82

Cell Biology of Insulin Action on Glucose Transport and Its Perturbation in Diabetes Mellitus B.B.KAHN,andS.W.CUSHMAN ............................. 94

Mechanisms of Insulin Resistance in Obese and Type II Diabetic Subjects A. D. BARON, O. G. KOLTERMAN, R. PRAGER, G. R. FREIDENBERG, R. R. HENRY, W. T. GARVEY, andJ. M. OLEFSKY . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 107

Abnormal Glucagon Secretion in Type 2 (Noninsulin-Dependent) Diabetes Mellitus: Causes and Consequences J.E. GERICH. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 127

Animal Models

Physiopathology and Possible Etiology of Hormonal Dysregulations and Insulin Resistance in Obese Rats: a Potential Model for Some Human Obesity B. JEANRENAUD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 137

Models for Studying Diabetic Complications J.R. WILLIAMSON,K CHANG, R. G. TILTON, andC. KILO

Pharmacology

Insulin Analogues - Potentials for Improving Diabetes Treatment F.B. HANSEN, I.G. CLAUSEN, B. DATH, E.B. JENSEN, B.R. JOHANSEN, I. JONASSEN, F. JUNKER, KD. J0RGENSEN, G. MEYN, J. PETERSEN,

142

and P. BALSCHMIDT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 155

Metabolic Inhibitors in the Treatment of Diabetes Mellitus K G.M.M.ALBERTI,H.S.A. SHERRATI, andP.L. SELBY. . . . . . . . . . . . .. 164

Inhibitors Influencing Carbohydrate Absorption W.F. CASPARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 172

Therapy

Comprehensive Approach to the Treatment of Diabetes Mellitus

Why and How to Involve the Diabetic Patient in his Treatment

R. TATTERSALL. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 197

Contents VII

Prevention of Late Complications

Advanced Non-Enzymatic Tissue Glycosylation: Biochemical Basis of Late Diabetic Complications

H. VLASSARA, M. BROWNLEE, and A. CERAMI. . . . . . . . . . . . . . . . . . . . .. 209

Is it Possible to Prevent Late Complications of Diabetes Mellitus?

J.D. WARD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 218

Recent Aspects of Insulin Therapy

Long-Term Efficacy and Safety of Intensified Insulin Treatment Strategies

M. BERGER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 225

Is Human Insulin Better than Animal Insulin in the Treatment of Insulin-Dependent Diabetes Mellitus?

G. SCHERNTHANER ...................................... 234

Specific Problems of Diabetes Mellitns in Youth

Natural History of Diabetes Mellitus in Children

D. D. ETZWILER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 245

Particular Aspects of the Management of Diabetes in Children

Z. LARON, S. AMIR, M. KARp, Z. FLEXER, G. FAIMAN, R. OFAN, Y. ALBAG, O. KALTER-LEIBOVICI, andA. GALATZER . . . . . . . . . . . . . . . . . . . . . . . .. 252

The Pregnant Diabetic

The State of the Art in Diabetic Pregnancy

J.D.BAIRD ........................................... 267

Relationship Between Maternal Glucose Levels and Congenital M,!lformations in the Infant of the Diabetic Mother

L. JOVANOVIC-PETERSON, and C. M. PETERSON ..................... 275

VTII Contents

Pancreas and Islet Transplantation

State of the Art in Pancreas Transplantation

D. E. R. SUTHERLAND .................................... 283

What Future for Islet Transplantation in Man?

R. LANDGRAF. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 288

Diet

Aims of Diet in Diabetes Management

D.J.A. JENKINS, A.L. JENKINS, TH.M.S. WOLEVER, V. VUKSAN, G.S. WONG,

andR.G.JoSSE ........................................ 299

Practicability of Diet in Diabetes Management

A.L. JENKINS, D.J.A. JENKINS, TH.M.S. WOLEVER, V. VUKSAN, G.S. WONG,

andR. G. JOSSE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 309

New Aspects of Diabetes Treatment

Induction of Partial Remission and Enhancement of Beta-Cell Function

By Cyclosporin in Type I Diabetes

J. DUPRE, and C. R. STILLER. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 321

Role of Abnormal Free Fatty Acid Metabolism in the Pathogenesis

and Treatment of Noninsulin-Dependent Diabetes Mellitus

G.M. REAVEN . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 335

Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 351

Contributors

Y. ALBAG

Institute of Pediatric and Adolescent Endocrinology, Beilinson Medical Center, Petah Tikva 49100, Israel

K. G. M. M. ALBERTI

Department of Medicine, Medical School, Framlington Place, Newcastle upon Tyne NE2 4HH, UK

S.AMIR Institute of Pediatric and Adolescent Endocrinology, Beilinson Medical Center, Petah Tikva 49100, Israel

J. BAIRD Department of Medicine, University of Edinburgh, Western General Hospital, Edinburgh EH4 2XV, UK

R. BALLOlTI

INSERM, Unite 145, Faculte de Medecine, avenue de Valombrose, 06034 Nice Cedex, France

P. BALSCHMIDT

Nordisk Gentofte AlS, Niels Steensensvej 1,2820 Gentofte, Denmark

A.D. BARON

Veterans Administration Medical Center, Medical Research Service (V-Ill G), 3350 La Jolla Village Drive, San Diego, CA 92161, USA

M. BERGER

Medizinische Einrichtungen der Universitat Dusseldorf, Medizinische Klinik und Poliklinik, Abteilung fUr Stoffwechsel und Erniihrung, MoorenstraBe 5, 4000 Dusseldorf 1, FRG

E. BONIFACIO

Department of Immunology, The University College and Middlesex School of Medicine, Arthur Stanley House, 40-50 Tottenham Street, London WIP 9PG, UK

X Contributors

E. BOSI

Department of Immunology, The University College and Middlesex School of Medicine, Arthur Stanley House, 40-50 Tottenham Street, London W1P 9PG, UK

G. F. BOTIAZZO


M. BROWNLEE

Laboratory of Medical Biochemistry, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA

W.-D. BUSSE

Bayer AG, Leitung Fachbereich Pharma-Forschung, Aprather Weg 18a, D-5600 Wuppertal1, FRG

W.F. CASPARY

Zentrum der Inneren Medizin, Abteilung fur Gastroenterologie, Johann-Wolfgang Goethe UniversiHi.t, Theodor-Stern-Kai 7,6000 FrankfurtlM. 70, FRG

A. CERAMI


K. CHANG

Department of Pathology, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA

I. G. CLAUSEN


S. W. CUSHMAN

National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

L. DALL WOGENSEN

Steno Memorial Hospital, Niels Steensensvej 2, 2820 Gentofte, Denmark

B. DATH


G. DOWSE

Lions-International Diabetes Institute, The Royal Southern Memorial Hospital, 260 Kooyong Road, Caulfield 3162, Australia

Contributors XI

J. DUPRE University of Western Ontario, University Hospital, P.O. Box 5339, Postal Stn., A., London, Ontario N6A 5A5, Canada

D. D. ETZWILER

International Diabetes Center, 5000 W. 39th St., 4959 Excelsior Boulevard, Minneapolis, MN 55416, USA

G. FAIMAN Institute of Pediatric and Adolescent Endocrinology, Beilinson Medical Center, Petah Tikva 49100 Israel

C. FINCH


z. FLEXER


G. R. FREIDENBERG


A. GALATZER


S. GAMMELTOFf


W.T. GARVEY


J.E. GERICH

University of Pittsburgh, Clinical Research Center, 3488 Presbyterian-University Hospital, 230 Lothrop Street, Pittsburgh, PA 15261, USA

F.B. HANSEN

Nordisk Gentofte NS, Niels Steensensvej 1,2820 Gentofte, Denmark

s. HELQVIST


XII Contributors

RR HENRY


B. JEANRENAUD

Laboratoires de Recherches Metaboliques, 64, avenue de la Roseraie, 1211 Geneva 4, Switzerland

A. L. JENKINS

Department of Nutritional Sciences, Faculty of Medicine and Division of Endocrinology and Metabolism, St. Michael's Hospital, University of Toronto, Toronto, Ontario M55 lAB, Canada

D.J.A. JENKINS

Department of Nutritional Sciences, Faculty of Medicine and Division of Endocrinology and Metabolism, St. Michael's Hospital, University of Toronto, Toronto, Ontario M551AB, Canada

E.B. JENSEN


B.R JOHANSEN


I. JONASSEN


K.D. Jf2lRGENSEN


RG. JOSSE


L. JOVANOVIC-PETERSON

Sansum Medical Research Foundation, 2219 Bath Street, Santa Barbara, CA 93105, USA

F. JUNKER


B.B. KAHN Harvard Medical School, Beth Israel Hospital, 330 Brookline Avenue, Boston, MA 02215, USA

Contributors xm

o. KALTER-LEmOVICI


M.KARP Institute of Pediatric and Adolescent Endocrinology, Beilinson Medical Center, Petah Tikva 49100, Israel

C. KILo Department of Internal Medicine, Washington University School of Medicine, 660 South Euclid Avenue, St. Louis, MO 63110, USA

J. KOBBERLING

Medizinische Klinik des Ferdinand-Sauerbruch-Klinikums Elberfeld, Akademisches Lehrkrankenhaus der Universitat Dusseldorf, Arrenberger StraBe 20, 5600 Wuppertal1, FRG

O. G. KOLTERMAN


R. LANDGRAF

Medizinische Klinik Innenstadt der Universitat Munchen, ZiemssenstraBe 1, 8000 Munchen 1, FRG

R. LAPORTE

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, P A 15261, USA

Z. LARoN


Y. LE MARCHAND-BRUSTEL


T. MANoRUP-POULSEN


G.MEYN Nordisk Gentofte AlS, Niels Steensensvej 1,2820 Gentofte, Denmark

R.MnwaAN Department of Immunology, The University College and Middlesex School of Medicine, Arthur Stanley House, 40-50 Tottenham Street, London W1P9PG, UK

XIV Contributors

J. M0LVIG


C.Moy

Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, PA 15261, USA

J. NERUP


E. VAN OBBERGHEN


R. OFAN


J.M.OLEFSKY


J. PETERSEN


C. M. PETERSON

Sansum Medical Research Foundation, 2219 Bath Street, Santa Barbara, A 93105, USA

K. S. POLONSKY

University of Chicago, Department of Medicine, Box 435, 5841 S. Maryland Avenue, Chicago, IL 60637, USA

R. PRAGER


R. PUJOL-BoRRELL


G.M. REAVEN

Department of Medicine, Stanford University Medical Center, Veterans Administration Medical Center, 3801 Miranda Avenue, Palo Alto, CA 94304, USA

Contributors XV

G. SCHERNTHANER

Department of Medicine n, University of Vienna and Department of Medicine I, Rudolfstiftung Hospital, Juchgasse 25, A-I030 Vienna, Austria

P.L. SELBY


H.S.A. SHERRATI


C.R STILLER

University of Western Ontario, University Hospital, P.O. Box 5339, Postal Stn., A., London, Ontario N6A 5A5, Canada

D.E.R SUTHERLAND

University of Minnesota, Hospital and Clinic, Department of Surgery, 420 Delaware St. S.E., Minneapolis, MN 55455, USA

R TATIERSALL

Department of Medicine, Queen's Medical Centre, University Hospital, Nottingham NG7 2UH, UK

H. TILLIL

Medizinische Klinik des Ferdinand-Sauerbruch-Klinikums Elberfeld, Akademisches Lehrkrankenhaus der Universitat Dusseldorf, Arrenberger StraBe 20, 5600 Wuppertall, FRG

RG. TILTON

Department of Pathology, Washington University School of Medicine, 660 Euclid Avenue, St. Louis, MO 63110, USA

1. TODD

Department of Immunology, The University College and Middlesex School of Medicine, Arthur Stanley House, 40-50 Tottenham Street, London WIP 9PG, UK

H. VLASSARA


V. VUKSAN


XVI Contributors

J.D. WARD Sheffield Health Authority, Royal Hallamshire Hospital, Glossop Road, Sheffield SlO 2JF, UK

P. WESTERMARK

Faculty of Health Sciences, Department of Pathology, 58185 Link6ping, Sweden

J. R. WILLIAMSON

Department of Pathology, Washington University School of Medicine, 660 Euclid Avenue, St. Louis, MO 63110, USA

TH.M.S. WOLEVER

Department of Nutritional Sciences, Faculty of Medicine and Division of Endocrinology and Metabolism, St. Michael's Hospital, University of Toronto, Toronto, Ontario M55 lAB, Canada

G.S. WONG

Department of Nutritional Sciences, Faculty of Medicine and Divison of Endocrinology and Metabolism, St. Michael's Hospital, University of Toronto, Toronto, Ontario M55 lAB, Canada

P. ZIMMET


Author Index

Albag, Y. 252 Garvey, W. T. 107 Nerup, J. 39 Alberti, K.G.M.M. 164 Gerich, J.E. 127 Amir, S. 252 van Obberghen, E. 73

Hansen, F. B. 155 Ofan, R. 252 Baird, J.D. 267 Helqvist, S. 39 Olefsky, J.M. 107 Ballotti, R. 73 Henry, R.R. 107

Polonsky, K.S. 82 Balschmidt, P. 155 Baron, A.D. 107 Jeanrenaud, B. 137 Petersen, J. 155

Berger, M. 225 Jenkins, A. L. 299,309 Peterson, Ch. M. 275

Bonifacio, E. 51 Jenkins, D.J.A. 299,309 Polonsky, K.S. 82

Bosi, E. 51 Jensen, E.B. 155 Prager, R. 107

Bottazzo, G.F. 51 Johansen, B.R. 155 Pujol-Borrell, R. 51

Brownlee, M. 209 Jonassen, I. 155 Reaven, G. M. 335 Busse, W.-D. XXI Jl'\rgensen, K.D. 155

Josse, R.G. 299,309 Schemthaner, G. 234 Caspary, W.F. 172 Jovanovic-Peterson, L. 275 Selby, P.L. 164 Cerami, A. 209 Junker, F. 155 Sherratt, H. S. A. 164 Chang, K. 142 Stiller, C. R. 321 Clausen I. G. 155 Kahn, B.B. 94 Sutherland, D.E.R. 283 Cushman, S. W. 94 Kalter-Leibovici, O. 252

Karp, M. 252 Tattersall, R. 197 Dall Wogensen, L. 39 Kilo, C. 142 Tillil, H. 27 Dath, B. 155 K6bberling, J. 27 Tilton, R. G. 142 Dowse, G. 5 Koltermann,O.G. 107 Todd, I. 51 Dupre, J. 321

Landgraf, R. 288 Vlassara, H. 209 Etzwiler, D.D. 245 LaPorte, R. 5 Vuksan, V. 299, 309

Laron, Z. 252 Faiman, G. 252 Le Marchand-Bruste1, Y. 73 Ward, J.D. 218 Finch, C. 5 Westermark, P. 63 Flexer, Z. 252 Mandrup-Poulsen, T. 39 Williamson, J.R. 142 Freidenberg, G.R. 107 Meyn, G. 155 Wolever, Th.M.S. 299,309

Mirakian, R. 51 Wong, G.S. 299,309 Galatzer, A. 252 Ml'\lvig, J. 39 Gammeltoft, S. 73 Moy, C. 5 Zimmet, P. 5

Albert E. Renold (1923-1988)

Introducti~n

This symposium had been organized in order to celebrate the centenary of the founding of a pharmaceutical department at the Bayer Company. The history and the eminence of Bayer pharmaceutical research has been summarized by Dr. Busse in a welcome speech included in this book. We would like to express our gratitude to the Bayer Research Centre at Wuppertal, represented by Dr. Busse, Prof. PuIs and Prof. Weihrauch for sponsoring most generously this symposium and, thus, to discuss here in Edinburgh for three days the state of the art in the pathophysiology and therapy of diabetes mellitus. We also want to thank Prof. Oliver and the Royal College of Physicians in Edinburgh for letting us use their marvellous facilities for this purpose.

Research in the field of diabetes mellitus has not a long tradition at Bayer. However, in the last years a new and very original way has been pursued by the pharmacologists, especially Prof. W. PuIs: the use of glucosidase inhibitors as therapeutic agents in order to delay the digestion and absorption of ingested carbohydrates.

When we received more than one year ago from Dr. Hillebrand and Prof. Puls the . offer to design this symposium we gladly accepted the invitation because complete freedom to select the topics and the speakers was guaranteed.

On top of this, all organization was done by the most efficient Congress Service of Bayer. It was a pleasure to prepare this symposium under such conditions. We are happy that so many eminent experts in their field decided to accept the invitation and to contribute up-to-date lectures and, subsequently, chapters to this book.

During the preparation of this meeting, on March 21st, 1988, our good friend for several decades, Professor Albert E. Renold, suddenly died shortly before his 65th birthday. He was supposed to be with us in Edinburgh because he had been a central figure in numerous international meetings on clinical and experimental diabetes and the pathophysiology of diabetes since more than 30 years. When Albert Renold died the international community of diabetologists and clinical biochemists lost one of its most prominent members.

Born in Switzerland, he received his postgraduate training for 15 years in Boston, Mass. /uSA. When he returned to Switzerland in 1963, he became the promotor of the foundation of several European Medical Societies and remained until his death an integrator, not only of basic and clinical research in diabetes mellitus, but also of the research and the people working in different European countries as well as in North America and in other parts of the world.

xx Introduction

His scientific contributions are regarded as classics: the studies about the insulin effect on adipose tissue (together with George F. Cahill Jr.), his work on the biosynthesis and secretion of insulin (together with Lelio Orci and Claes W ollheim) and his studies on various spontaneous and induced diabetes syndromes in rodents (together with Bernard Jeanrenaud and Eleazar Shafrir). Albert Renold will be remembered for a long time by all who knew him for his achievements, for his kindness and his humanity.

We dedicate the Proceedings of this symposium to his memory.

Werner Creutzfeldt G6ttingen

Pierre Lefebvre Liege

History and Philosophy of Bayer Pharmaceutical Research

W.-D. Busse

Fachbereich Forschung Pharma, Bayer AG, D-5600 Wuppertal, FRG

Research has a long tradition at Bayer. This year, 1988, marks 100 years of our pharmaceutical activities. In 1888 the first Bayer drug - phenacetin, an antipyretic -was synthesized, starting from a by-product of dye manufacture. This finding led to the establishment of a Pharmaceutical Department within Friedrich Bayer and Co. in Elberfeld, with all its associated facilities (Fig. 1). The beginning of the company itself, however, dates back to 1863. In that year, Friedrich Bayer started the production of aniline dyestuffs in his private house in Barmen-Rittershausen. During the 125 years of the company's life and the 100 years of pharmaceuticals, many developments and products have been discovered by Bayer researchers and launched by Bayer. But we need consider only the landmarks of these pharmaceutical achievements to illustrate how man's research works for men.

Fig. 1. Original head offices of the company at Barmen-Rittershausen at 1888

XXII W.-D. Busse

Fig. 2. Felix Hoffmann (1868-1946) synthesized acetyl salicylic acid in 1897

Fig. 3. The first stable form of acetyl salicylic acid was developed in 1899. The Aspirin bottle from 1900 contains the powder

Felix Hoffmann, born in 1868, was searching for a drug to help his father, who suffered from rheumatism. He developed a pure and stable form of acetylsalicylic acid, better known under the trade name aspirin, which was launched in 1899 by Bayer. It became the analgesic of choice for millions of people, and even today 80 years later, it has not lost its importance in the pharmaceutical field (Figs. 2, 3). Moreover, its indications have been extended, after the elucidation of its mechanism of action in the late 1970s, and more recently by the results of clinical trials which demonstrated its efficacy in the prevention of myocardial infarction.

Worldwide recognition of Bayer was firmly established after the substantial achievements in the treatment of tropical diseases. Bayer 205 or germanin, active against sleeping sickness and launched in 1923, was developed by the Bayer chemists Oscar Dressel and Richard Kothe from an idea of Wilhelm Rohl. This achievement of curing sleeping sickness was regarded as so significant that a South American farmer and composer wrote the Bayer 205 tango. Thus, germanin is probably the only drug for which a piece of music has been composed.

The antimalarials Atebrin, Plasmochin, and Resochin came soon afterwards. Resochin is today still the most widely used antimalarial drug. These achievements in tropical medicine have made the Bayer cross a symbol for achievement, trust, safety, and quality.

There is no better example of therapeutic success and progress in the history of medicinal chemistry than the advances made in the chemotherapy of infectious

History and Philosophy of Bayer Pharmaceutical Research XXIII

Fig. 4. Professor Gerhard Domagk (1895-1964) in his laboratory in Wuppertal-Elberfeld

diseases. The way was paved by Gerhard Domagk's discovery of the therapeutic effects of a sulfonamide that was introduced into medical therapy under the trade name of Prontosil. This compound, synthesized by Josef Klarer and Fritz Mietzsch, was a giant leap towards the therapeutic control of bacterial infections. For this discovery, Gerhard Domagk received the Nobel Prize for Medicine in 1939 (Fig. 4).

Domagk and his colleagues also made major contributions to the chemotherapy of tuberculosis. Conteben (synthesized by Behnisch, Mietzsch, and Schmidt) was launched in 1946. Shortly afterwards, Offe and Siefken discovered isoniazid (Neoteben). These drugs were the first effective agents against the scourge of tuberculosis. The development of these drugs had a significant impact on pharmacotherapy in medicine, and our company is certainly proud of the significance of her scientific contributions.

The progress and the demands of modern pharmaceutical research made the laboratories located within the Bayer plant at Wuppertal obsolete. During the early 1960s, the building of the Pharma Research Center at Wuppertal was started (Fig. 5). Today, more than 1300 employees work in pharmaceutical research and development. Of these, 260 are senior scientists. In addition, about 30 scientists are professors and exercise teaching responsibilities at universities.

The expenditure of time and finances for the development of new drugs has increased steadily over the years. Of approx. 10000 new chemical compounds synth-

XXIV W.-D. Busse

Fig. 5. Phanna Research Center at Wuppertal-Elberfeld 1988

esized and tested in our laboratories, only 1 will make it to the market place - and hopefully will also become a commercial success. Today, investment for the research and development of a new drug has reached a volume of DM 250-400 million. At the same time, the time needed to develop a drug has significantly increased to more than 10 years after discovery. It is clear that such high expenditure requires us to focus upon a limited number of areas in pharmaceutical research. We have, therefore, concentrated our efforts on the following indications: a) cardiovascular diseases, b) infectious diseases, c) metabolic diseases, d) diseases of the CNS, and e) chronic inflammatory diseases and arthritis.

The dramatic increase in cardiovascular diseases over the past decades and the discovery and successful development of drugs to treat these diseases have encouraged us to further intensify our research efforts in this field. A breakthrough was achieved with the discovery of a new therapeutic principle - the calcium antagonism of the dihydropyridines - by Bossert and Vater. This principle was introduced into medical therapy in 1975 under the trade name of Adalat (nifedipine). Adalat was awarded the Prix Galien for excellent achievements in pharmacotherapy in Paris in 1980.

New dihydropyridines, such as nitrendipine and nisoldipine, are being developed for the treatment of hypertension and coronary heart disease. A further dihydropyridine, nimodipine, exhibits selective activity in cerebrovascular disorders. Clinical trials on a variety of disorders of the CNS (such as stroke, dementia, and Alzheimer's disease) are in progress.

History and Philosophy of Bayer Pharmaceutical Research XXV

In the field of anti-infective therapy, a wide variety of new drugs with improved activity and tolerability have been developed for the treatment of bacterial infections since the first sulfonamides and penicillins. These new drugs include mezlocillin (Baypen), a broad-spectrum penicillin that is also effective against bacterial pathogens outside the range of ampicillin, and azlocillin (Securopen), which additionally exhibits very good activity against Pseudomonas. A recent development is ciprofloxacin, an antibacterial of the quinolone class. This drug can be applied by the oral and parenteral routes, to treat a broad spectrum of bacterial infections.

Another breakthrough was achieved with the discovery of the antimycotic activity of azoles by K. H. Buchel and M. Plempel, which led to the compounds clotrimazole and bifonazole. Both drugs have set new standards in the chemotherapy of mycoses, clotrimazole being the first broad-spectrum antifungal drug.

The development of praziquantel (Biltricide) for the therapy of schistosomiasis in cooperation with E. Merck, Darmstadt, carried on Bayer's tradition in the therapy of tropical diseases. The cure of schistosomiasis - which affects 200 - 300 million people -by a single-dose treatment is regarded as a significant achievement. This therapeutic advance was honored by the renowned Prix Galien in 1987, the second time that a Bayer drug had received this award.

The research activities of our company have been extended into new indications and new technologies. Our new Miles Research Center (West Haven, USA) was opened in April 1988. This research center will house research groups dedicated to the study of autoimmune diseases, molecular pharmacology, and molecular diagnostic methods.

Despite all the impressive achievements and progress in pharmacotherapy, only one-third of known diseases can be attacked causally. Two-thirds of all diseases either cannot be treated or can only be treated palliatively, i. e., by the relief of symptoms. Due to the increase in the size of the elderly population in the Western world, the incidence of age-related diseases (such as cardiovascular, degenerative and chronic inflammatory diseases, and malignant tumors) is expected to rise dramatically. The urgent need for new drugs is best demonstrated by the rapid spread of the human immunodeficiency virus and its sequelae AIDS. We have taken up this challenge by cooperating with Hoechst AG in order to maximize our resources in drug research and development.

The complex diseases with a multifactorial pathogenesis represent the important challenges for pharmaceutical research today. The availability of new technologies, especially recombinant DNA techniques and monoclonal antibodies, and the intense utilization of cellular biology and immunology will lead us to the molecular basis of diseases, thus enabling us to develop specific drugs. Besides these more futuristic approaches, a vast number of regulatory factors have been identified and isolated by the new technologies, e. g. insulin, the interferons, and the clotting factor Factor VIII. These new biological agents are produced in cell culture rather than by chemistry. Within our company, we have developed production methods for the recombinant Factor VIII, and the early-phase clinical trials are scheduled to start this year. This project is regarded as an important milestone in modern pharmaceutical technologies at Bayer.

The new molecular pharmacology allows not only the identification of specific receptors but also the characterization and elucidation of their chemical and three-

XXVI W.-D. Busse

dimensional structure. We expect that this new knowledge, in combination with computer technology , will guide us to a more rational design of new and specific drugs.

Along these lines, in the field of metabolic research we were able to find substances which inhibit digestive enzymes. These enzymes - alphaglucosidases - play an important part in the utilisation of carbohydrates taken up from food. The new developments Acarbose and Miglitol represent a novel approach for the treatment of diabetes, which results in a flattening and thus near-normalisation of elevated 24-hour blood sugar profiles. It thus counteracts late diabetic damage which may develop as a result of the marked variations of blood glucose and plasma insulin levels.

This Centenary Symposium: "Diabetes mellitus: Pathophysiologie and Therapy"

will move the spotlight from the achievements of the past onto the new perspectives in research and the management of the disease in the future.

With further progress in the understanding of the pathophysiology of diabetes, new methods of diagnosis, biomedical technologies and pharmacotherapy - tomorrow's patients will benefit from todays research efforts.

The fact that we are celebrating our Centenary with a Symposium dedicated to this subject indicates that we remain firmly committed to innovation in this important healthcare field.

I wish the Symposium the best success.

Documents

Diabetes Mellitus: Pathophysiology and Therapy978-3-642-74255-2/1.pdf · On the Pathogenesis of Insulin-Dependent Diabetes Mellitus A Discussion of Three Recently Proposed Models