Treatment of EARL Y DIABETES

ADV ANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY Editorial Board:

Nathan Back State University 0/ New York at Buffalo

N. R. Di Luzio Tulane University School 0/ Medicine

Ephraim Katchalski The Wei::mann Institute of Science

David Kritchevsky Wistar Institute

Abel Lajtha New York State Research Institute for Neurochemistry and Drug Addiction

Rodolfo Paoletti University 0/ Milan

Recent Volumes in this Series

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Edited by David M. Klachko, Ralph R. Anderson, and Murray Heimberg

Volumt' 112 OV ARIAN FOLLICULAR AND CORPUS LUTEUM FUNCTION

Edited by Cornelia P. Channing, John M. Marsh, and William A. Sadler

Volume 113 PARKINSON'S DISEASE -II: Aging and Neuroendocrine Relationships

Edited by Caleb E. Finch, David E. Potter, and Alexander D. Kenny

Volume 114 FUNCTION AND STRUCTURE OF THE IMMUNE SYSTEM

Edited by Wolfgang Mtiller-Ruchholtz and Hans Konrad Miilll'r-Hermelink

Volume 115 DYNAMICS OF ARTERIAL FLOW

Edited by Stewart Wolf and Nicholas T. Werthessen

Volume 116 MODULATORS, MEDIATORS, AND SPECIFIERS IN BRAIN FUNCTION

Edited by Yigal H. Ehrlich, Jan Volavka, Leonard G. Davis, and Eric G. Brunngraber

Volume 117 STEROID HORMONE RECEPTOR SYSTEMS

Edited by Wendell W. Leavitt and James H. Clark

Volume 118 CELL SUBSTRATES: Their Use in the Production of Vaccines and Other Biologicals

Edited by John C. Petricciani, Hope E. Hopps, and Paul J. Chapple

Volume 119 TREATMENT OF EARLY DIABETES

Edited by Rafael A. Camerini-Davalos and Bernard Hanover

Volume 120A KININS - II: Biochemistry, Pathophysiology, and Clinical Aspects

Edited by Setsuro Fujii, Hiroshi Moriya, and Tomoji Suzuki

Volume 120B KININS - II: Systemic Proteases and Cellular Function

Edited by Setsuro Fujii, Hiroshi Moriya, and Tomoji Suzuki

Treatment of EARLY DIABETES

Edited by

Rafael A. Camerini-Davalos and

Bernard Hanover Diabetes Center New York Medical College New York, New York

PLENUM PRESS • NEW YORK AND LONDON

Library of Congress Cataloging in Publication Data

International Symposium on Early Diabetes, 4th, Algarve, 1978. Treatment of early diabetes.

(Advances in experimental medicine and biology; v. 119) "Sponsored by the Diabetes Center of New York Medical College." Includes index. 1. Diabetes - Congresses. I. Camerini-Davalos, Rafael A., 1916- 11. New

York Medical College, Flower and Fifth Avenue Hospitals. Diabetes Center. IlI. Tide. IV. Series. RC660.A1I59 1978

ISBN 978-1-4615-9112-2 DOI 10.1007/978-1-4615-9110-8

616.4'62'06 79-16121

ISBN 978-1-4615-9110-8 (eBook)

Proceedings of the Fourth International Symposium on Early Diabetes, sponsored by the Diabetes Center of New Y ork Medical College, held in Algarve, Portugal, November 7-11, 1978.

© 1979 Plenum Press, New York Softcover reprint ofthe hardcover 1st edition 1979

A Division of Plenum Publishing Corporation 227 West 17th Street, New York, N.Y. lOOl1

All rights reserved

No part of this book may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means electronic, mechanical, photocopying, microfilming, recording, or otherwise, without wriUen permission from the Publisher

Preface

To obey the precepts of therapeutic rationality, we should avoid treating the "effect" when there is a way to attack the cause. But what is the cause of diabetes?

Diabetes is a molecular disease, that is, a disease in which important cellular components are seriously impaired. Eventually, the activities or the products arising from the impairment find expression in various ways, finally culminating in the abnormalities of diabetes.

How early is early enough to attempt to delay this sequence of events? What will provide us with the basis to explore ways and means of halting the progression of the pathological process? What are the new approaches for the treatment of early diabetes?

The Fourth International Symposium on Early Diabetes, sponsored by the Diabetes Center of the New York Medical College, held in Algarve, Portugal in November 1978, from which this book evolved, attempted to answer some of these questions.

A list of the participants, including their affiliations, will be found preceding the index.

Rafael A. Camerini-Davalos

v

Acknowledgments

To our sponsors, U.S.V. Pharmaceutical Corp., Pfizer Pharmaceuticals, Ames Company, Hoechst, Frankfurt; supporters, Boehringer, Manheim, Laboratoires Servier, Nordisk Laboratory, The Upjohn Company, Eli Lilly and Company, F. Hoffman La Roche; and contributors, Bayer A. G. Leverkusen, McNeil, Novo Research Institute, ICI Belgium, Hope for Diabetics Foundation, New York, we express our appreciation for the financial support which made possible the Fourth International Symposium on Early Diabetes.

THE ORGANIZING COMMITTEE

Rafael A. Camerini-Davalos, M.D.

vii

Stefan S. Fajans, M.D. Norbert Freinkel, M.D.

J.J. Hoet, M.D. Ernst Pfeiffer, M.D.

Contents

EARLY DIABETES: DEFINITION, PRESENT CONCEPT

Early Diabetes. Concept. Terminology. • • • • • • • • • 1 R.A. Camerini-DavaZos

Early Stages of Diabetes: Definitions and Present Concepts ••••

S.S. Fajans

Prediabetes in the Pima Indians • • • • P.J. Savage~ R.F. Hamman and P.H. Bennett

The Prognosis of Insulin Dependent Diabetes Mellitus and the Importance of Supervision •

T. Deckert and M. Larsen

Discussion • • • • • •

GENETIC INFLUENCES ON ISLET CELL FUNCTION

HLA System

HLA and the Genetic Aspects of the Predisposition to Juvenile Diabetes Mellitus. A Follow-Up

P. Rubenstein and N. Suciu-Foca

HLA Studies in Diabetics • • • • • • • • • • • • L.P. Ryder~ M. Christy~ J. Nerup, P. PZatz, A. Svejgaard and M. Thomsen

Discussion • • •

Familial Patterns of Inheritance

On the Genetic Heterogeneity of Juvenile

7

13

21

29

33

41

49

Hyperglycemia • • • • • • • • • • • • • • 51 J. Barbosa and M.M. Chern

ix

x

Familial Patterns of Inheritance of Diabetes Mellitus. Maturity-Onset Type Diabetes of Young People (MODY) • • • • • • • • • • • • •

M.C. Cloutier and S.S. Fajans

Discussion • • • • • • . . . . . •

METABOLIC ASPECTS OF ISLET CELL FUNCTION

Phosphate Trans10cations During Secretory Stimulation of Pancreatic Islets • • • • •

N. Freinkel

The Role of Phosphoenolpyruvate and Lactate Production in Insulin Secretion • • • • • •

C.J. Hedeskov and K. Capito

Effects of Insu1inotropic Agents on Cationic Fluxes in Islet Cells • • • • • • • • • • •

W.J. Malaisse~ A. Sener and A. Herchuelz

Glucose-Induced Changes of the Membrane Potential of Pancreatic B-Ce11s: Their Significance for the Regulation of Insulin Release • • • • • • •

H.P. Meissner and M. Preissler

Discussion • • • •

ABNORMAL DEVELOPMENT OF THE PANCREAS

Effect of Maternal Carbohydrate Intolerance on the Development of the Autonomic Innervation of the Fetal Rat Pancreas •••••••••

M. de Gasparo~ P. de Herdt and J.J. Hoet

Discussion

CONTENTS

59

67

71

79

85

97

109

115

123

ENVIRONMENTAL FACTORS INFLUENCING ISLET CELL FllICTION

Nutritional

Suppression of Insulin Secretion by Protein Deprivation in Obesity • • • • • • • • • • • • • • •

D.E. Schteingart~ A.K. McKenzie~ R.S. Victoria and H.S. Tsao

125

CONTENTS

Discussion

Viruses

Virus-Induced Diabetes Mellitus: Infection of Mice with Variants of Encepha1omyocarditis Coxsackievirus B4, and Reovirus Type 3 ••

A.L. Notkins~ J. Yoon~ T. Onode~a and A.B. Jenson

Autoimmunity

Immunological Aspects of Diabetes Mellitus W. J. Irvine

Virus,

. . . . . . . Detection and Possible Functional Influence of Antibodies Directed Against the Pancreatic Islet Cell Surface • • • • • • • • • • • • • • • • • •

A. LePnma~k~ T. Kanatsuna~ A.H. Rubenstein and D.F. Steine~

Discussion • • • • • •

PATTERNS OF INSULIN SECRETION

Heterogeneity of Insulin Responses in Maturity­Onset Type Diabetes (MOD) and in Maturity-Onset Type Diabetes of Young People (MODY) • • • • • •

S.S. Fajans

Progression of Early Diabetes • • • • • • • W. Oppe~ann~ C.A. VeZasao~ A.S. Reddi~ B. Hanove~ and R.A. Came~ini-Davatos

Insulin Resistance and Insulin Secretion in Patients with Chemical Diabetes: Implications Concerning the Pathogenesis of Idiopathic Diabetes Mellitus •••••• • • • • • • • •

G.M. Reaven

Inquiries into the Pathogenesis of Gestational Diabetes • • • • • • • • • • • • •

B.E. Metzge~ and N. F~einkeZ

Effect of Intravenous Glucose, Leucine and ' Arginine on Concentration of Insulin in Maternal

xi

133

137

147

157

165

171

177

187

201

and Umbilical Cord Serum • • • • • • • • • • • • • • • • 209 S. G~asso~ G. PaZumbo~ S. RugoZo~ R. Vigo and G. Turnino

Discussion

MECHANISM OF SALVAGING BETA CELL FUNCTION

Beta Cell Dysfunction in Maturity-Onset Diabetes: Reversible Loss of Glucose-Induced Insulin Secretion with Retention of Response to Arginine •

P.J. Savage~ L.J. Bennion~ E.V. FZock and P.H. Bennett

Improvement of Insulin Secretion in Diabetics by a Prostaglandin Synthesis Inhibitor

R.P. Robertson~ M. Chen~ J.R. McRae and S.A. Metz

Discussion • •

DIET THERAPY

Decreased Food Intake

Effect of Diet Limitation on Development of Diabetes in Non-Hyperphagic Prediabetic Chinese Hamsters • • • • • • • • •

C. Gerritsen and M.C. BZanks

Riboflavin in CHO Metabolism

The Role of Riboflavin in Carbohydrate Metabolism A.S. Reddi~ P.K. Ho and R.A. Camerini-DavaZos

Discussion

Responses to Different Complex Carbohydrates

Effect of Variations in Carbohydrate Intake on Plasma Glucose, Insulin and Triglyceride Responses in Normal Subjects and Patients with Chemical Diabetes • • • •

G.M. Reaven

High Carbohydrate, High Fiber Diets for Patients with Diabetes • • • • • • • • • • • • • • •

J.W. Anderson

Dietary Fiber and Diabetic Therapy: A Progressive Effect with Time • • • • • • • • • • • • • • • • • • • •

D.J.A. Jenkins~ T.M.S. WoZever~ R. Nineham~ S. Bacon~ R. Smith and T.D.R. Hockaday

CONTENTS

213

219

227

233

237

243

251

253

263

275

CONTENTS

Discussion

High Myoinositol

Dietary myo-Inositol and Diabetic Neuropathy R.S. CZements, Jr.

Discussion • • • • • • • . . . . . . . . . . . . . . . . LONG TERM TREATMENT WITH INSULIN

Animals

Effect of Insulin Treatment on the Mesangial Structure of KK Mice • • • • • • •

W. OppeTImann, H. Wehner, A.S. Reddi and R.A. Camerini-DavaZos

Humans

Insulin Treatment for Adult Onset Diabetes: A Report of the University Group Diabetes Program • • • • • • • • • • • • • • • . • •

T.E. Prout

Refuting the UGDP Conclusion That Insulin Treatment Does Not Prevent Vascular Complications in Diabetes • • • • • • • • • • •

C. KiZo, J.R. WiZZiamson, S.C. Choi and J.P. MiUer

Discussion • • •

New Synthetic Insulins P.G. Katsoyannis

NEW INSULINS

Differential Response of Insulin-Dependent Diabetics to Infusions of Bovine and Highly­Purified Porcine Insulins: A Preliminary Report

K.G.M.M. AZberti, R. Nosadini, G. Noy and A.B. Kurtz

Discussion • • •

xiii

281

287

293

295

301

307

313

319

329

337

xiv

ENZYME INHIBITORS

Delay of Carbohydrate Absorption by Inhibitors of Intestinal ~-Glucosidases •••••••

W. PuZs and H.P. Krause

Inhibition of Polyol Pathway Activity in Diabetic and Galactosemic Rats by the Aldose Reductase Inhibitor CP-45,634 •••••••

M.J. Peterson, R. Sarges, C.E. AZdinger and D.P. MacDonaZd

Discussion • • • • • • •

MECHANISM OF ACTION OF ORAL COMPOUNDS

Genetic Control of Tolbutamide Metabolism in Humans • • • • • • • • • • • • • • ill • • • • •

J. Scott, A.D. Henderson and P.L. Poffenbarger

Insulin Resistance in Patients with Insulin Independent Diabetes Mellitus: Partial Amelioration by the Sulfonylurea Glipizide •

H. Lebovitz and M.N. FeingZos

Discussion • • •

LONG TERM TREATMENT WITH ORAL COMPOUNDS

Animals

Diabetic Glomerulosclerosis in KK Mice and Its Prevention by Glyburide and Pyridinolcarbamate

R.A. Camerini-DavaZos, A.S. Reddi, T.H. Ehrenreich, L.H. Strugatz and W. Oppermann

Discussion • • • •

Humans

Long Term Treatment of Asymptomatic Diabetes J.A. BuZZ, H. Dies, J. SchuZte, F.J. Gomez-Perez, J. Sanchez-Gochicoa, J. Figueroa and O. Lozano-Castaneda

CONTENTS

341

347

357

361

371

381

387

399

401

CONTENTS

Metabolic Fate, Vascular Outcome and the Effect of Treatment in Borderline Diabetics • • • • • •

J.C. Pickup~ H. Keen and R.J. Jarrett

Long-Term Treatment of Subjects with Borderline Glucose Tolerance • • • • • • • • • • • • •

S. Carlstrom, G. Persson, G. Sartor and B. Schersten

Discussion • • • •

NEW ORAL AGENTS: COMPARISONS

Glipizide: A New Second Generation Sulfonylurea E. Norris

Effect of the Oral Hypoglycemic Agent Pirogliride Tartrate on Insulin and Glucagon Secretion In Vivo and In Vitro • • • • • • • •

G.F. Tutwiler, H.C. Fawthrop, R.T. Krill and S. Pek

Gliclazide in the Treatment of Diabetic Retinopathy • • • • • • • • • • • •

F. RegnauZt

Discussion • • •

EXERCISE

The Effect of Repetitive Exercise on Daily Control of Glycemia in Insulin-Dependent Diabetic Patients • • • • • • • • • • • • • •

R. Coce, R. Femenic, Z. Skrabalo and M. Vranic

Discussion • •

SUBSTITUTION OF ISLET CELL FUNCTION

Transplant

Isolation and Preservation In Vitro of Human Pancreatic Islets Intended for Transplantation

C. Hellerstrom~ B. Nilsson, S. sandler, A. Andersson, A. Agren and B. Petersson

xv

407

411

419

427

435

443

449

453

463

465

xvi

The Development, Enhancement and Reversibility of Diabetic Glomerulopathy • • • • • • • • • • • •

M.W. Steffes~ D.M. Brown and S.M. Mauer

Discussion • • • • . . . . . . . . . . Newer Delivery Systems

Substitution of Islet-Cell Function with "Open-Loop" Insulin Infusion Systems • •

K.D. Hepp~ R. Renner~ M. Franetzki and H. Mehnert

Newer Insulin Delivery Systems: Continuous Subcutaneous Insulin Infusion • • • • •

J.C. Pickup~ H. Keen~ J.A. Parsons~ and K.G.M.M. AZberti

Discussion • • • • • •

Mechanical Devices

Substitution of Islet Cell Function by Mechanical Device: Extracorporeal Artificial Pancreas • • . • . • • • . . . • • • • • . . •

E.F. Pfeiffer~ W. Kerner and W. Beischer . . . . .

Glycemic Normalization Using a Preprogrammed Insulin Delivery Device in Unrestrained Diabetic Dogs • • • • • • • • • • • • • • • • • • • • •

A.M. AZbisser~ Y. Goriya~ A. Bahoric and E.B. MarZiss

Discussion • • • • •

List of Participants •

Index

CONTENTS

473

479

485

491

497

501

509

515

519

529