The Polyol Paradigm and Complications of Diabetes
Margo Panush Cohen The Polyol Paradigm and Complications of Diabetes With a Foreword by Harold Rifkin With 25 Figures Springer-Verlag New York Berlin Heidelberg London Paris Tokyo
Margo Panush Cohen, M.D.,Ph.D. Professor of Medicine and Director Division of Endocrinology and Metabolism University of Medicine and Dentistry of New Jersey Newark, New Jersey 07103 USA The quotation on pp. 2-3 is reprinted by permission of The Wall Street Journal, Dow Jones and Company, Inc. 1986. All rights reserved. Library of Congress Cataloging in Publication Data Cohen, Margo P. The polyol paradigm and complications of diabetes. Bibliography: p. Includes index. 1. Diabetes-Complications and sequelae. 2. Polyols-Physiological effect. 3. Aldose reductase. 1. Title. [DNLM: 1. Diabetes Mellituscomplications. 2. Diabetes Mellitus-enzymology. 3. Sugar Alcohol Dehydrogenases-metabolism. WK 895 C678p] RC660.C474 1987 616.4'62 86-26022 1987 by Springer-Verlag New York Inc. All rights reserved. This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer-Verlag, 175 Fifth Avenue, New York, New York 10010, USA), except for brief excerpts in connection with reviews or scholarly analysis. Use in connection with any form of information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed is forbidden. The use of general descriptive names, trade names, trademarks, 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. While the advice and information in this book are believed to be true and accurate at the date of going to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Typeset by Publishers Service, Bozeman, Montana. 987654321 ISBN-13: 978-1-4612-9108-4 DOl: 10.10071978-1-4612-4670-1 e-isbn-13: 978-1-4612-4670-1
To Louis and Tillie Panush and to Perry, Michael, Daniel, and Jonathan Cohen
Foreword In the last decade, it has become increasingly evident that the clinical and morphologic changes underlying many of the complications of diabetes, including cataract formation, retinopathy, nephropathy, neuropathy, and macrovascular disease, are preceded by a variety of disturbances of biochemical and physiologic origin. Dr. Cohen has recently written a superb monograph, entitled Diabetes and Protein Glycosylation: Measurement and Biologic Relevance, in which she thoroughly explores how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for maintenance of long-term euglycemia. In the present volume, The Polyol Paradigm and Complications of Diabetes, she reviews, in a most succinct and thorough manner, how another biochemical mechanism, involving the polyol pathway, is involved in the pathogenesis of such diabetes complications as retinopathy, neuropathy, nephropathy, and cataract formation. Dr. Cohen gives us a clearly written and comprehensive monograph, reviewing the chemistry of the polyol pathway and of the aldose reductase inhibitors, and the pathophysiologic significance of increased polyol pathway activity in a variety of tissues affected by
Vlll Foreword diabetes mellitus. She insightfully describes the relationship of increased polyol pathway activity to altered metabolism of inositolcontaining phospholipids and to changes in various tissue concentrations of myo-inositol. Finally, she provides us with a careful review of the existing experimental and clinical studies with a variety of different aldose reductase inhibitors that have been and are being performed in the hope of preventing or reversing long-term complications of diabetes. This monograph is a most welcome addition to the literature on diabetes and its chronic complications, particularly since its author is a world-renowned endocrinologist and diabetes specialist who, throughout the years, has focused the major portion of her research activities on the biochemical and metabolic aberrations underlying the long-term complications of diabetes. It should appeal to the basic and clinical investigator, as well as to the clinician, and should be present in every medical school and hospital library where it is easily accessible and available to all who are concerned and involved with the management of diabetic patients. HAROLD RIFKIN, M. D. Clinical Professor of Medicine Albert Einstein College of Medicine Professor of Clinical Medicine New York University School of Medicine Principal Consultant Diabetes Research and Training Center Albert Einstein College of Medicine Montefiore Medical Center New York, New York
Preface The polyol paradigm is one of two major theories that have been advanced to explain the pathogenesis of the complications of diabetes. The other, which implicates excess nonenzymatic glycosylation, has been described in the companion volume Diabetes and Protein Glycosylation, also published by Springer-Verlag. The polyol pathway originally was described in the ocular lens, where it was implicated in the development of sugar cataracts. It now is clear that the polyol pathway is present in diverse tissues, where it may participate in the pathogenesis of diabetic neuropathy, retinopathy, and microvascular disease. The pathway involves two enzymes, aldose reductase and sorbitol dehydrogenase, the first of which converts sugars into their respective alcohols (polyols). It is believed that activation of the polyol pathway has deleterious metabolic effects in several organs. Blocking the pathway by inhibiting aldose reductase, the responsible enzyme, thus may interrupt or forestall development of tissue damage in diabetes. The Polyol Paradigm and Complications of Diabetes comprehensively reviews the biochemistry and pathophysiologic consequences
x Preface of enhanced polyol pathway activity, with discussions oriented around the organ systems affected. Insights gained from experimental studies and clinical trials with aldose reductase inhibitors are critically analyzed. M.P. COHEN
Contents Foreword....................................... vii Preface......................................... ix 1. Introduction.... 2. Chemistry... 5 Aldose Reductase and Sorbitol Dehydrogenase... 5 Aldose Reductase Inhibitors........................ 14 3. Aldose Reductase and Complications of the Eye....... 25 Cataracts....................................... 25 Retinopathy..................................... 33 Keratopathy... " 45 4. Diabetic Neuropathy... 59 5. Diabetic Nephropathy... 79
xii Contents 6. Aldose Reductase and the Vascular System............ 93 Microvasculature... 93 Macrovasculature................................ 94 Erythrocytes.................................... 96 7. Clinical Trials................................... 105 Bibliography.................................... 113 Index... 139