Diabetes and the Endocrine Pancreas: A Biochemical Approach PDF
Preview Diabetes and the Endocrine Pancreas: A Biochemical Approach
DIABETES AND THE ENDOCRINE PANCREAS: A Biochemical Approach CROOM HELM BIOLOGY IN MEDICINE SERIES STEROID HORMONES D.B. Gower NEUROTRANSMITTERS AND DRUGS Zygmunt L. Kruk and Christopher J. Pycock DEVELOPMENT, GROWTH AND AGEING Edited by Nicholas Carter INBORN ERRORS OF METABOLISM Edited by Roland Ellis MEMBRANE PHYSIOLOGY AND CELL EXCITATION Bruce Hendry THE BIOCHEMISTRY AND PHARMACOLOGY OF ANTIBACTERIAL AGENTS R.A.D. Williams and Z.L. Kruk NEUROTRANSMITTERS AND DRUGS Second Edition Zygmunt L. Kruk and Christopher J. Pycock Diabetes and the Endocrine Pancreas A Biochemical Approach William Montague CROOM HELM London & Canberra © 1983 William Montague Croom Helm Ltd, Provident House, Burrell Row, Beckenham, Kent BR3 1AT British Library Cataloguing in Publication Data Montague, William Diabetes and the endocrine pancreas. - (Croom Helm biology in medicine series) 1. Endocrinology. 2. Metabolism 3. Diabetes I. Title 616.4'62 RC660 a ISBN 978-0-85664-888-5 ISBN 978-94-011-6379-8 (eBook) DOI 10.1007/978-94-011-6379-8 CONTENTS Preface vii Acknowledgements ix l. Introduction 11 2. Structure of the Endocrine Pancreas 14 3. Insulin Synthesis, Storage and Secretion 27 4. Insulin Action 61 5. Glucagon 86 6. Somatostatin 103 7. Pancreatic Polypeptide 110 8. Function of the Islets of Langerhans 116 9. Diabetes Mellitus 132 10. Diabetic Complications 153 Index 168 v PREFACE This book attempts to explore the contribution that biochemistry has made, thus far, to our understanding of the endocrine pancreas and its relationship to diabetes mellitus. It was written with the aim of using an important clinical problem to illustrate, to medical students, that there are many aspects of the biochemistry taught in the early years which have direct relevance to clinical medicine. Furthermore, it is hoped that such information might provide biochemistry students with a frame work on which to base further studies. To this end a selection of recent references has been placed at the end of each chapter. In spite of considerable advances in our understanding of diabetes mellitus, it is still a disease which many physicians do not seem to com prehend. This is in part related to their lack of understanding of the molecular biology of the disease. Advances in this area have been dramatic in recent years and we are now able to offer a molecular basis for a rational approach to therapy. It may be therefore that this book will provide some physicians with the information they require to help them gain a deeper understanding of the disease. I hope that everyone who reads this book is able to capture some of the fascination that the islets of Langerhans hold for myself and the many other workers actively engaged in trying to unravel their mys teries. vii ACKNOWLEDGEMENTS I am indebted to Simon Howell, Peter Watkins and my wife for their patient reading of the manuscript and to Simon Howell and Lelio Orci for allowing me to reproduce some of their beautiful electron micro graphs. In addition, I wish to thank Pamela Broster, Amelia Dunning and Ulla Gervind-Richards for their patient typing of the manuscript. ix For Agnes, Claire and Lisa 1 INTRODUCTION Diabetes mellitus is at present one of the major health problems in Europe and North America affecting at least 1 per cent of the popula tion. Moreover, although the acute and potentially lethal metabolic derangements of diabetes can be controlled with insulin therapy, the long-term complications of the disease which may involve the cardio vascular, renal and nervous sytems reduce life expectancy by as much as a third. In spite of intensive research into the aetiology and pathogenesis of the disease many aspects of diabetes remain a mystery. However, it is now clear that diabetes is not a single disease entity, but rather a syn drome composed of a number of diseases that share glucose intolerance as a common feature. Two major types of primary diabetes mellitus are now recognised clinically, Type 1 or insulin-dependent diabetes mellitus (IDD) and Type 2 or non-insulin-dependent diabetes mellitus (NIDD). They both appear to result from a complex interaction between the individual and the environment and in some cases the outcome of this interaction may be influenced by the genetic constitution of the indi vidual. Diabetes mellitus is known to have affected man for many thousands of years, the earliest recorded description of the symptoms being found in the Ebers papyrus of Egypt which dates back to 1500 BC. However, it was not until the second century AD that Aretaeus of Cappadocia named the disease diabetes, the Greek word meaning 'to flow through a siphon'. He wrote 'Diabetes is a remarkable disorder. It consists of a moist and cold wasting of the flesh and limbs into urine. The disease is chronic in its character, and is slowly engendered, though the patient does not survive long when it is completely established, for the maras mus produced is rapid and death speedy'. This was a masterly description of the striking symptoms of severe diabetes, a copious flow of urine accompanied by the wasting away of both muscle and fat. In the sixth century, Hindu physicians recognised that the urine from diabetic patients tasted sweet, although it was not until the eighteenth century that the sweet-tasting substance was identified as the sugar glucose and the word mellitus, or 'honeyed', was added. One of the first clues to the pathology underlying diabetes came in 11 12 Introduction 1889 from the experimental work of Von Mering and Minkowski. They found that removal of the pancreas from dogs gave rise to a syndrome resembling diabetes, i.e. increased production of urine containing glucose. They went on to show that the pancreas was a gland of internal secretion which produced a substance that regulated glucose metabol ism. Laguesse, in 1894, drew attention to the original observations of Paul Langerhans, who had in 1869 described small 'heaps' or islands of a previously unknown cell type in the pancreas. Laguesse suggested that these islands of cells should be called the islets of Langerhans, and that they were the gland of internal secretion of the pancreas. The hypothet ical pancreatic secretion, the lack of which induced the diabetic state was given the name 'insuline' by De Meyer in 1900 to denote its origin from the 'insulae' of Langerhans. Further work developed in two major directions. One consisted of extensive histological studies of the islets which led to the finding of several distinct cell types and foreshadowed our present knowledge that the islets produce and secrete several different hormones. The other pathway consisted of the numerous attempts to extract from the pan creas a potent, antidiabetic material, the insuline of De Meyer. Many technical problems had to be overcome before insulin could be ex tracted from the pancreas in sufficient quantities and pure enough for human use. With the benefit of hind-sight, we now know that most of the problems were due to the facts that insulin is a protein and the pancreas is rich in proteolytic enzymes. This meant that steps had to be taken to minimise proteolytic destruction during extraction. Moreover, any material isolated could not be given orally to test its antidiabetic activity as it would be degraded by the digestive enzymes. Banting and Best successfully overcame these problems and in 1921 produced the first useful and consistently successful insulin preparation for the treat ment of diabetes. The discovery of insulin was hailed as a cure for diabetes because it lowered blood-glucose levels, controlled the acute symptoms of the disease and prevented the coma and death that some times came within days of the onset of symptoms. However, it became apparent several years later that diabetics who had been on insulin for a long time were found to have an unusually high incidence of cardiovascular disease, renal disease, gangrene and blindness. Insulin treatment thus controlled the early metabolic symp toms of diabetes, but in some cases not the development of long-term complications. These observations raised the question as to whether the long-term complications of diabetes are the result of inadequate or inappropriate therapy or whether they represent a generalised tissue
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