Table Of ContentDIABETES 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
