The Biology of the Pancreatic β-Cell PDF
Preview The Biology of the Pancreatic β-Cell
ADVANCES IN MOLECULAR AND CELL BIOLOGY THE BIOLOGY OF THE PANCREATIC P-CELL Series Editor: E. EDWARD BITTAR Department of Physiology Uni versi t y of Wisconsin- M ad is on Madison, Wisconsin Guest Editor: SIMON L. HOWELL School of Biomedical Sciences King’s College London London, England VOLUME 29 1999 @ J A1 PRESS INC. Stamford, Connecticut Copyright 0 7999 ]A/ PRESS INC 700 Prospect Street Stamford, Connecticut 06907 A//r ight, reserved. No part of this publication may be reproduced, stored on a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, filming, recording, or otherwise, without prior permission in writing from the publisher. ISBN: 0-7623-0547-9 Manufactured in the United States of America LIST OF CONTRIBUTORS Lydia Aguilar-Bryan Division of Endocrinology Baylor College of Medicine Houston, Texas Bo Ahr6n Department of Medicine Malmo University Hospital Malmo, Sweden Michael R. Christie Department of Medicine King’s College School of Medicine and Dentistry London, England John W M. Creemers Laboratory of Molecular Oncology University of Leuven Leuven, Belgium Philippe Detimary Department de Physiologie et de Pharmacologie Unit6 d’Endocrinologie et M6tabolisme Universit6 Catholique de Louvain Brussels, Belgium Kevin Docherty Molecular and Cell Biology Department Institute of Medical Sciences University of Aberdeen Foresterhill, Aberdeen, Scotland Dkio 1. Eizirik Diabetes Research Centre Vrije Universiteit Brussel Brusse Is, Belgium Patrick Cilon Department de Physiologie et de Pharmacologie Unit6 d’Endocrinologie et M6tabolisme Universiti. Catholique de Louvain Brussels, Belgium vii viii LIST OF CONTRIBUTORS Tracey E. Harris School of Biomedical Sciences King’s College London London, England Jean-Claude Henquin Department de Physiologie et de Pharmacologie Unit6 d’Endocrinologie et M6tabolisme Universite Catholique de Louvain Brussels, Belgium Simon L. Howell School of Biomedical Sciences King’s College London London, England Anne Hoorens Diabetes Research Centre Vrije Universiteit Brussel Brussels, Belgium lohn C. Hutton Barbara Davis Center for Childhood Diabetes University of Colorado Health Sciences Center Chicago, Illinois Robert S. Jackson Department of Clinical Biochemistry Addenbrooke’s Hospital Cambridge, England Jean-ChristopheJ onas Department de Physiologie et de Pharmacologie Unit6 d’Endocrinologie et Metabolisme Universit6 Catholique de Louvain Brussels, Belgium Peter M. Jones School of Biomedical Sciences King’s College London London, England Stewart A. Metz Diabetes Laboratories Pacific Northwest Research Institute Seattle, Washington Shanta 1. Persaud School of Biomedical Sciences King’s College London London, England List of Contributors IX Arun S. Rajan Division of Endocrinology Baylor College of Medicine Houston, Texas Romano Regazzi lnstitut de Biologie Cellulaire et de Morph ologi e Universitg de Lausanne Lausanne, Switzerland Yoshihiko Sato Department of Geriatrics Shinshu University School of Medicine Matsumoto, Japan lonathan M. W Slack Developmental Biology Programme Department of Biology and Biochemistry University of Bath Bath, England Emile Van Schaftingen Lab de Chimie Physiologique Faculte de Medecine Universiti. Catholique de Louvain Brussels, Belgium Frans Schuit Laboratory of Biochemistry Diabetes Research Center Vrije Universiteit Brussel Brussels, Belgium Christina Wasmeier Barbara Davis Center for Childhood Diabetes University of Colorado Health Sciences Center Denver, Colorado PR E FACE As a result of the key advances made more than 30 years ago, specifically the abil- ity to isolate islets of Langerhans from the pancreas, the ability to measure insulin accurately by immunoassay, and the development of microchemical techniques for studying cells and their components, many research volumes, symposium reports, and original papers have been produced. This explosion of interest has probably had at least three stimuli: 1. the inherent scientific interest in understanding secretion of the pancreatic f3-cell 2. the p-cells relevance to a very common disease 3. the availability of funding from specific sources related to diabetes research, for instance, Juvenile Diabetes Foundation International and the British Diabetic Association As a result of all this activity, detailed scientific literature including research reviews are readily available. Surprisingly enough, there are relatively few attempts to summarize this great bulk of knowledge in a way that is accessible to the newcomer to this field and this book is intended to bridge this gap. We hope it will be useful for postgraduate stu- dents setting out on their PhD studies, for established scientific investigators enter- ing this field for the first time, and for advanced undergraduate and postgraduate xi xii PREFACE students seeking to undertake special study of this subject. Each contributor has written an objective overview of his or her particular subject in a way that should allow the reader within a short period to obtain a comprehensive and up-to-date picture of the present state of the art. Where appropriate, the information about p human cells and changes that are known to occur in diabetes are highlighted. Each chapter has references pointing the way to more detailed information. The contributors and editor hope very much that this book will be useful in pro- viding background information to trigger the imagination of scientists of all ages and experience entering this exciting field for the first time. Simon L. Howell Guest Editor DEVELOPMENTAL BIOLOGY OF THE P-CELL Jonathan M.W. Slack I. Introduction ....................................................... 3 11. Embryology ....................................................... 4 111. Pancreatic Determination ............................................ 7 IV. CelllineageStudies ................................................ 10 V. Growth Control ................................................... 13 VI. Conclusions.. .................................................... 16 1. INTRODUCTION Many misconceptions abound on the subject of the origin of the pancreatic p-cells. This is perhaps surprising because the understanding of p-cell biology is poten- tially an important practical issue in terms of its significance for novel therapies for diabetes. One commonly encountered error is the idea that pancreatic endo- crine cells have their origin in the neural crest of the early embryo, now known to be incorrect. A more subtle misconception is found in most textbooks of pathol- ogy or histology insofar as they devote separate chapters to the exocrine and the endocrine pancreas. Because they secrete enzymes into the duodenum, the exo- Advances in Molecular and Cell Biology Volume 29, pages 3-19. Copyright 0 1999 by JAI Press Inc. All rights of reproduction in any form reserved. ISBN: 0-7623-0547-9 3 4 JONATHAN M.W. SLACK crine cells are seen as an integral part of the digestive system. In contrast, the endo- crine cells are seen as belonging in the domain of endocrinology and the control of metabolism. While this is understandable in terms of the different medical spe- cialists who deal with these two respective areas of disease, it is not helpful to an understanding of the biology of the organ, since the evidence is now very good that both cell types arise from a common source in the endodermal epithelium. Another idea that is not necessarily incorrect, but rather takes too much for granted, is that of “precursor cells” for the mature p-cells of the pancreas. It is not self-evident that a precursor cell population should necessarily exist. For example, if the final cell division of a pancreatic epithelial cell gave rise to both endocrine and exocrine daughters, then it would not be correct to refer to endocrine precursor cells. If the final division of an endocrine cell gave rise both to a p-cell and to a cell of another endocrine type, then it might be correct to speak of endocrine pre- cursors, but not of p-cell precursors. If p-cell precursors do exist, then we would need to know about where they come from, when they are produced, and what properties they have. 11. EMBRYOLOGY Pancreatic development has been studied mainly in rodents (Pictet and Rutter, 1972; Slack, 1995). Although much of the earlier work was done on the rat, it is likely that future experimental work will concentrate on the mouse, which is now the most popular mammal for studies in developmental biology. The reasons for this are twofold: first, more genes have been cloned from the mouse than from the rat; second, the genetic technology in terms of making transgenic and knockout strains is well established for the mouse but not for the rat. Although physiologists are desperate to have transgenic rats at their disposal, it seems likely that they will eventually have to reduce the size of their instruments and settle for working on mice. Thus, the timings given here relate to the mouse, although the overall course of pancreatic development is similar for all vertebrates. The main difference between human and mouse is that the pancreas in the adult is compact in the human but diffuse in the mouse, meaning that there are many small nodules of pancreatic tissue scattered across the mesentery in the vicinity of the main pancre- atic mass. In this chapter, the terms “anterior” and “posterior” will be used in the zoological sense to denote the head and tail ends of the body, or the gut, rather than in the human anatomical sense in which they are synonymous with ventral and dorsal respectively. The pancreas originates from a region of the gut endoderm very close to that giving rise to the liver and gall bladder. This tissue is normally considered to lie in the foregut, although it occasionally is described as being in the midgut. The dis- tinction is that the foregut is that part of the gut tube lying anterior (i.e., cranial) to the anterior intestinal portal (Figure 1). Since the opening in the gut tube is ini- Developmental Biology of the p-Ce// 5 anterior intestinal portal I septum tra allantois Figure 7. General view of a mammalian embryo at an early stage of gut closure, showing the location of the foregut. tially enormous and later constricts down to a small orifice at the umbilicus, it is by no means obvious what comes from the foregut and what comes from the mid- gut. Indeed, it is likely that much of the gut becomes passively transferred from midgut to foregut as the ventral closure of the umbilical opening proceeds. A sat- isfactory fate map showing which areas in the early endodermal sheet become the pancreatic buds has yet to be produced, and such a fate map is obviously necessary in order to find which genes are active in the pancreatic anlagen prior to outgrowth of the buds. The first appearance of the pancreas is as two small buds, one on the dorsal and one on the ventral side of the duodenum (Figure 2). The dorsal bud is visible from 10.5 days and the ventral bud from 12.5 days of gestation in the mouse. The two buds are initially separate but quite soon fuse into a single organ. The duct of the ventral pancreas normally becomes the main pancreatic duct, and in the human, the ventral pancreas remains visible postnatally as the uncinate process. Although they look solid, the early pancreatic buds are actually highly convoluted infoldings of the gut epithelium. They undergo repeated branching during growth, with the stems of the branches becoming the ductal system and the acini developing at the tips. The first endocrine cells become visible at 9.5 days by immunostaining with antibodies to glucagon and insulin C-peptide. Over the period from 10.5 to 14.5 days, many of the cells present in the pancreatic buds stain simultaneously with
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