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Hindrik Mulder

Hindrik Mulder

Principal investigator

Hindrik Mulder

Expression of Islet Amyloid Polypeptide - Localization and regulation in the pancreatic islets, gastrointestinal tract and sensory nervous system.

Author

  • Hindrik Mulder

Summary, in English

Islet amyloid polypeptide (IAPP; also named ”amylin”) is a member of the calcitonin superfamily of peptides, displaying the closest structural relationship to the neuropeptide calcitonin gene-related peptide (CGRP). It is expressed in islet beta-cells and forms islet amyloid in type 2 diabetic patients. IAPP may restrain release and peripheral actions of insulin. Thus, IAPP has been implicated in the pathogenesis of type 2 diabetes. By examinations of tissue-specific expression of IAPP and its regulation under normal and experimental conditions, we aimed to illuminate a possible role of IAPP.



IAPP was expressed in islet beta-cells in nearly all species examined; in some species IAPP occurred also in delta-cells. IAPP expression was of early onset during embryonic islet development. In vivo, we found a parallel regulation of IAPP and insulin expression by administration of glucose. These findings agree with a role for IAPP in glucose homeostasis by autocrine/paracrine regulation of islet function as well as by endocrine secretion.



Following dexamethasone treatment of rats, a model for type 2 diabetes, we found a non-parallel expression of IAPP and insulin; in relative terms, IAPP was over-expressed compared with insulin. In rodents given streptozotocin or alloxan, conferring beta-cell depletion reminiscent of type 1 diabetes, IAPP expression was consistently less impaired than that of insulin. These studies show that IAPP and insulin gene expression are differentially regulated. Apparently, beta-cell stress, regardless of ethiology, results in over-expression of IAPP.



IAPP was also found to be expressed in the gastrointestinal tract in a region- and species-dependent manner; when present, IAPP expression was most abundant proximally, occurring in somatostatin and gastrin cells. Also gastrointestinal IAPP expression was of early embryonic onset. In vitro, IAPP relaxed pre-contracted gut musculature.



In the sensory nervous system IAPP was expressed in CGRP neurons and displayed a distribution typical of sensory neuropeptides. Upon sciatic axotomy, IAPP and CGRP expression were co-ordinately downregulated. In contrast, following adjuvant-induced rat paw inflammation, IAPP expression was upregulated in innervating neurons, indicating that IAPP may play a role in neurogenic inflammation.



In conclusion, our studies have expanded the view of IAPP as an exclusive islet hormone to become a ”classical” neurohormonal peptide, with several endocrine and neuronal expression sites. The studies on the regulation of islet IAPP and insulin expression in response to glucose and in experimental diabetes may form the basis for an understanding of the role of IAPP in diabetes. Provided that the amyloidogenic mechanisms and metabolic effects of IAPP are elucidated, an over-expression of IAPP may prove to be relevant for diabetes development.

Department/s

  • Department of Experimental Medical Science

Publishing year

1997

Language

English

Document type

Dissertation

Publisher

Neuroendocrine Cell Biology, EA-Blocket, 5th Floor, Lund University Hospital, S-221 85 Lund; Sweden

Topic

  • Cell and Molecular Biology

Keywords

  • sekretion
  • Endokrinologi
  • diabetologi
  • Endocrinology
  • secreting systems
  • diabetology

Status

Published

Supervisor

  • [unknown] [unknown]

ISBN/ISSN/Other

  • ISBN: 91-628-2534-8
  • ISRN: LUMEDW/MEFN-08-SE

Defence date

16 May 1997

Defence time

10:15

Defence place

Lecture room 6, Centralblocket, Lund University Hospital

Opponent

  • Anne Clark (Dr)