Islet amyloid polypeptide (IAPP), or ‘amylin’, is co-stored with insulin in secretory granules of pancreatic islet β-cells. In Type 2 diabetes, IAPP converts into a β-sheet conformation and oligomerizes to form amyloid fibrils and islet deposits. Granule components, including insulin, inhibit spontaneous IAPP fibril formation in vitro. To determine the mechanism of this inhibition, molecular interactions of insulin with human IAPP (hIAPP), rat IAPP (rIAPP) and other peptides were examined using surface plasmon resonance (BIAcore), CD and transmission electron microscopy (EM). hIAPP and rIAPP complexed with insulin, and this reaction was concentration-dependent. rIAPP and insulin, but not pro-insulin, bound to hIAPP. Insulin with a truncated B-chain, to prevent dimerization, also bound hIAPP. In the presence of insulin, hIAPP did not spontaneously develop β-sheet secondary structure or form fibrils. Insulin interacted with pre-formed IAPP fibrils in a regular repeating pattern, as demonstrated by immunoEM, suggesting that the binding sites for insulin remain exposed in hIAPP fibrils. Since rIAPP and hIAPP form complexes with insulin (and each other), this could explain the lack of amyloid fibrils in transgenic mice expressing hIAPP. It is likely that IAPP fibrillogenesis is inhibited in secretory granules (where the hIAPP concentration is in the millimolar range) by heteromolecular complex formation with insulin. Alterations in the proportions of insulin and IAPP in granules could disrupt the stability of the peptide. The increase in the proportion of unprocessed pro-insulin produced in Type 2 diabetes could be a major factor in destabilization of hIAPP and induction of fibril formation.
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February 2004
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Research Article|
February 01 2004
Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation
Emma T. A. S. JAIKARAN;
Emma T. A. S. JAIKARAN
1
*Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, U.K.
†Department of Human Anatomy and Genetics, Oxford University, South Parks Road, Oxford OX1 3QX, U.K.
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Melanie R. NILSSON;
Melanie R. NILSSON
2
*Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, U.K.
‡Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, U.K.
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Anne CLARK
Anne CLARK
3
*Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Oxford OX3 7LJ, U.K.
†Department of Human Anatomy and Genetics, Oxford University, South Parks Road, Oxford OX1 3QX, U.K.
3To whom correspondence should be addressed (e-mail [email protected].).
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Publisher: Portland Press Ltd
Received:
June 09 2003
Revision Received:
September 17 2003
Accepted:
October 20 2003
Accepted Manuscript online:
October 20 2003
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London ©2004
2004
Biochem J (2004) 377 (3): 709–716.
Article history
Received:
June 09 2003
Revision Received:
September 17 2003
Accepted:
October 20 2003
Accepted Manuscript online:
October 20 2003
Citation
Emma T. A. S. JAIKARAN, Melanie R. NILSSON, Anne CLARK; Pancreatic beta-cell granule peptides form heteromolecular complexes which inhibit islet amyloid polypeptide fibril formation. Biochem J 1 February 2004; 377 (3): 709–716. doi: https://doi.org/10.1042/bj20030852
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