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Diabetologia
Published in: Diabetologia 11/2012

01-11-2012 | Article

Degradation of islet amyloid polypeptide by neprilysin

Authors: H. Guan, K. M. Chow, R. Shah, C. J. Rhodes, L. B. Hersh

Published in: Diabetologia | Issue 11/2012

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Abstract

Aims/hypothesis

A progressive loss of pancreatic beta cell function, a decrease in beta cell mass and accumulation of islet amyloid is characteristic of type 2 diabetes mellitus. The main constituent of islet amyloid is islet amyloid polypeptide (IAPP). In this study, we examined the ability of the peptidase neprilysin to cleave IAPP and prevent human IAPP-induced pancreatic beta cell toxicity.

Methods

Neprilysin and a catalytically compromised neprilysin mutant were tested for their ability to inhibit human IAPP fibrillisation and human IAPP-induced pancreatic beta cell cytotoxicity. Degradation of human IAPP by neprilysin was followed by HPLC, and the degradation products were identified by MS.

Results

Neprilysin prevented IAPP fibrillisation by cleaving IAPP at Arg11-Leu12, Leu12-Ala13, Asn14-Phe15, Phe15-Leu16, Asn22-Phe23 and Ala25-Ile26. It also appears to prevent human IAPP fibrillisation through a non-catalytic interaction. Neprilysin protected against beta cell cytotoxicity induced by exogenously added or endogenously produced human IAPP.

Conclusions/interpretation

The data presented support a potential therapeutic role for neprilysin in preventing type 2 diabetes mellitus. This study supports the hypothesis that extracellular human IAPP contributes to human IAPP-induced beta cell cytotoxicity. Whether human IAPP exerts its cytotoxic effect through a totally extracellular mechanism or through a cellular reuptake mechanism is unclear at this time.
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Metadata
Title
Degradation of islet amyloid polypeptide by neprilysin
Authors
H. Guan
K. M. Chow
R. Shah
C. J. Rhodes
L. B. Hersh
Publication date
01-11-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 11/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2678-y

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