Degradation of islet amyloid polypeptide by neprilysin

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

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

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, Leu 12-Ala13, Asn14-Phe15, Phe 15- Leu16, Asn22-Phe23 and Ala 25-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 IAPPinduced 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.

Original languageEnglish
Pages (from-to)2989-2998
Number of pages10
JournalDiabetologia
Volume55
Issue number11
DOIs
StatePublished - Nov 2012

Bibliographical note

Funding Information:
Funding This work was supported in part by grants from the National Institutes of Health RO1DA02243 and P20RR020171 (to L.B. Hersh) and R01DK50610 (to C.J. Rhodes). University of Kentucky Center for Structural Biology Proteomics Core Facility is supported in part by grant P20RR020171 from the NIH/NCRR and currently NIGMS.

Keywords

  • Beta cell apoptosis
  • Cleavage
  • Human islet amyloid polypeptide
  • Islet amyloid
  • Neprilysin
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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