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Diabetologia

Erschienen in:

01.11.2012 | Article

Degradation of islet amyloid polypeptide by neprilysin

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

Erschienen in: Diabetologia | Ausgabe 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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Titel: Degradation of islet amyloid polypeptide by neprilysin
verfasst von: H. Guan
K. M. Chow
R. Shah
C. J. Rhodes
L. B. Hersh
Publikationsdatum: 01.11.2012
Verlag: Springer-Verlag
Erschienen in: Diabetologia / Ausgabe 11/2012
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-012-2678-y

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Abstract

Aims/hypothesis

Methods

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Conclusions/interpretation

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