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Diabetologia
Published in: Diabetologia 4/2012

01-04-2012 | Article

Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide

Authors: Y. J. Park, S. Lee, T. J. Kieffer, G. L. Warnock, N. Safikhan, M. Speck, Z. Hao, M. Woo, L. Marzban

Published in: Diabetologia | Issue 4/2012

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Abstract

Aims/hypothesis

Islet amyloid, which is mainly composed of human islet amyloid polypeptide (hIAPP), is a pathological characteristic of type 2 diabetes and also forms in cultured and transplanted islets. We used islet beta cells as well as two ex vivo models of islet amyloid formation, cultured human islets and hIAPP-expressing transgenic mouse islets with or without beta cell Fas deletion, to test whether: (1) the aggregation of endogenous hIAPP induces Fas upregulation in beta cells; and (2) deletion or blocking of Fas protects beta cells from amyloid toxicity.

Methods

INS-1, mouse or human islet cells were cultured with hIAPP alone, or with amyloid inhibitor or Fas antagonist. Non-transduced islets, and human islets or hIAPP-expressing mouse islets transduced with an adenovirus that delivers a human proIAPP-specific small interfering RNA (siRNA) (Ad-ProhIAPP-siRNA) were cultured to form amyloid. Mouse islets expressing hIAPP with or without Fas were similarly cultured. Beta cell Fas upregulation, caspase-3 activation, apoptosis and function, and islet IL-1β levels were assessed.

Results

hIAPP treatment induced Fas upregulation, caspase-3 activation and apoptosis in INS-1 and islet cells. The amyloid inhibitor or Fas antagonist reduced apoptosis in hIAPP-treated beta cells. Islet cells with Fas deletion had lower hIAPP-induced beta cell apoptosis than those expressing Fas. Ad-ProhIAPP-siRNA-mediated amyloid inhibition reduced Fas upregulation and IL-1β immunoreactivity in human and hIAPP-expressing mouse islets. Cultured hIAPP-expressing mouse islets with Fas deletion had similar amyloid levels, but lower caspase-3 activation and beta cell apoptosis, and a higher islet beta:alpha cell ratio and insulin response to glucose, compared with islets expressing Fas and hIAPP.

Conclusions/interpretation

The aggregation of biosynthetic hIAPP produced in islets induces beta cell apoptosis, at least partially, via Fas upregulation and the Fas-mediated apoptotic pathway. Deletion of Fas protects islet beta cells from the cytotoxic effects of endogenously secreted (and exogenously applied) hIAPP.
Appendix
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Metadata
Title
Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide
Authors
Y. J. Park
S. Lee
T. J. Kieffer
G. L. Warnock
N. Safikhan
M. Speck
Z. Hao
M. Woo
L. Marzban
Publication date
01-04-2012
Publisher
Springer-Verlag
Published in
Diabetologia / Issue 4/2012
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-012-2451-2

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