[HTML][HTML] Deletion of Fas protects islet beta cells from cytotoxic effects of human islet amyloid polypeptide
YJ Park, S Lee, TJ Kieffer, GL Warnock, N Safikhan… - Diabetologia, 2012 - Springer
Diabetologia, 2012•Springer
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 h IAPP-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 …
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 h IAPP-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 …
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.
Springer