The role of caspase-8 in amyloid-induced beta cell death in human and mouse islets.
Diabetologia
; 57(4): 765-75, 2014 Apr.
Article
em En
| MEDLINE
| ID: mdl-24442508
ABSTRACT
AIMS/HYPOTHESIS:
Reduced beta cell mass due to increased beta cell apoptosis is a key defect in type 2 diabetes. Islet amyloid, formed by the aggregation of human islet amyloid polypeptide (hIAPP), contributes to beta cell death in type 2 diabetes and in islet grafts in patients with type 1 diabetes. In this study, we used human islets and hIAPP-expressing mouse islets with beta cell Casp8 deletion to (1) investigate the role of caspase-8 in amyloid-induced beta cell apoptosis and (2) test whether caspase-8 inhibition protects beta cells from amyloid toxicity.METHODS:
Human islet cells were cultured with hIAPP alone, or with caspase-8, Fas or amyloid inhibitors. Human islets and wild-type or hIAPP-expressing mouse islets with or without caspase-8 expression (generated using a Cre/loxP system) were cultured to form amyloid. Caspase-8 and -3 activation, Fas and FLICE inhibitory protein (FLIP) expression, islet beta cell and amyloid area, IL-1ß levels, and the betaalpha cell ratio were assessed.RESULTS:
hIAPP treatment induced activation of caspase-8 and -3 in islet beta cells (via Fas upregulation), resulting in apoptosis, which was markedly reduced by blocking caspase-8, Fas or amyloid. Amyloid formation in cultured human and hIAPP-expressing mouse islets induced caspase-8 activation, which was associated with Fas upregulation and elevated islet IL-1ß levels. hIAPP-expressing mouse islets with Casp8 deletion had comparable amyloid, IL-1ß and Fas levels with those expressing hIAPP and Casp8, but markedly lower beta cell apoptosis, higher betaalpha cell ratio, greater beta cell area, and enhanced beta cell function. CONCLUSIONS/INTERPRETATION:
Beta cell Fas upregulation by endogenously produced and exogenously applied hIAPP aggregates promotes caspase-8 activation, resulting in beta cell apoptosis. The prevention of amyloid-induced caspase-8 activation enhances beta cell survival and function in islets.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ilhotas Pancreáticas
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Células Secretoras de Insulina
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Caspase 8
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Amiloide
Limite:
Adult
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Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article