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Τετάρτη 5 Απριλίου 2017

Pannexin-2-deficiency sensitizes pancreatic β-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo

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Publication date: Available online 5 April 2017
Source:Molecular and Cellular Endocrinology
Author(s): Lukas A. Berchtold, Michela Miani, Thi A. Diep, Andreas N. Madsen, Valentina Cigliola, Maikel Colli, Jelena M. Krivokapic, Flemming Pociot, Decio L. Eizirik, Paolo Meda, Birgitte Holst, Nils Billestrup, Joachim Størling
Pannexins (Panx's) are membrane proteins involved in a variety of biological processes, including cell death signaling and immune functions. The role and functions of Panx's in pancreatic β-cells remain to be clarified. Here, we show Panx1 and Panx2 expression in isolated islets, primary β-cells, and β-cell lines. The expression of Panx2, but not Panx1, was downregulated by interleukin-1β (IL-1β) plus interferon-γ (IFNγ), two pro-inflammatory cytokines suggested to contribute to β-cell demise in type 1 diabetes (T1D). siRNA-mediated knockdown (KD) of Panx2 aggravated cytokine-induced apoptosis in rat INS-1E cells and primary rat β-cells, suggesting anti-apoptotic properties of Panx2. An anti-apoptotic function of Panx2 was confirmed in isolated islets from Panx2-/- mice and in human EndoC-βH1 cells. Panx2 KD was associated with increased cytokine-induced activation of STAT3 and higher expression of inducible nitric oxide synthase (iNOS). Glucose-stimulated insulin release was impaired in Panx2-/- islets, and Panx2-/- mice subjected to multiple low-dose Streptozotocin (MLDS) treatment, a model of T1D, developed more severe diabetes compared to wild type mice. These data suggest that Panx2 is an important regulator of the insulin secretory capacity and apoptosis in pancreatic β-cells.



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