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Mol Cell Endocrinol. 2017 Jun 15;448:108-121. doi: 10.1016/j.mce.2017.04.001. Epub 2017 Apr 5.

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

Author information

1
Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
2
ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgium.
3
Department of Neurosciences and Pharmacology, University of Copenhagen, Denmark.
4
Department of Genetic Medicine and Development, University of Geneva, Switzerland.
5
Department of Biomedical Sciences, University of Copenhagen, Denmark.
6
Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark.
7
Department of Cellular Physiology and Metabolism, University of Geneva, Switzerland.
8
Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark. Electronic address: Joachim.stoerling.01@regionh.dk.

Abstract

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.

KEYWORDS:

Apoptosis; Cytokine; Insulin; Type 1 diabetes; β-cell

PMID:
28390953
DOI:
10.1016/j.mce.2017.04.001
[Indexed for MEDLINE]

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