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

• Published in: Molecular and cellular endocrinology Vol. 448; pp. 108 - 121
• Main Authors: Berchtold, Lukas A., Miani, Michela, Diep, Thi A., Madsen, Andreas N., Cigliola, Valentina, Colli, Maikel, Krivokapic, Jelena M., Pociot, Flemming, Eizirik, Decio L., Meda, Paolo, Holst, Birgitte, Billestrup, Nils, Størling, Joachim
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 15.06.2017
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Connexins - deficiency; Connexins - metabolism; Cytokine; Cytokines - pharmacology; Gene Knockdown Techniques; Glucose Intolerance - metabolism; Glucose Intolerance - pathology; Humans; Hyperglycemia - pathology; Inflammation - pathology; Insulin; Insulin-Secreting Cells - metabolism; Mice, Inbred C57BL; Nitric Oxide Synthase Type II - metabolism; Phosphorylation - drug effects; Rats; STAT3 Transcription Factor - metabolism; Streptozocin; Type 1 diabetes; β-cell; β-cell; Type 1 diabetes; Insulin; Cytokine; Apoptosis
• ISSN: 0303-7207; 1872-8057
• DOI: 10.1016/j.mce.2017.04.001

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. •Pannexin 2 is expressed in pancreatic islets and β-cells.•Pannexin 2-deficiency is associated with aggravated islet apoptosis.•Pro-inflammatory cytokines suppress pannexin 2 expression.•Pannexin 2-deficiency increases the severity of chemically-induced diabetes in mice.