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

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

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Connexins / deficiency*
  • Connexins / metabolism
  • Cytokines / pharmacology*
  • Gene Knockdown Techniques
  • Glucose Intolerance / metabolism*
  • Glucose Intolerance / pathology
  • Humans
  • Hyperglycemia / pathology
  • Inflammation / pathology
  • Insulin-Secreting Cells / metabolism*
  • Mice, Inbred C57BL
  • Nitric Oxide Synthase Type II / metabolism
  • Phosphorylation / drug effects
  • Rats
  • STAT3 Transcription Factor / metabolism
  • Streptozocin

Substances

  • Connexins
  • Cytokines
  • PANX2 protein, human
  • Panx2 protein, mouse
  • STAT3 Transcription Factor
  • pannexin 2, rat
  • Streptozocin
  • Nitric Oxide Synthase Type II