title: Pannexin-2-deficiency sensitizes pancreatic β-cells to cytokine-induced apoptosis in vitro and impairs glucose tolerance in vivo.
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.
authors.affiliation: Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark; Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors.forename: Lukas A
authors.initials: LA
authors.lastname: Berchtold
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgium.
authors.forename: Michela
authors.initials: M
authors.lastname: Miani
authors.affiliation: Department of Neurosciences and Pharmacology, University of Copenhagen, Denmark.
authors.forename: Thi A
authors.initials: TA
authors.lastname: Diep
authors.affiliation: Department of Neurosciences and Pharmacology, University of Copenhagen, Denmark.
authors.forename: Andreas N
authors.initials: AN
authors.lastname: Madsen
authors.affiliation: Department of Genetic Medicine and Development, University of Geneva, Switzerland.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cigliola
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgium.
authors.forename: Maikel
authors.initials: M
authors.lastname: Colli
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors.forename: Jelena M
authors.initials: JM
authors.lastname: Krivokapic
authors.affiliation: Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark.
authors.forename: Flemming
authors.initials: F
authors.lastname: Pociot
authors.affiliation: ULB Center for Diabetes Research, Université Libre de Bruxelles, Belgium.
authors.forename: Decio L
authors.initials: DL
authors.lastname: Eizirik
authors.affiliation: Department of Cellular Physiology and Metabolism, University of Geneva, Switzerland.
authors.forename: Paolo
authors.initials: P
authors.lastname: Meda
authors.affiliation: Department of Neurosciences and Pharmacology, University of Copenhagen, Denmark.
authors.forename: Birgitte
authors.initials: B
authors.lastname: Holst
authors.affiliation: Department of Biomedical Sciences, University of Copenhagen, Denmark.
authors.forename: Nils
authors.initials: N
authors.lastname: Billestrup
authors.affiliation: Copenhagen Diabetes Research Center, Pediatric Department, University Hospital Herlev, Denmark. Electronic address: Joachim.stoerling.01@regionh.dk.
authors.forename: Joachim
authors.initials: J
authors.lastname: Størling
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D017630:Connexins / Q000172:deficiency* / Q000378:metabolism; D016207:Cytokines / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D018149:Glucose Intolerance / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D006943:Hyperglycemia / Q000473:pathology; D007249:Inflammation / Q000473:pathology; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D013311:Streptozocin
chemical_list: D017630:Connexins; D016207:Cytokines; C492765:PANX2 protein, human; C516139:Panx2 protein, mouse; D050796:STAT3 Transcription Factor; C479937:pannexin 2, rat; D013311:Streptozocin; D052247:Nitric Oxide Synthase Type II
keywords: Apoptosis; Cytokine; Insulin; Type 1 diabetes; β-cell