CRFR1 activation protects against cytokine-induced beta cell death

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Lykke Blaabjerg
  • Gitte Lund Christensen
  • Masahito Matsumoto
  • Talitha van der Meulen
  • Mark O Huising
  • Billestrup, Nils
  • Wylie Vale

During diabetes development beta cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL-1β which in vitro, induce beta cell death. The class B G-protein-coupled receptors (GPCRs): Corticotropin releasing factor receptor 1 (CRFR1) and CRFR2 are expressed in pancreatic islets. As downstream signalling by other class B GPCRs can protect against cytokine-induced beta cell apoptosis we evaluated the protective potential of CRFR activation in beta cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signalling reduced apoptosis in human islets. In rat and mouse insulin secreting cell lines (INS-1 and MIN6) CRFR1 agonists upregulated insulin receptor substrate 2 (IRS2) expression, increased AKT activation, counteracted cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signalling was dependent on prolonged exposure to CRF family peptides and following PKA activation mediating IRS2 upregulation. This suggests that CRFR signalling counteracts proinflammatory cytokine-mediated apoptotic pathways by upregulation of survival signalling in beta-cells. Interestingly, CRFR signalling also counteracts basal apoptosis in both cultured INS-1 cells and intact human islets.

TidsskriftJournal of Molecular Endocrinology
Sider (fra-til)417-427
Antal sider10
StatusUdgivet - 16 okt. 2014

ID: 125787127