CRFR1 activation protects against cytokine-induced β-cell death

J Mol Endocrinol. 2014 Dec;53(3):417-27. doi: 10.1530/JME-14-0056. Epub 2014 Oct 16.


During the development of diabetes β-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFα and IL1β, which in vitro induce β-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 signaling by other class B GPCRs can protect against cytokine-induced β-cell apoptosis, we evaluated the protective potential of CRFR activation in β-cells in a pro-inflammatory setting. CRFR1/CRFR2 ligands activated AKT and CRFR1 signaling and 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 the cytokine-mediated decrease in BAD phosphorylation, and inhibited apoptosis. The anti-apoptotic signaling was dependent on prolonged exposure to corticotropin-releasing factor family peptides and followed PKA-mediated IRS2 upregulation. This indicates that CRFR signaling counteracts proinflammatory cytokine-mediated apoptotic pathways through upregulation of survival signaling in β-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

Keywords: CRFR; GPCR; apoptosis; cytokines; survival; urocortins; β cells.

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Cell Death / drug effects
  • Cells, Cultured
  • Corticotropin-Releasing Hormone / pharmacology*
  • Cytokines / adverse effects*
  • Cytoprotection / drug effects*
  • Humans
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / physiology
  • Interleukin-1beta / adverse effects
  • Mice
  • Rats
  • Receptors, Corticotropin-Releasing Hormone / agonists*
  • Tumor Necrosis Factor-alpha / adverse effects


  • Cytokines
  • IL1B protein, human
  • Interleukin-1beta
  • Receptors, Corticotropin-Releasing Hormone
  • Tumor Necrosis Factor-alpha
  • CRF receptor type 1
  • Corticotropin-Releasing Hormone