CRFR1 activation protects against cytokine-induced β-cell death

Lykke Blaabjerg, Gitte L. Christensen, Masahito Matsumoto, Talitha Van Der Meulen, Mark O. Huising, Nils Billestrup, Wylie W. Vale

Research output: Contribution to journalArticlepeer-review

Abstract

During the development of diabetes b-cells are exposed to elevated concentrations of proinflammatory cytokines, TNFa and IL1b, which in vitro induce b-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 b-cell apoptosis, we evaluated the protective potential of CRFR activation in b-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 b-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.

Original languageEnglish (US)
Pages (from-to)417-427
Number of pages11
JournalJournal of Molecular Endocrinology
Volume53
Issue number3
DOIs
StatePublished - Oct 16 2014
Externally publishedYes

Keywords

  • Apoptosis
  • CRFR
  • Cytokines
  • GPCR
  • Survival
  • Urocortins
  • β cells

ASJC Scopus subject areas

  • Molecular Biology
  • Endocrinology

Fingerprint Dive into the research topics of 'CRFR1 activation protects against cytokine-induced β-cell death'. Together they form a unique fingerprint.

Cite this