Journal
JOURNAL OF MOLECULAR ENDOCRINOLOGY
Volume 53, Issue 3, Pages 417-427Publisher
BIOSCIENTIFICA LTD
DOI: 10.1530/JME-14-0056
Keywords
β cells; apoptosis; survival; urocortins; GPCR; CRFR; cytokines
Categories
Funding
- Alfred Benzon Foundation
- Clayton Medical Research Foundation, Inc.
- Juvenile Diabetes Research Foundation
- National Institute of Diabetes, and Digestive and Kidney Diseases (NIDDK) [PO1 DK026741-30]
- Danish Council for Independent Research, Medical Sciences
- Novo Nordisk Foundation
- Danish Diabetes Academy
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During the development of diabetes beta-cells are exposed to elevated concentrations of proinflammatory cytokines, TNF alpha and IL1 beta, 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 signaling 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 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 beta-cells. Interestingly, CRFR signaling also counteracted basal apoptosis in both cultured INS-1 cells and intact human islets.
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