TY - JOUR

T1 - CRFR1 activation protects against cytokine-induced beta cell death

AU - Blaabjerg, Lykke

AU - Christensen, Gitte Lund

AU - Matsumoto, Masahito

AU - van der Meulen, Talitha

AU - Huising, Mark O

AU - Billestrup, Nils

AU - Vale, Wylie

PY - 2014/10/16

Y1 - 2014/10/16

N2 - 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.

AB - 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.

U2 - 10.1530/JME-14-0056

DO - 10.1530/JME-14-0056

M3 - Journal article

C2 - 25324488

VL - 53

SP - 417

EP - 427

JO - Journal of Molecular Endocrinology

JF - Journal of Molecular Endocrinology

SN - 0952-5041

ER -