Blaabjerg Lykke, Christensen Gitte L, Matsumoto Masahito, van der Meulen Talitha, Huising Mark O, Billestrup Nils, Vale Wylie W
Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark
Clayton Foundation Laboratories for Peptide BiologySalk Institute, 10100 North Torrey Pines Road, La Jolla, California 92037, USACellular and Metabolic Research SectionDepartment of Biomedical Sciences, Faculty of Health Sciences, University of Copenhagen, Blegdamsvej 3, 2200 Copenhagen N, Denmark.
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.
在糖尿病发展过程中，β细胞会暴露于促炎细胞因子TNFα和IL1β的浓度升高环境中，这些因子在体外会诱导β细胞死亡。B类G蛋白偶联受体（GPCRs）：促肾上腺皮质激素释放因子受体1（CRFR1）和CRFR2在胰岛中表达。由于其他B类GPCRs的下游信号传导可保护细胞免受细胞因子诱导的β细胞凋亡，我们评估了在促炎环境中CRFR激活对β细胞的保护潜力。CRFR1/CRFR2配体激活AKT和CRFR1信号传导，并减少人胰岛中的细胞凋亡。在大鼠和小鼠胰岛素分泌细胞系（INS-1和MIN6）中，CRFR1激动剂上调胰岛素受体底物2（IRS2）表达，增加AKT激活，抵消细胞因子介导的BAD磷酸化降低，并抑制细胞凋亡。抗凋亡信号传导依赖于长时间暴露于促肾上腺皮质激素释放因子家族肽，并遵循PKA介导的IRS2上调。这表明CRFR信号传导通过上调β细胞中的存活信号来抵消促炎细胞因子介导的凋亡途径。有趣的是，CRFR信号传导还抵消了培养的INS-1细胞和完整人胰岛中的基础细胞凋亡。
