Exendin-4 protects β-cells against interleukin-1β-induced apoptosis via upregulating GMRP-1.

OBJECTIVE: To elucidate whether Exendin-4 (Ex-4) protects β cells against interleukin-1β (IL-1β)-induced apoptosis by regulating glucose metabolism-related protein-1 (GMRP-1) and suppressing the Jun N-terminal kinase (JNK) signaling pathway. METHODS: Pancreatic β cells were treated with Ex-4 either in the presence or absence of IL-1β. Alterations in the expression of GMRP-1 and JNK signaling pathway-related proteins were examined by quantitative PCR, western blotting, and immunofluorescence. The anti-apoptotic efficacy of Ex-4 against IL-1β-induced apoptosis was assessed using flow cytometry. In vivo, a non-obese diabetic (NOD) mouse model was established, and lentivirus-mediated transfection was employed to knock down GMRP-1 expression. RESULTS: Ex-4 inhibited IL-1β-induced activation of the JNK pathway and subsequent β-cell apoptosis. This inhibitory effect was associated with the upregulation of the level of GMRP-1. Mechanistically, Ex-4 upregulated GMRP-1 expression in a time- and dose-dependent manner and reversed the IL-1β-induced suppression of GMRP-1. Both in vivo and in vitro experiments confirmed that RNA interference-mediated inhibition of GMRP-1 abolished the protective effect of Ex-4 on JNK pathway activation and apoptosis. CONCLUSION: GMRP-1 serves as an essential mediator of Ex-4's cytoprotective effects. Ex-4 safeguards β cells against IL-1β-induced apoptosis primarily by upregulating GMRP-1, which in turn suppresses the pro-apoptotic JNK pathway. These results provide new insights into the molecular mechanisms underlying diabetes pathogenesis and identify GMRP-1 as a potential therapeutic target for the treatment of diabetes.