MiR‐195 promotes pancreatic β‐cell dedifferentiation by targeting Mfn2 and impairing Pi3k/Akt signaling in type 2 diabetes

Abstract Objective The aim of this study was to research the role and underlying mechanism of miR‐195 involved in pancreatic β‐cell dedifferentiation induced by hyperlipemia in type 2 diabetes mellitus. Methods High‐fat‐diet‐induced obese C57BL/6J mice and palmitate‐stimulated Min6 cells were used as the models of β‐cell dedifferentiation in vivo and in vitro , respectively. The expression of miR‐195 and insulin secretion during β‐cell dedifferentiation were measured. Also, the influence of regulated miR‐195 expression on β‐cell dedifferentiation was examined. Meanwhile, the IRS‐1/2/Pi3k/Akt pathway and mitofusin‐2 (Mfn2) expression were investigated during β‐cell dedifferentiation. Results MiR‐195 was upregulated during lipotoxicity‐induced β‐cell dedifferentiation in both in vivo and in vitro experiments, and miR‐195 functionally contributed to lipotoxicity‐induced β‐cell dedifferentiation. Furthermore, miR‐195 inhibited IRS‐1/2/Pi3k/Akt pathway activation, which accompanied β‐cell dedifferentiation. Mfn2, a target of miR‐195, was found to be downregulated and was associated with increased mitochondrial production of reactive oxygen species during β‐cell dedifferentiation. Instructively, inhibition of miR‐195, at least partially, reversed the downregulation of Mfn2, restored IRS‐1/2/Pi3k/Akt pathway activation, and prevented β‐cell dedifferentiation. Conclusions MiR‐195 promoted β‐cell dedifferentiation through negatively regulating Mfn2 expression and inhibiting the IRS‐1/2/Pi3k/Akt pathway, providing a promising treatment for type 2 diabetes mellitus.