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

Objective The aim of this study was to research the role and underlying mechanism of miR-195 involved in pancreatic beta-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 beta-cell dedifferentiation in vivo and in vitro, respectively. The expression of miR-195 and insulin secretion during beta-cell dedifferentiation were measured. Also, the influence of regulated miR-195 expression on beta-cell dedifferentiation was examined. Meanwhile, the IRS-1/2/Pi3k/Akt pathway and mitofusin-2 (Mfn2) expression were investigated during beta-cell dedifferentiation. Results MiR-195 was upregulated during lipotoxicity-induced beta-cell dedifferentiation in both in vivo and in vitro experiments, and miR-195 functionally contributed to lipotoxicity-induced beta-cell dedifferentiation. Furthermore, miR-195 inhibited IRS-1/2/Pi3k/Akt pathway activation, which accompanied beta-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 beta-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 beta-cell dedifferentiation. Conclusions MiR-195 promoted beta-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.