According to this context, we established a T2DM rat model in vivo and cultured high-glucose INS-1 cells in vitro, to detect changes to glucose metabolism and insulin secretion as well as the expression levels of relevant factors employing pretreatment with E2, GPER antagonist (G15), Akt inhibitor (PF 04691502), and mTOR inhibitor (rapamycin) to explore the possible molecular mechanism of GPER via Akt/mTOR pathway in islet β cells. Here, INS is linked to type 2 diabetes mellitus.