Moreover, progesterone caused an augmentation of oxidative species generation in RINm5F insulin-producing cells, and low expression of ESRα impairs the ability to circulate E2 to prevent β-cell apoptosis after exposure to oxidative stress, thus the combination of high ESRα methylation and high progesterone may lead to a greater susceptibility to IFG and T2DM. This evidence concerns the gene INS and type 2 diabetes mellitus.