Type 2 diabetes (T2D) is considered a protein misfolding disorder. Hyperfunction of the islet β-cells leads to protein misfolding, endoplasmic reticulum (EndRetic) stress and activates the unfolded protein response (UPR). There is disruption of the endoplasmic reticulum-associated protein degradation (ERAD) pathway which normally removes misfolded proteins. If protein misfolding is not resolved, β-cells die. Thus, to protect functional β-cell mass in T2D, we must explore new therapeutic approaches to enhance the removal of misfolded proteins β-cells. Our laboratory was a pioneer in showing that the female estrogens protect islet β-cells from pro-apoptotic injuries in mice of both sexes via direct activation of estrogen receptor(ER)α, ERβ and the G-protein coupled ER. We showed that these effects are present in human islets. During the previous funding period of this R01DK074970, we made the new and far-reaching observation that estrogens activation of ERα prevents β-cell destruction from EndRetic stress during severe protein misfolding. The specific aims of this application will use FDA-approved estrogens in mouse models and human islets to 1) determine the mechanism by which activation of ERα in β-cells attenuates EndoRetic stress by increasing the ERAD pathway, thus promoting misfolded protein degradation, and 2) dissect the mechanism by which bazedoxifene acts as ERα agonist to promote the effect described in specific aim 1, selectively in β-cells of females but not males.