Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice

摘要

In diabetes, the death of insulin-producing β-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from β-cell injury. Consistent with this hypothesis, 17β-estradiol (estradiol) manifests antidiabetic actions in humans and rodents. In addition, estradiol has antiapoptotic actions in cells that are mediated by the estrogen receptor-a (ERα), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of β-cell apoptosis via ERα. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERα (αERKO) respectively. We show here that in both genders, ArKO~(-/-) mice are vulnerable to β-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-induced β-cell apoptosis, helps sustain insulin production, and prevents diabetes. In vitro, in mouse pancreatic islets and β-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in β-cells and islets treated with an ERα antagonist and in αERKO islets. Accordingly, αERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating β-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ERα by using the antagonist tamox-ifen. This study demonstrates that estradiol, acting, at least in part, through ERα, protects β-cells from oxidative injury and prevents diabetes in mice of both genders.