期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 24, 页码 9232-9237出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0602956103
关键词
estradiol; oxidative stress
资金
- NIDDK NIH HHS [R21 DK069362-01, R01 DK074970, R21 DK069362] Funding Source: Medline
In diabetes, the death of insulin-producing beta-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from beta-cell injury. Consistent with this hypothesis, 17 beta-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 (ER alpha), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of beta-cell apoptosis via ER alpha. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ER alpha (alpha ERKO) respectively. We show here that in both genders, ArKO-/- mice are vulnerable to beta-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-incluced, beta-cell apoptosis, helps sustain insulin production, and prevents diabetes. In vitro, in mouse pancreatic islets and beta-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in beta-cells and islets treated with an ER alpha antagonist and in alpha ERKO islets. Accordingly, alpha ERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating beta-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ER alpha by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ER alpha, protects beta-cells from oxidative injury and prevents diabetes in mice of both genders.
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