Estrogens protect pancreatic [beta]-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice

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Publisher: National Academy of Sciences
Document Type: Author abstract
Length: 257 words
Lexile Measure: 60L

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Abstract :

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, ArK[O.sup.-/-] 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-induced [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. estradiol | oxidative stress

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Gale Document Number: GALE|A147875140