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

Division of Diabetes, Endocrinology and Metabolism, Department of , Baylor College of Medicine, Houston, TX 77030, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 07/2006; 103(24):9232-7. DOI: 10.1073/pnas.0602956103
Source: PubMed


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, 17beta-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 (ERalpha), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of beta-cell apoptosis via ERalpha. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ERalpha (alphaERKO) 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-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 ERalpha antagonist and in alphaERKO islets. Accordingly, alphaERKO 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 ERalpha by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ERalpha, protects beta-cells from oxidative injury and prevents diabetes in mice of both genders.

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Available from: Franck Mauvais-Jarvis,
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    • "Estrogen is known to exert its effects mainly through estrogen receptor (ER), and estrogen/ER signaling is a well-known regulator of metabolic and glucose sensing tissues, including the pancreatic β-cells, liver, adipocyte, and skeletal muscle (Faulds et al. 2012). Le May et al. (2006) reported that 17β-estradiol acting through ER-α prevented pancreatic β-cell apoptosis and diabetes in an insulin-deficient diabetic mouse model. Hormone replacement therapy has also been found to improve hyperglycemic control and to decrease the incidence of type 2 diabetes in postmenopausal women (Khoo and Perera 2005). "
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    Cell Metabolism 01/2015; 21(1):126-37. DOI:10.1016/j.cmet.2014.12.010 · 17.57 Impact Factor
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    • "In fact, my laboratory has been studying the role of gender and sex differences in diabetes since its inception, in both rodents and humans. Two of my first publications as an independent investigator in France and the United States introduced the importance of sex in diabetes and the role of the female hormone estrogen in diabetes prevention, respectively (Le May et al., 2006; Mauvais-Jarvis et al., 2004). "

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