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, Sep 29, 2015
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    • "Guanosine analogs may increase the amount of guanosine triphosphate in beta cells, which can directly stimulate insulin secretion (Wollheim and Maechler, 2002). Our screens also identified classes of compounds that decreased luciferase secretion, including some common medications that have been implicated previously in inhibiting insulin release: SERMs (Le May et al., 2006), progestogens (Shao et al., 2004), SSRIs (Isaac et al., 2013), and the PPAR-gamma agonist pioglitazone (Lamontagne et al., 2009). The PPAR-a agonist fenofibrate , not previously known to affect beta-cell function, was found to robustly block glucose-mediated stimulation of secretion in both rodent and human beta cell models in a dose-dependent manner. "
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    ABSTRACT: Defects in insulin secretion play a central role in the pathogenesis of type 2 diabetes, yet the mechanisms driving beta-cell dysfunction remain poorly understood, and therapies to preserve glucose-dependent insulin release are inadequate. We report a luminescent insulin secretion assay that enables large-scale investigations of beta-cell function, created by inserting Gaussia luciferase into the C-peptide portion of proinsulin. Beta-cell lines expressing this construct cosecrete luciferase and insulin in close correlation, under both standard conditions or when stressed by cytokines, fatty acids, or ER toxins. We adapted the reporter for high-throughput assays and performed a 1,600-compound pilot screen, which identified several classes of drugs inhibiting secretion, as well as glucose-potentiated secretagogues that were confirmed to have activity in primary human islets. Requiring 40-fold less time and expense than the traditional ELISA, this assay may accelerate the identification of pathways governing insulin secretion and compounds that safely augment beta-cell function in diabetes. Copyright © 2015 Elsevier Inc. All rights reserved.
    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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    • "Further, glucolipotoxicity, upregulates ERα mRNA in young rats, but this feature is lost in older animals. Since ERα improves β-cell survival [3], [5], [9], the loss of ERα induction in old islets may alter their resistance to diabetic injuries, as we observe in the PERαKO−/− mouse. This weakness may further increase β-cell susceptibility to oxidative injuries such as glucotoxicity, setting the stage for β-cell failure in old age. "
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    ABSTRACT: The female steroid, 17β-estradiol (E2), is important for pancreatic β-cell function and acts via at least three estrogen receptors (ER), ERα, ERβ, and the G-protein coupled ER (GPER). Using a pancreas-specific ERα knockout mouse generated using the Cre-lox-P system and a Pdx1-Cre transgenic line (PERαKO(-/-)), we previously reported that islet ERα suppresses islet glucolipotoxicity and prevents β-cell dysfunction induced by high fat feeding. We also showed that E2 acts via ERα to prevent β-cell apoptosis in vivo. However, the contribution of the islet ERα to β-cell survival in vivo, without the contribution of ERα in other tissues is still unclear. Using the PERαKO(-/-) mouse, we show that ERα mRNA expression is only decreased by 20% in the arcuate nucleus of the hypothalamus, without a parallel decrease in the VMH, making it a reliable model of pancreas-specific ERα elimination. Following exposure to alloxan-induced oxidative stress in vivo, female and male PERαKO(-/-) mice exhibited a predisposition to β-cell destruction and insulin deficient diabetes. In male PERαKO(-/-) mice, exposure to E2 partially prevented alloxan-induced β-cell destruction and diabetes. ERα mRNA expression was induced by hyperglycemia in vivo in islets from young mice as well as in cultured rat islets. The induction of ERα mRNA by hyperglycemia was retained in insulin receptor-deficient β-cells, demonstrating independence from direct insulin regulation. These findings suggest that induction of ERα expression acts to naturally protect β-cells against oxidative injury.
    PLoS ONE 02/2014; 9(2):e87941. DOI:10.1371/journal.pone.0087941 · 3.23 Impact Factor
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