Article

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: 9.81). 07/2006; 103(24):9232-7. DOI: 10.1073/pnas.0602956103
Source: PubMed

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, 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.

Download full-text

Full-text

Available from: Franck Mauvais-Jarvis, Aug 18, 2015
0 Followers
 · 
154 Views
  • Source
    • "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). "
    Journal of Diabetes and its Complications 11/2014; 29(2). DOI:10.1016/j.jdiacomp.2014.11.011 · 1.93 Impact Factor
  • Source
    • "The mean plasma levels of insulin of diabetic rats were significantly decreased than those of groups III and IV. It is suggested that the elevated levels of sex steroid hormones (particularly estrogens) during pregnancy may stimulate the proliferation of islet βcell growth, which then results in increased insulin synthesis and release [21]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: To study the possible beneficial effect of estrogen (17β-estradiol E(2)) on hyperglycemia, oxidative stress and liver dysfunctions in STZ-induced diabetic rats. A total of 40 albino male rats were randomly divided into four groups: a control group (I), a diabetic group (II), a group given 17β estradiol (E(2)) for 15 days (III), and a diabetic group given E(2) for 30 days (IV). Diabetes was induced in the rats by 65 mg/kg streptozosin (STZ) via an intraperitoneal (i.p.) injection. E(2) was given in a dose of 500ug/kg/day by oral gavage. E(2) administration significantly lowered plasma glucose levels, increased plasma insulin levels, and improved glucose tolerance of groups III and IV. In addition, E(2) enhanced glutathione peroxidase (GPX) and reduced lipid peroxidation in the hepatic tissues (as compared to diabetic rats). E(2) caused significant decrease of plasmatic phosphatase alkaline (PAL), lactate dehydrogenase (LDH), aspartate and lactate transaminases (AST and ALT) activities of group III and IV compared to group II. Moreover, E(2) restored the histological structure of the liver and pancreas of treated groups and increased the insulin receptors expression in the liver of groups III and IV compared to diabetic rats. Notably, these beneficial effects of E(2) on diabetic rats were more prominent in group IV compared to those of group III. E(2) has a beneficial effect on hyperglycemia, oxidative stress and ameliorates the liver dysfunction in diabetic rats and these effects may be mediated through stimulating β-cell proliferation in pancreas and increased the insulin receptor expression in the liver tissues.
    International Journal of Physiology, Pathophysiology and Pharmacology 01/2012; 4(3):156-66.
  • Source
    • "ERαknockout mice have an obese phenotype and develop insulin resistance (Heine et al., 2000), yet 17β-estradiol is without effect in increasing insulin levels in isolated islets from ERαknockout animals compared to controls or to ERβ-knockout mice (Alonso-Magdalena et al., 2008). Moreover, in the absence of ERα, 17β-estradiol only partially protects pancreatic βcells from apoptosis (Le May et al., 2006). A recent study investigated the role of ERs in vascular inflammation associated with diabetes. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Obesity increases the risk of coronary artery disease through insulin resistance, diabetes, arterial hypertension and dyslipidemia. The prevalence of obesity has increased worldwide and is particularly high among middle-aged women and men. After menopause, women are at an increased risk to develop visceral obesity due to the loss of endogenous ovarian hormone production. Effects of oestrogens are classically mediated by the two nuclear oestrogen receptors (ERs) α and β. In addition, more recent research has shown that the intracellular transmembrane G-protein-coupled oestrogen receptor (GPER) originally designated as GPR30 also mediates some of the actions attributed to oestrogens. Oestrogen and its receptors are important regulators of body weight and insulin sensitivity not only in women but also in men as demonstrated by ER mutations in rodents and humans. This article reviews the role of sex hormones and ERs in the context of obesity, insulin sensitivity and diabetes as well as the related clinical issues in women and men.
    Acta Physiologica 02/2011; 203(1):259-69. DOI:10.1111/j.1748-1716.2010.02237.x · 4.25 Impact Factor
Show more