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

Abstract

In diabetes, the death of insulin-producing ␤-cells by apoptosis leads to insulin deficiency. The lower prevalence of diabetes in females suggests that female sex steroids protect from ␤-cell injury. Consistent with this hypothesis, 17␤-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␣), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of ␤-cell apoptosis via ER␣. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ER␣ (␣ERKO) respectively. We show here that in both genders, ArKO ؊/؊ mice are vulnerable to ␤-cell apoptosis and prone to insulin-deficient diabetes after exposure to acute oxidative stress with streptozotocin. In these mice, estradiol treatment rescues streptozotocin-induced ␤-cell apoptosis, helps sustain insulin production, and prevents diabetes. In vitro, in mouse pancreatic islets and ␤-cells exposed to oxidative stress, estradiol prevents apoptosis and protects insulin secretion. Estradiol protection is partially lost in ␤-cells and islets treated with an ER␣ antagonist and in ␣ERKO islets. Accordingly, ␣ERKO mice are no longer protected by estradiol and display a gender nonspecific susceptibility to oxidative injury, precipitating ␤-cell apoptosis and insulin-deficient diabetes. Finally, the predisposition to insulin deficiency can be mimicked in WT mice by pharmacological inhibition of ER␣ by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ER␣, protects ␤-cells from oxidative injury and prevents diabetes in mice of both genders.estradiol ͉ oxidative stress

Grade of inflammation in boys with type 1 diabetes depends on the IVS1 −397T>C estrogen receptor α polymorphism

“…Moreover, NF-κB participates in endogenous CRP induction (Agrawal, Cha-Molstad, Samols, & Kushner, 2003). Moreover, the TT variant of genotype in male mice, which decreases ER-α gene transcription, predisposes to the inflammatory streptozotocin effect on the insulin-producing β-cells (Le May et al, 2006).…”

Selective estrogen receptor modulation in pancreatic β-cells and the prevention of type 2 diabetes

“…In vivo treatment with E2 suppressed all steps of islet lipogenesis thus providing lipo-detoxification. Using pharmacological agonists for the estrogen receptor (ER)α, ERβ and the G-protein coupled estrogen receptor (GPER), 5,6 in cultured rodent and human β-cells, we observed a similar reduction in fatty acid synthase (FAS) expression and enzymatic activity resulting in decreased lipogenesis and TG accumulation. These E2 antilipogenic effects were mediated by E2 acting directly on islet ERs in vivo as E2 failed to suppress islet lipogenesis in a mouse with pancreas-specific elimination of ERα (PERαKO -/-).…”

Progesterone induces apoptosis of insulin-secreting cells: insights into the molecular mechanism

“…In contrast to the effects of progesterone, data from human and animal studies indicate that 17b-estradiol (estradiol) prevents a decrease in insulin production in the diabetic state (Le May et al 2006). Also, estradiol, at pharmacological concentrations, protects human pancreatic islets from apoptosis induced by proinflammatory cytokines in vitro (Contreras et al 2002).…”