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
OBJECTIVEWe showed that 17β-estradiol (E2) favors pancreatic β-cell survival via the estrogen receptor-α (ERα) in mice. E2 activates nuclear estrogen receptors via an estrogen response element (ERE). E2 also activates nongenomic signals via an extranuclear form of ERα and the G protein–coupled estrogen receptor (GPER). We studied the contribution of estrogen receptors to islet survival.RESEARCH DESIGN AND METHODSWe used mice and islets deficient in estrogen receptor-α (αERKO−/−), estrogen receptor-β (βERKO−/−), estrogen receptor-α and estrogen receptor-β (αβERKO−/−), and GPER (GPERKO−/−); a mouse lacking ERα binding to the ERE; and human islets. These mice and islets were studied in combination with receptor-specific pharmacological probes.RESULTSWe show that ERα protection of islet survival is ERE independent and that E2 favors islet survival through extranuclear and membrane estrogen receptor signaling. We show that ERβ plays a minor cytoprotective role compared to ERα. Accordingly, βERKO−/− mice are mildly predisposed to streptozotocin-induced islet apoptosis. However, combined elimination of ERα and ERβ in mice does not synergize to provoke islet apoptosis. In αβERKO−/− mice and their islets, E2 partially prevents apoptosis suggesting that an alternative pathway compensates for ERα/ERβ deficiency. We find that E2 protection of islet survival is reproduced by a membrane-impermeant E2 formulation and a selective GPER agonist. Accordingly, GPERKO−/− mice are susceptible to streptozotocin-induced insulin deficiency.CONCLUSIONSE2 protects β-cell survival through ERα and ERβ via ERE-independent, extra-nuclear mechanisms, as well as GPER-dependent mechanisms. The present study adds a novel dimension to estrogen biology in β-cells and identifies GPER as a target to protect islet survival.
Aims/hypothesis Mutations in BSCL2/seipin cause Berardinelli-Seip congenital lipodystrophy (BSCL), a rare recessive disorder characterised by near absence of adipose tissue and severe insulin resistance. We aimed to determine how seipin deficiency alters glucose and lipid homeostasis and whether thiazolidinediones can rescue the phenotype. Methods Bscl2−/− mice were generated and phenotyped. X. Prieur, L. Dollet and M. Takahashi contributed equally to this study.Electronic supplementary material The online version of this article
The failure of pancreatic β cells to adapt to an increasing demand for insulin is the major mechanism by which patients progress from insulin resistance to type 2 diabetes (T2D) and is thought to be related to dysfunctional lipid homeostasis within those cells. In multiple animal models of diabetes, females demonstrate relative protection from β cell failure. We previously found that the hormone 17β-estradiol (E2) in part mediates this benefit. Here, we show that treating male Zucker diabetic fatty (ZDF) rats with E2 suppressed synthesis and accumulation of fatty acids and glycerolipids in islets and protected against β cell failure. The antilipogenic actions of E2 were recapitulated by pharmacological activation of estrogen receptor α (ERα) or ERβ in a rat β cell line and in cultured ZDF rat, mouse, and human islets. Pancreas-specific null deletion of ERα in mice (PERα -/-) prevented reduction of lipid synthesis by E2 via a direct action in islets, and PERα -/-mice were predisposed to islet lipid accumulation and β cell dysfunction in response to feeding with a high-fat diet. ER activation inhibited β cell lipid synthesis by suppressing the expression (and activity) of fatty acid synthase via a nonclassical pathway dependent on activated Stat3. Accordingly, pancreas-specific deletion of Stat3 in mice curtailed ER-mediated suppression of lipid synthesis. These data suggest that extranuclear ERs may be promising therapeutic targets to prevent β cell failure in T2D.
Estrogen receptors (ERs) protect pancreatic islet survival in mice through rapid extranuclear actions. ERα also enhances insulin synthesis in cultured islets. Whether ERα stimulates insulin synthesis in vivo and, if so, through which mechanism(s) remain largely unknown. To address these issues, we generated a pancreas-specific ERα knockout mouse (PERαKO −/− ) using the Cre-loxP strategy and used a combination of genetic and pharmacologic tools in cultured islets and β cells. Whereas 17β-estradiol (E2) treatment up-regulates pancreatic insulin gene and protein content in control ERαlox/lox mice, these E2 effects are abolished in PERαKO −/− mice. We find that E2-activated ERα increases insulin synthesis by enhancing glucose stimulation of the insulin promoter activity. Using a knock-in mouse with a mutated ERα eliminating binding to the estrogen response elements (EREs), we show that E2 stimulation of insulin synthesis is independent of the ERE. We find that the extranuclear ERα interacts with the tyrosine kinase Src, which activates extracellular signalregulated kinases 1/2 , to increase nuclear localization and binding to the insulin promoter of the transcription factor NeuroD1. This study supports the importance of ERα in β cells as a regulator of insulin synthesis in vivo.diabetes | islet
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