Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice
Estrogens protect pancreatic β-cells from apoptosis and prevent insulin-deficient diabetes mellitus in mice
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DOI：
10.1073/pnas.0602956103
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发表时间：
2006-06-13
影响因子：
11.1
通讯作者：
Mauvais-Jarvis, Franck
中科院分区：
文献类型：
--
作者：
Le May, Cedric;Chu, Khoi;Mauvais-Jarvis, Franck
在糖尿病中，细胞凋亡导致产生胰岛素的β细胞死亡导致胰岛素缺乏。女性糖尿病患病率较低表明女性性类固醇可以保护β细胞免受损伤。与这一假设一致，17 β-雌二醇（雌二醇）在人类和啮齿动物中表现出抗糖尿病作用。此外，雌二醇在由雌激素受体-α（ER α）介导的细胞中具有抗凋亡作用，这增加了雌二醇抗糖尿病功能可能部分归因于通过ER α保护β细胞凋亡的前景。为了解决这个问题，我们使用了分别通过芳香酶（ArKO）或ER α（α ERKO）的靶向破坏而导致雌二醇缺乏或雌二醇抗性的小鼠。我们在这里表明，在两种性别中，ArKO-/-小鼠在暴露于链脲佐菌素的急性氧化应激后容易发生β细胞凋亡，并容易患胰岛素缺乏型糖尿病。在这些小鼠中，雌二醇治疗挽救了链脲佐菌素诱导的β细胞凋亡，帮助维持胰岛素的产生，并预防糖尿病。在体外，在暴露于氧化应激的小鼠胰岛和β细胞中，雌二醇可防止细胞凋亡并保护胰岛素分泌。在用ER α拮抗剂处理的β-细胞和胰岛中以及在α ERKO胰岛中，内皮素保护部分丧失。因此，α ERKO小鼠不再受到雌二醇的保护，并显示出对氧化损伤的性别非特异性易感性，从而导致β细胞凋亡和胰岛素缺乏型糖尿病。最后，通过使用拮抗剂他莫昔芬药理学抑制ER α，可以在WT小鼠中模拟胰岛素缺乏的易感性。这项研究表明，雌二醇至少部分通过ER α起作用，保护β细胞免受氧化损伤，并预防两种性别小鼠的糖尿病。
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, 17 beta-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 alpha), raising the prospect that estradiol antidiabetic function may be due, in part, to a protection of beta-cell apoptosis via ER alpha. To address this question, we have used mice that were rendered estradiol-deficient or estradiol-resistant by targeted disruption of aromatase (ArKO) or ER alpha (alpha ERKO) 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-incluced, 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 ER alpha antagonist and in alpha ERKO islets. Accordingly, alpha ERKO 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 ER alpha by using the antagonist tamoxifen. This study demonstrates that estradiol, acting, at least in part, through ER alpha, protects beta-cells from oxidative injury and prevents diabetes in mice of both genders.