Selenoproteins in Arsenic-Induced Metabolic Dysfunction

项目摘要/摘要 预计到2040年，全球将有6.42亿人罹患糖尿病，这是一种毁灭性的代谢性疾病 与环境毒物的联系越来越紧密。其中一种对公共卫生具有巨大意义的污染物是 砷，污染全球1亿多人的饮用水，包括许多生活在 美国。流行病学证据将砷暴露与糖尿病联系起来；然而，其机制 砷会增加糖尿病的风险，调节这种风险的因素仍然不完全清楚。 有趣的是，已知砷和必需元素硒具有相反的生物学特性。 运行了近80年。硒被结合到25种独特的蛋白质中，即硒蛋白，参与 细胞过程，如免疫功能、细胞分裂、甲状腺激素代谢和氧化还原处理。 基于更有力的证据表明，分泌胰岛素的胰腺β细胞是砷的主要靶点 代谢毒性和我们的初步研究表明，硒蛋白缺乏会增加砷的含量 对于葡萄糖代谢的不利影响，我们提出了以下中心假设：硒蛋白发挥作用 保护分泌胰岛素的胰腺β细胞在维持血糖稳态中的重要作用 由砷引起的功能障碍。为了解决这一假设，在特定目标1中，我们将使用一种新的β- 细胞特异性硒蛋白敲除研究这种组织特异性改变对全身的影响 能量生理学以及胰岛结构。要了解减少砷暴露如何 影响糖尿病风险，在特定的目标2中，我们将询问以下猜想，即硒蛋白是 从砷引起的葡萄糖代谢损伤中恢复；此外，我们将使用同步加速器X- 射线荧光显微镜对胰腺组织中的砷和硒进行组织水平测绘 验证硒蛋白通过保护胰岛免受砷影响而促进代谢恢复的假设 积累和便利其清除。在特定的目标3中，我们将扩展我们的体内和细胞系数据 确定β细胞生理学中的细胞缺陷--硒蛋白加重砷引起的细胞生理学缺陷 缺乏症。特别是，我们将集中于细胞生理学方面的证据表明砷。 而硒/硒蛋白具有相反的作用，即氧化应激、AMP激活的蛋白激酶 活性和三磷酸腺苷生成。此外，这个目标将缩小到一个特定的硒蛋白牵连在一起 糖尿病风险，谷胱甘肽过氧化物酶1，以确定该酶如何影响砷诱导的β细胞 并确定GPX1中常见的等位基因变异是否导致对 砷导致人类患糖尿病的风险。总的来说，拟议的研究将提供新的知识 关于硒蛋白在抵抗砷引起的葡萄糖稳态破坏中的重要作用， 包括确定因缺硒和地方病共存而处于高危状态的人群 砷暴露以及硒蛋白多态可增强砷敏感性的人群。

PROJECT SUMMARY/ABSTRACT Projected to afflict 642 million individuals globally by 2040, diabetes is a devastating metabolic disease that is increasingly tied to environmental toxicants. One such pollutant of immense public health significance is arsenic, which contaminates the drinking water for over 100 million individuals globally, including many living in the United States. Epidemiological evidence links arsenic exposure with diabetes; however, the mechanisms by which arsenic increases diabetes risk and the factors that modulate this risk remain incompletely known. Interestingly, arsenic and the essential element selenium have been known to have opposing biological functions for nearly 80 years. Selenium is incorporated into 25 unique proteins, selenoproteins, involved in cellular processes such as immune function, cell division, thyroid hormone metabolism, and redox handling. Built upon strengthening evidence that insulin-secreting pancreatic β-cells are a primary target of arsenic's metabolic toxicity and our preliminary studies demonstrating that selenoprotein deficiency augments arsenic's adverse effects on glucose metabolism, we propose the following central hypothesis: selenoproteins play an essential role in preserving glucose homeostasis by protecting insulin-secreting pancreatic β-cells from arsenic-induced dysfunction. To address this hypothesis, in Specific Aim 1 we will employ a novel β- cell-specific knockout of selenoproteins to examine the impact of this tissue-specific alteration on whole-body energy physiology as well as pancreatic islet architecture. To understand how reducing exposure to arsenic impacts diabetes risk, in Specific Aim 2 we will interrogate the conjecture that selenoproteins are required for recovery from arsenic-induced impairments in glucose metabolism; moreover, we will employ synchrotron X- ray fluorescence microscopy to perform tissue-level mapping of arsenic and selenium in pancreatic tissue to test the hypothesis that selenoproteins promote metabolic recovery by protecting pancreatic islets from arsenic accumulation and facilitating its clearance. In Specific Aim 3 we will expand upon our in vivo and cell line data to define the cellular defects in β-cell physiology induced by arsenic that are exacerbated by selenoprotein deficiency. In particular, we will focus on aspects of cellular physiology for which evidence suggests arsenic and selenium/selenoproteins have opposing actions, namely oxidative stress, AMP-activated protein kinase activity, and ATP generation. Furthermore, this aim will narrow in on a specific selenoprotein implicated in diabetes risk, glutathione peroxidase 1 (GPx1), to determine how this enzyme impacts arsenic-induced β-cell dysfunction and to ascertain whether common allelic variations in GPx1 account for differential sensitivity to arsenic-induced diabetes risk in humans. Collectively, the proposed studies will provide new knowledge regarding the essential role of selenoproteins in resisting arsenic-induced disruptions in glucose homeostasis, including identification of populations at heightened risk due to coexisting selenium deficiency and endemic arsenic exposure as well as those with polymorphisms in selenoproteins that enhance arsenic sensitivity.