GNPS Metabolomics Workbench ST001314 - GNPS Metabolomic Profiles of Pancreatic b-Cells and Islets Exposed to Arsenic, Islets (part-II)

b'Type-2 diabetes (T2D) is a complex metabolic disorder that affects hundreds of millions of people world-wide and is a growing public health concern. Despite recent advances in T2D research, the etiology of this disease and the mechanisms underlying the metabolic defects remain poorly understood. While obesity is thought to be the main cause for the rising prevalence of T2D, obesity alone cannot explain differences in the trends of T2D among different geographical regions and populations. Growing evidence suggests that environmental exposures to toxic and diabetogenic substances must play important roles. Inorganic arsenic (iAs) is a naturally occurring toxic metalloid. Hundreds of millions of people worldwide are exposed to unsafe levels of iAs in drinking water and food. iAs is a potent carcinogen, but iAs exposure has also been linked to increase risk of T2D. While the link between iAs exposure and T2D is well-established, the mechanisms underlying the diabetogenic effects of iAs exposure remain unclear. Results of our previously published and ongoing studies suggest that pancreatic islets are a primary target for iAs and its metabolites and that impaired insulin secretion by islets is the mechanism by which iAs exposure leads to diabetes. The proposed project will use metabolomics to identify metabolic pathways in -cells that are targeted by iAs and its metabolites, monomethyl-As (MAs) and dimethyl-As (DMAs). The metabolomics data combined with results of our ongoing mechanistic studies will provide a comprehensive picture of the metabolic dysfunction leading to the development of diabetes in individuals exposed to iAs and of the molecular mechanisms that underlie this dysfunction. Identifying the affected pathways and mechanisms will ultimately help to improve strategies for prevention and/or treatment of T2D associated with chronic exposure to iAs.'

2型糖尿病（Type-2 diabetes, T2D）是一种复杂的代谢紊乱疾病，全球数亿人受其困扰，已成为日益严峻的公共卫生问题。尽管近年来T2D研究取得了一定进展，但该病的病因及代谢缺陷背后的机制仍不甚明晰。虽然肥胖被认为是T2D患病率上升的主要诱因，但仅用肥胖无法解释不同地理区域和人群间T2D流行趋势的差异。越来越多的证据表明，环境暴露于有毒及致糖尿病物质必然发挥着重要作用。
无机砷（inorganic arsenic, iAs）是一种天然存在的有毒类金属。全球范围内有数亿人通过饮用水和食物接触到不安全水平的无机砷。无机砷是强效致癌物，但其暴露还与T2D风险升高相关。尽管无机砷暴露与T2D之间的关联已得到广泛证实，但无机砷暴露产生致糖尿病效应的潜在机制仍不明确。
我们已发表及正在进行的研究结果表明，胰腺胰岛是无机砷及其代谢产物的主要靶标，胰岛胰岛素分泌受损是无机砷暴露引发糖尿病的作用机制。本拟开展的研究将利用代谢组学（metabolomics）技术，鉴定无机砷及其代谢产物一甲基砷（monomethyl-As, MAs）与二甲基砷（dimethyl-As, DMAs）所靶向的胰岛β细胞代谢通路。将代谢组学数据与我们正在进行的机制研究结果相结合，将为阐明无机砷暴露个体发生糖尿病时的代谢功能障碍，以及该功能障碍背后的分子机制提供全面的认知图景。明确受影响的通路与机制，最终将有助于优化与慢性无机砷暴露相关的T2D的预防和/或治疗策略。