Mechanisms of Arsenic-Induced Diabetes Mellitus

砷诱发糖尿病的机制

• 批准号: 8785124
• 负责人: Miroslav Styblo
• 金额: $ 34.87万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-13 至 2017-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8785124
• 关键词: Address; Adipocytes; Arsenic; Arsenicals; Beta Cell; C57BL/6 Mouse; Cell Line; Cell physiology; Cells; Chemicals; Chronic; Data; Defect; Diabetes Mellitus; Diagnosis; Disease; Environmental Exposure; Environmental Pollution; Enzymes; Exposure to; Fasting; Functional disorder; Glucose; Glucose Intolerance; Goals; Health; Human; Hyperglycemia; Impairment; In Vitro; Incubated; Individual Differences; Inhibitory Concentration 50; Insulin; Insulin Resistance; Islets of Langerhans; Knockout Mice; Laboratories; Laboratory Study; Link; Liver; Malignant Neoplasms; Measures; Metabolic; Metabolism; Methylation; Methyltransferase; Mexico; Molecular; Mus; National Institute of Environmental Health Sciences; National Toxicology Program; Non-Insulin-Dependent Diabetes Mellitus; Non-Malignant; Occupational; Pathway interactions; Peripheral; Phase; Phenotype; Plasma; Play; Poison; Population; Population Study; Predisposition; Prevalence; Production; Research; Risk; Role; Structure of beta Cell of islet; Tissues; Toxicant exposure; Work; blood glucose regulation; diabetes risk; disease registry; drinking water; fasting plasma glucose; glucose metabolism; glucose tolerance; glucose uptake; impaired glucose tolerance; improved; in vivo; inhibitor/antagonist; insulin secretion; insulin signaling; insulinoma; islet; metabolomics; oxidation; research study; urinary

DESCRIPTION (provided by applicant): Millions of people in the U.S. and worldwide are exposed to unsafe levels of inorganic arsenic (iAs) in drinking water. These people are at risk of developing cancer and nonmalignant diseases, including diabetes mellitus. Results of our previous population and laboratory studies challenge the existing paradigm that the iAs-induce diabetes is typical of type 2 diabetes mellitus, which is characterized primarily by insulin resistance due to nonresponsiveness of the liver and peripheral tissues to insulin signaling. In fact, we found significant negative correlations between iAs exposure and fasting plasma insulin and insulin resistance, suggesting impairment in pancreatic beta-cell function. We have also shown that the methylated metabolites of iAs play important roles in the diabetogenic effects of iAs exposure. Our population studies have linked the risk of developing diabetes to the production and urinary levels of one of the toxic metabolites of iAs, dimethylarsinite (DMAsIII). Our laboratory experiments have shown that DMAsIII and its metabolic precursor, methylarsonite (MAsIII), inhibit insulin signaling, but are even more potent as inhibitors of glucose-stimulated insulin secretion (GSIS) in pancreatic islets. Notably, the inhibition of insuli secretion by either MAsIII or DMAsIII was reversed by incubating islets in arsenic-free medium. Taken together, these data suggest that pancreatic beta-cells are the primary targets for iAs exposure and that the toxic methylated metabolites of iAs, MAsIII and DMAsIII, play an important role in beta-cell dysfunction. The goal of this project is to characterize the role of MAsIII and DMAsIII in the diabetogenic effects of iAs exposure and to identify molecular mechanisms by which these arsenicals inhibit GSIS in pancreatic beta- cells. We will use both in vivo and in vitro studies to address this goal. We will compare the susceptibility to develop diabetes in C57BL/6 mice which effectively methylate iAs and C57BL/6/As3mt-KO mice with limited capacity to produce MAsIII and DMAsIII. We will use insulinoma (INS-1/832-13) cells and isolated murine and human pancreatic islets to identify molecular mechanisms by which MAsIII and DMAsIII inhibit GSIS. Finally, we will determine whether the diabetogenic effects of in vivo iAs exposure in mice and in vitro MAsIII and DMAsIII exposures in INS-1 cells or pancreatic islets can be reversed by discontinuing the exposure. This is the first project to examine the role of MAsIII and DMAsIII in the diabetogenic effects of iAs exposure in the endocrine pancreas and to identify the mechanisms by which these metabolites of iAs inhibit pancreatic beta-cell function. Results of this work will help to better understand the phenotype of diabetes associated with iAs exposure. Additionally, data generated by this project will help to improve the diagnosis and treatment of diabetes in populations chronically exposed to environmental or occupational iAs.

描述（由申请人提供）：美国和全球数百万的人暴露于饮用水中的无机砷（IAS）水平。这些人有患癌症和非恶性疾病（包括糖尿病）的风险。我们先前的人口和实验室研究的结果挑战了IAS-诱导糖尿病的典型范围的现有范式，这是2型糖尿病的糖尿病，主要是由于肝脏和周围组织对胰岛素信号的无反应性而引起的胰岛素抵抗。实际上，我们发现IAS暴露与空腹血浆胰岛素和胰岛素抵抗之间的显着负相关，这表明胰腺β细胞功能受损。我们还表明，IAS的甲基化代谢产物在IAS暴露的糖尿病作用中起重要作用。我们的人口研究将患糖尿病的风险与IAS有毒代谢产物之一的二甲基二甲基（DMASIII）的产生和尿液水平联系起来。我们的实验室实验表明，DMASIII及其代谢前体甲基肌（MASIII）抑制胰岛素信号传导，但随着胰岛中葡萄糖刺激的胰岛素分泌（GSIS）的抑制剂的抑制作用甚至更有效。值得注意的是，通过在无砷培养基中孵育胰岛来逆转MASIII或DMASIII的胰岛分泌的抑制作用。综上所述，这些数据表明胰腺β细胞是IAS暴露的主要靶标，并且IAS，MASIII和DMASIII的有毒甲基化代谢产物在β细胞功能障碍中起着重要作用。该项目的目的是表征MASIII和DMASIII在IAS暴露的糖尿病生成作用中的作用，并鉴定这些砷在胰腺β细胞中抑制GSIS的分子机制。我们将使用体内和体外研究来解决这一目标。我们将比较在C57BL/6小鼠中发展糖尿病的易感性，该糖尿病有效地甲基酸IAS和C57BL/6/AS3MT-KO小鼠产生MASIIII和DMASIII的能力有限。我们将使用胰岛素瘤（INS-1/832-13）细胞以及分离的鼠和人类胰岛来鉴定MASIII和DMASIII抑制GSIS的分子机制。最后，我们将确定在INS-1细胞或胰岛中，体内IAS暴露在小鼠，体外MASIII和DMASIII暴露中的糖尿病生成作用是否可以通过中断暴露来逆转。这是检查角色的第一个项目 MASIII和DMASIII在内分泌胰腺中IAS暴露的糖尿病生成作用中，并确定这些IAS这些代谢物抑制胰腺β细胞功能的机制。这项工作的结果将有助于更好地了解与IAS暴露相关的糖尿病的表型。此外，该项目产生的数据将有助于改善长期暴露于环境或职业IAS的人群中糖尿病的诊断和治疗。