Environmental arsenic and diabetes mellitus

环境砷与糖尿病

基本信息

批准号：
7909590
负责人：
Miroslav Styblo
金额：
$ 45.8万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-06 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7909590
关键词：
Accounting Acids Acute Adipocytes Adipose tissue Adult Adverse effects Animals Area Arsenic Arsenicals Arsenites Bangladesh Blood Glucose C57BL/6 Mouse Cell Culture Techniques Cell physiology Cells Chronic Complex Cultured Cells Cytotoxin Data Defect Development Diabetes Mellitus Diagnosis Diet Dose Environmental Pollutants Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epidemic Epidemiologic Studies Experimental Designs Exposure to Fasting Fatty acid glycerol esters Genetic Polymorphism Glucose Goals Human In Vitro Individual Insulin Insulin Resistance Knowledge Laboratory Research Laboratory mice Life Style Link Liver Malignant Neoplasms Mediator of activation protein Metabolic Activation Metabolic Diseases Metabolism Methods Methylation Methyltransferase Mexico Mining Molecular Mus Muscle Muscle Cells Muscle Fibers Mutagens Non-Insulin-Dependent Diabetes Mellitus OGTT Obesity Occupational Pancreas Pathology Pathway interactions Pattern Peripheral Play Predisposition Prevalence Production Proto-Oncogene Proteins c-akt Reporting Research Research Design Research Project Grants Risk Risk Assessment Role Signal Transduction Pathway Skeletal Muscle Source Stimulus Symptoms Taiwan Testing Tissues Toxic Environmental Substances Translational Research Urine base blood glucose regulation data integration diabetes risk dimethylarsinous acid drinking water environmental toxicology exposed human population glucose metabolism glucose tolerance glucose uptake human population study human tissue impaired glucose tolerance improved in vitro activity inhibitor/antagonist insulin signaling novel oxidation public health relevance research study response translational approach urinary

项目摘要

DESCRIPTION (provided by applicant): Millions of people in various geographical regions, including the US, are exposed to unsafe levels of inorganic arsenic (iAs) in drinking water. The research of the effects of chronic exposure to iAs has commonly focused on its carcinogenic potency. However, epidemiologic studies indicate that iAs exerts other adverse effects that do not involve cancer. Several studies in arseniasis-endemic areas of Taiwan, Bangladesh, and Mexico have linked chronic exposures to high or moderate levels of iAs in drinking water to an increased risk for type 2 diabetes mellitus (T2D). Although results of epidemiologic studies in low-exposure areas or occupational settings have been inconclusive, laboratory research shows that exposures to iAs can produce symptoms that are consistent with T2D. In our preliminary studies, mice chronically exposed to iAs in drinking water developed impaired glucose tolerance. The major fraction of arsenic retained in tissues of these mice, including liver, pancreas, adipose and skeletal muscle tissues, was represented by methylated arsenicals, the products of the methylation of iAs by arsenic (3+ oxidation state) methyltransferase (AS3MT). Our in vitro studies showed that methylated trivalent arsenicals are more potent than iAs as inhibitors of insulin signaling and insulin-stimulated glucose uptake in cultured adipocytes. Notably, concentrations of arsenicals that inhibit glucose uptake by adipocytes and arsenic concentrations in tissues of mice that developed impaired glucose tolerance after exposure to iAs in drinking water are similar to arsenic concentrations in livers of residents in the arseniasis areas of Bangladesh. These results suggest that the formation of methylated trivalent arsenicals in the course of iAs metabolism may be a determining factor for development of T2D in individuals exposed to iAs in drinking water and that insulin-activated signal transduction pathway is the key target for these arsenicals. Based on these findings, we propose a translational research project that will examine diabetogenic effects of iAs in cultured cells, laboratory mice, and in humans. The main goals of this project are (i) to further characterize the association between iAs exposure and T2D, (ii) to identify molecular mechanisms for the diabetogenic effects of iAs exposure, (iii) to evaluate the roles specific metabolites of iAs play in these effects, and (iv) to characterize AS3MT polymorphisms that are associated with the increased production of these metabolites. Results of this project will advance knowledge in the area of environmental toxicology of As that has not been systematically studied, providing novel information that will improve the risk assessment of diabetes in arseniasis-endemic areas and the identification of individuals with increased susceptibility to the diabetogenic effects of chronic exposures to iAs. PUBLIC HEALTH RELEVANCE: Millions of people worldwide are exposed to arsenic in drinking water. Previous epidemiologic studies have linked chronic exposures to arsenic to an increased risk for type 2 diabetes mellitus. We propose a translational research project that will examine diabetogenic effects of arsenic in cultured cells, laboratory mice, and in humans. The goals of this project are to identify mechanisms by which exposures to arsenic induce diabetes and to characterize genetic polymorphisms that are associated with increased risk of diabetes for individuals exposed to arsenic in drinking water.

描述（由申请人提供）：包括美国在内的各个地理区域中的数百万人暴露于饮用水中不安全的无机砷（IAS）水平。长期暴露于IAS的影响的研究通常集中在其致癌效力上。但是，流行病学研究表明，IAS会发挥其他不涉及癌症的不良反应。在台湾，孟加拉国和墨西哥的阿森病 - 流行地区的几项研究将慢性暴露与饮用水中高或中等水平的IAS联系在一起，与增加2型糖尿病的风险增加了。尽管在低暴露区域或职业环境中流行病学研究的结果尚无定论，但实验室研究表明，对IAS的暴露会产生与T2D一致的症状。在我们的初步研究中，长期暴露于饮用水中IAS的小鼠会导致葡萄糖耐受性受损。这些小鼠的组织中保留的砷的主要部分，包括肝脏，胰腺，脂肪和骨骼肌组织，由甲基化的砷代表，甲基化的砷是通过砷（3+氧化态）甲基化酶（AS3MT）通过砷（3+氧化态）甲基化IAS化的产物。我们的体外研究表明，作为胰岛素信号传导和胰岛素刺激的葡萄糖在培养的脂肪细胞中的抑制剂，甲基化的三价砷比IAS更有效。值得注意的是，抑制脂肪细胞和砷浓度抑制饮用水中IAS后葡萄糖耐受性受损的小鼠组织中葡萄糖摄取的砷浓度类似于跨越曼德兰群岛阿森氏症地区居民肝脏中砷浓度。这些结果表明，在IAS代谢过程中形成甲基化三价砷的形成可能是饮用水中暴露于IAS的个体中T2D发展的决定因素，并且胰岛素激活的信号转导途径是这些砷的关键目标。基于这些发现，我们提出了一个转化研究项目，该项目将检查IAS在培养细胞，实验室小鼠和人类中的糖尿病生成作用。该项目的主要目标是（i）进一步表征IAS暴露与T2D之间的关联，（ii），以确定IAS暴露的糖尿病生成作用的分子机制，（III）评估IAS在这些效果中发挥特定角色的作用，以及（iv）与AS3MT Polimphists相关的生产，这些作用在这些效果中扮演的角色。该项目的结果将促进尚未系统地研究的环境毒理学领域的知识，从而提供新的信息，从而改善砷病态地区糖尿病的风险评估，并鉴定具有增加对IAS慢性疾病影响糖尿病效应的人的识别。公共卫生相关性：全世界数百万的人在饮用水中暴露于砷。先前的流行病学研究已将慢性暴露与砷与2型糖尿病的风险增加联系起来。我们提出了一个翻译研究项目，该项目将检查砷在培养的细胞，实验室小鼠和人类中的糖尿病生成作用。该项目的目标是确定暴露于砷的机制，并诱导糖尿病，并表征与饮用水中暴露于砷的个体糖尿病风险增加有关的遗传多态性。