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.