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Record Count: 2
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DESCRIPTION (provided by applicant)
There is growing evidence that chronic exposure of humans to inorganic arsenic, a potent environmental oxidative stressor, is associated with the incidence of Type 2 diabetes. In contrast to what has been a prevailing beneficial view of antioxidants in preventing pancreatic ?-cell dysfunction in diabetes, this project proposes that in response to arsenic exposure, transcription factor Nrf2-mediated adaptive induction of endogenous antioxidant enzymes plays paradoxical roles in ?-cell function. The investigators hypothesize that, on the one hand, Nrf2-mediated antioxidant response blunts glucose-triggered `ROS signaling' that plays an important role in glucose-stimulated insulin secretion (GSIS); on the other hand, the response protects ?-cells from oxidative damage and subsequent apoptosis/necrosis. The investigators propose three specific aims: (1) Test the hypothesis that induction of antioxidant enzymes in response to arsenic exposure and related oxidative stress impedes glucose-triggered `ROS signaling' and thus GSIS; (2) Test the hypothesis in silico that adaptive induction of antioxidant enzymes in response to chronic oxidative stress impedes `ROS signaling', and explore intervention approaches that can improve `ROS signaling'; (3) Test the hypothesis that Nrf2-mediated antioxidant response is critical for protecting ?-cells from oxidative damage and apoptosis/necrosis induced by arsenic and/or glucose toxicity. The integrated wet-lab and computational approaches will allow to: (1) understand how environmental arsenic exposure impairs ?-cell function; (2) characterize the quantitative nature of the effect of arsenic-induced oxidative stress on `ROS signaling' that is involved in GSIS; (3) distinguish the specific roles of Nrf2 and its target antioxidant enzymes in `ROS signaling' and ?-cell function; and (4) identify novel targets and approaches to modulate insulin secretion and protect ?-cells from oxidative damage. This project will investigate the pathogenic mechanisms of Type 2 Diabetes caused by environmental arsenic exposure. The results may enable new therapeutic managements and preventive strategies for arsenic or other environmental oxidative stress-associated diabetes.
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.
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