This project examines the role of arsenicals in the induction of diabetes mellitus. Inorganic forms of arsenic (iAs) are highly toxic and are classified as human carcinogens. Drinking water contaminated with iAs, along with industrial emissions, are major sources of exposure to iAs for populations worldwide. Numerous epidemiological studies have linked environmental exposures to iAs to increased incidences of various types of cancer and noncancerous diseases. Among diseases associated with chronic exposure to iAs, diabetes mellitus remains a significant problem especially in arsenic-endemic areas with large populations exposed to this metalloid from drinking water (e.g., Taiwan and Bangladesh). The adverse health effects associated with chronic exposure to iAs are also being intensively studied in the U.S. where hundreds of thousands of residents drink water with iAs levels that exceed the current maximum contaminant level (MCL) of 50 milligrams of arsenic per liter of water. Mechanisms by which iAs induces cancer, diabetes mellitus or other noncancerous disease are unknown. iAs species that contain trivalent arsenic (iAs-III) are potent oxidants that induce oxidative stress in laboratory animals and cultured cells. iAs-III species are also inhibitors of numerous enzymes and receptors involved in key metabolic and cell signaling pathways. Interactions of iAs-III with catalytically-active thiols have been shown to underlie these effects. In humans, iAs is metabolized to yield methylarsenic (MAs) and dimethylarsenic (DMAs) metabolites. Because of the redox nature of the metabolic reactions, both trivalent and pentavalent arsenicals (iAs-III, iAs-V, Mas-V, DMAs-III, DMAs-V) are intermediates of final metabolites in this pathway. Recent reports from this and other laboratories have shown that trivalent methylated metabolites (Mas-III and DMAs-III) are more potent cytotoxins and enzyme inhibitors than iAs-III. The thioredoxin reductase/thioredoxin (TR/Trx) system that plays a key role in numerous regulatory mechanisms in the cell (e.g., antioxidant defense, activation of transcriptional factors and cellular receptors, cytokine expression or insulin excretion by B cells) has been shown to be a primary target for MAs-III in intact cells. In addition, unlike iAs-III, Mas-III and DMAs-III can damage DNA in intact cells. The investigators have shown that both Mas-III and DMAs-III are produced by human hepatic cells exposed to iAs and are present in the urine of individuals chronically exposed to iAs from drinking water. Thus, Mas-III and DMA-III, toxic products of iAs metabolism in humans, can significantly contribute to adverse affects associated with exposure to iAs. This pilot project is designed to examine effects of trivalent arsenicals, especially Mas-III and DMAs-III, on basic mechanisms that regulate utilization of glucose: (1) production of insulin in the pancreas and (2) metabolism of glucose in peripheral tissues. Effects of arsenicals will be examined in cultured cells (pancreatic B cell lines, adipocytes and skeletal muscle cells) and in mice. Induction of oxidative stress and inhibition of TR/Trx activities will be examined as possible mechanisms underlying the induction of diabetic symptoms. Arsenic metabolites responsible for these effects will be identified. In addition, the role of cellular and nutritional antioxidants in protection against arsenic-induced diabetes will be examined, providing information that may be critical for prevention and/or treatment of diabetes in arsenic-exposed individuals.