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Grant Abstract: Mechanisms of Arsenic-Induced Diabetes Mellitus

Grant Number: 5R01ES022697-03
PI Name: Styblo
Project Title: Mechanisms of Arsenic-Induced Diabetes Mellitus

Abstract: Abstract: 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 have shown that the toxic methylated metabolites of iAs, methylarsonite (MAsIII) and dimethylarsinite (DMAsIII), play important roles in the diabetogenic effects of iAs exposure. The main goal of our ongoing R01 project (the Parent project) “Mechanisms of Arsenic-Induced Diabetes, (R01ES022697) 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 impair glucose homeostasis in laboratory mice. The specific aims of the Parent project are: 1. To characterize the diabetogenic effects of iAs exposure in mice with limited capacity to produce MAsIII and DMAsIII (i.e., mice knocked out for As3mt – the enzyme that methylates iAs). 2. To identify mechanisms underlying the inhibition of insulin secretion by ß-cells exposed to MAsIII or DMAsIII. 3. To determine whether the diabetogenic effects of iAs exposure are reversible. The current application seeks supplemental funding to characterize the role of dietary folate as a potential modifier of the diabetogenic effects of iAs exposure. Folate is an essential micronutrient that is required for synthesis of S-adenosylmethionine (SAM), a methyl group donor for the methylation of iAs by AS3MT. Folate intake has been shown to modify iAs metabolism and toxicity in population studies. Results of our recent study in Chihuahua suggest that while elevated folate intake stimulates iAs methylation, it is also positively associated with diabetes indicators. The goal of this administrative supplement is to explore these findings using an established mouse model. We hypothesize that folate intake impairs glucose homeostasis in a dose dependent manner by stimulating MAsIII and DMAsIII production and by increasing accumulation of these metabolites in tissues regulating glucose metabolism. The following supplemental aim will test this hypothesis:
Aim 1S: Characterize the effects of folate intake on the metabolic phenotype of mice exposed to iAs. We will compare measures of fasting glycemia, glucose tolerance, ß-cell function and insulin resistance in adult male wt C57BL/6J mice exposed to iAs in drinking water (0.1 or 1 mg As/L) and fed a diet with low, adequate or high folate (folic acid) content. We will correlate these measures with the concentrations of iAs and its methylated metabolites in urine and in tissues regulating glucose homeostasis (pancreas, liver, skeletal muscle and fat).

This project will be the first to characterize side-by-side the effects of low, adequate and high folate intakes on iAs metabolism and to link these effects to dysregulation of specific mechanisms that maintain glucose homeostasis, thus providing important clues for human epidemiologic and intervention studies examining the associations between iAs exposure and diabetes

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