Epidemiologic evidence has linked chronic exposure to inorganic
arsenic (iAs) with an increased prevalence of
diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair
glucose homeostasis. We have previously shown that micromolar concentrations of
arsenite (iAs(III)) or its methylated trivalent metabolites,
methylarsonite (MAs(III)) and
dimethylarsinite (DMAs(III)), inhibit the
insulin-activated signal transduction pathway, resulting in
insulin resistance in adipocytes. Our present study examined effects of the trivalent
arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs(III), MAs(III) or DMAs(III) inhibited
glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs(III) and DMAs(III) were more potent than iAs(III) as GSIS inhibitors with estimated IC(50)≤0.1 μM. The exposures had little or no effects on
insulin content of the islets or on
insulin expression, suggesting that trivalent
arsenicals interfere with mechanisms regulating packaging of the
insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs(III), MAs(III) or DMAs(III) could be reversed by a 24-hour incubation of the islets in
arsenic-free medium. These results suggest that the
insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes.