Linus Pauling Institute

Pancreatic beta cells produce and release insulin, a hormone that regulates blood glucose levels, and their dysfunction contributes to the development of diabetes mellitus. Zinc deficiency and inorganic arsenic exposure both independently associate with the development of diabetes, although the effects of their combination on pancreatic beta cell health and function remain unknown. We hypothesized zinc deficiency increases the toxicity associated with arsenic exposure, causing an increased susceptibility to DNA damage and disruption of insulin production. Zinc deficiency decreased cell proliferation by 30% in pancreatic INS-1 rat insulinoma cells. Arsenic exposure (0, 50 or 500 ppb exposures) significantly decreased cell proliferation, and increased mRNA levels of genes involved in stress response (Mt1, Mt2, Hmox1) and DNA damage (p53, Ogg1). When co-exposed to both zinc deficiency and arsenic, zinc deficiency attenuated this response to arsenic, decreasing the expression of Mt1, Hmox1, and Ogg1, and significantly increasing DNA double-strand breaks 2.9-fold. Arsenic exposure decreased insulin expression, but co-exposure did not decrease insulin levels beyond the arsenic alone condition, but did result in a further 33% decline in cell proliferation at the 500 ppb arsenic dose, and a significant increase in beta cell apoptosis. These results suggest zinc deficiency and arsenic, both independently and in combination, adversely affect pancreatic beta cell health and both factors should be considered in the evaluation of health outcomes for susceptible populations.