Impact of in vitro heavy metal exposure on pancreatic β-cell function

Susceptibility to type-2 diabetes mellitus (DM) is determined, in part, by a variety of environmental factors, including exposure to metals. Heavy metals including inorganic arsenic (iAs), zinc (Zn), manganese (Mn), and cadmium (Cd) have been reported to affect glucose homeostasis or DM risk in population-based and/or laboratory studies. Previous evidence from our lab has shown that iAs can increase DM risk by impairing mitochondrial metabolism, one of the key steps in the regulation of glucose-stimulated insulin secretion (GSIS) in pancreatic beta-cells. The goal of the current study was to compare the effects of iAs on GSIS and mitochondrial function in INS-1 832/13 beta-cells with those of Cd, Mn, and Zn, and to evaluate effects of binary mixtures of these metals. As expected, 24-hour exposure to iAs (arsenite, >= 1 mu M) significantly inhibited GSIS as did Cd (5 mu M) and Mn (12.5, 25, or 50 mu M). Zn had no effects on GSIS at concentrations up to 50 mu M. Mitochondrial function was assessed by measuring oxygen consumption rate (OCR) after glucose stimulation and during simulated mitochondrial stress. While both iAs and Mn impaired mitochondrial function (inhibiting OCR, maximal respiration, and/or spare respiratory capacity of mitochondria), no significant effects were found in cells exposed to Cd. Interestingly, no additive or synergistic effects on GSIS or OCR were observed in binary mixtures of iAs with either Mn or Cd. These data suggest that Mn, like iAs, may inhibit GSIS by impairing mitochondrial function, whereas Cd may target other mechanisms that regulate GSIS in beta-cells.