In vitro toxic interaction of arsenic and hyperglycemia in mitochondria: an important implication of increased vulnerability in pre-diabetics.

Abstract

Environmental pollutants and lifestyle both contribute to the rapidly increasing prevalence of type 2 diabetes mellitus (T2DM) worldwide. Evidence suggests that exposure to environmental contaminants such as arsenic is associated with impaired glucose metabolism and insulin signaling. In the present study, isolated rat liver mitochondria (1mg/ml) were co-exposed to low concentration of arsenic trioxide (ATO) ( IC25 = 40µM) and hyperglycemic condition (20, 40, 80, 160mM glucose or 20, 40, 80, 160mM pyruvate (PYR)). Mitochondrial dehydrogenase activity (complex II), glutathione content (GSH), reactive oxygen species (ROS), lipid peroxidation, mitochondrial membrane potential (ΔΨ), and mitochondrial swelling were then evaluated in the presence of ATO 40µM and PYR 40mM. Unexpectedly, glucose alone (20, 40, 80, 160mM) had no toxic effect on mitochondria, even at very high concentrations and even when combined with ATO. Interestingly, PYR at low concentrations (≤ 10mM) has a protective effect on mitochondria, but at higher concentrations (≥ 40mM) with ATO, it decreased the complex II activity and increased mitochondrial ROS production, lipid peroxidation, GSH depletion, mitochondrial membrane damage, and swelling (p < 0.05). In conclusion, PYR but not glucose increased ATO mitochondrial toxicity even at low concentrations. These results suggest that pre-diabetics with non-clinical hyperglycemia, who are inevitably exposed to low concentrations of arsenic through food and water, may develop mitochondrial dysfunction that accelerates their progression to diabetes over time.