Prolonged exposure to free fatty acids induces β-cell cytotoxicity. We investigated whether this fatty-acid-induced cytotoxicity is affected by high glucose levels. In clonal β-cell HIT-T15, palmitate-induced cytotoxicity was potentiated depending on elevated glucose concentrations due to increased apoptosis without cytotoxic effects of high glucose per se. This palmitate cytotoxicity was blocked by NO synthase inhibitors, and palmitate actually increased cellular NO production. The potentiation of palmitate cytotoxicity under high glucose was reversed by decreasing superoxide production, suggesting that superoxide overproduction under high glucose enhances NO-mediated cytotoxicity in β-cells, which may explain the mechanism of synergistic deterioration of pancreatic β-cells by free fatty acids and high glucose.
