Peroxynitrite contributes to high fat diet‐induced insulin resistance

Obesity‐induced insulin resistance is a problem of utmost clinical significance. Nitric oxide (NO) is a key player in the regulation of the metabolic homeostasis. Peroxynitrite, a toxic metabolite of NO, is elevated in diabetic patients, but its pathophysiological significance is not known. We hypothesized that peroxynitrite contributes to high fat diet‐induced insulin resistance. To test this hypothesis, we assessed insulin sensitivity in high fat diet‐fed mice treated with FeTPPS, a peroxynitrite decomposition catalyst, or vehicle. The major new finding was that FeTPPS significantly improved insulin sensitivity, as evidenced by decreased fasting plasma glucose (8.6 ± 0.5 vs. 10.9 ± 0.6 mmol/l, p<0.05) and smaller increase of plasma glucose levels after an intraperitoneal glucose challenge (18.4 ± 1.6 vs. 23.4 ± 1.1 mmol/l, p<0.01). Furthermore, intraperitoneal insulin injection induced a more than twofold larger fall in plasma glucose levels in FeTPPS‐treated than in control mice (24 ± 4 % vs. 9 ± 4 % from baseline 15 min after injection, p<0.05). Finally, FeTPPS markedly improved insulin‐stimulated glucose uptake in isolated skeletal muscles (63 ± 7 % vs. 12 ± 6 % increase, p<0.05). These data demonstrate for the first time that peroxynitrite significantly contributes to high fat diet‐induced insulin resistance in mice. It does so, at least in part, by causing insulin resistance in skeletal muscle tissue.