Stimulation of peroxynitrite catalysis improves insulin sensitivity in high fat diet-fed mice

Peroxynitrite synthesis is increased in insulin resistant animals and humans. Peroxynitirite-induced nitration of insulin signalling proteins impairs insulin action in vitro , but the role of peroxynitrite in the pathogenesis of insulin resistance in vivo is not known. We therefore assessed the effects of a 1-week treatment with the peroxynitrite decomposition catalyst FeTPPS on insulin sensitivity in insulin resistant high fat diet-fed (HFD) and control mice. FeTPPS normalized the fasting plasma glucose and insulin levels ( P < 0.01), attenuated the hyperglycaemic response to an intraperitoneal glucose challenge by roughly 50% ( P < 0.05), and more than doubled the insulin-induced decrease in plasma glucose levels in HFD-fed mice ( P < 0.001). Moreover, FeTPPS restored insulin-stimulated Akt phosphorylation and insulin-stimulated glucose uptake in isolated skeletal muscle in vitro . Stimulation of peroxynitrite catalysis attenuates HFD-induced insulin resistance in mice by restoring insulin signalling and insulin-stimulated glucose uptake in skeletal muscle tissue.