(The FASEB Journal. 2007;21:893.7)
© 2007 FASEB
Peroxynitrite contributes to high fat diet-induced insulin resistance
Hervé Duplain1,
Claudio Sartori1,
Pierre-Yves Jayet1,
Sébastien Thalmann2,
Pierre Dessen1,
Pascal Nicod1 and
Urs Scherrer1
1 Internal Medicine and Botnar Center for Clinical Research, CHUV, Rte du Bugnon, Lausanne, 1011, Switzerland,
2 Endocrinology, HUG, Micheli-du-Crest, Genève, 1211, Switzerland
ABSTRACT
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.
