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J Physiol Volume 586, Number 16, 4011-4016, August 15, 2008 DOI: 10.1113/jphysiol.2008.154302
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Stimulation of peroxynitrite catalysis improves insulin sensitivity in high fat diet-fed mice

 Hervé Duplain1, Claudio Sartori1, Pierre Dessen1, Pierre-Yves Jayet1, Marcos Schwab1, Jonathan Bloch1, Pascal Nicod1 and Urs Scherrer1

1 Department of Internal Medicine and Botnar Center for Clinical Research, University Hospital Center and University of Lausanne, Switzerland

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.

(Received 23 March 2008; accepted after revision 19 June 2008; first published online 26 June 2008)
Corresponding author H. Duplain: Department of internal medicine, BH 10-640, 1011 Lausanne-CHUV, Switzerland. Email: herve.duplain{at}chuv.ch






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