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Diabetes 53:2067-2072, 2004
© 2004 by the American Diabetes Association, Inc.

Partial Gene Deletion of Endothelial Nitric Oxide Synthase Predisposes to Exaggerated High-Fat Diet—Induced Insulin Resistance and Arterial Hypertension

Stéphane Cook1, Olivier Hugli1, Marc Egli1, Barbara Ménard1, Sébastien Thalmann1, Claudio Sartori1, Christophe Perrin2, Pascal Nicod1, Bernard Thorens3, Peter Vollenweider1, Urs Scherrer1, and Rémy Burcelin2,3

1 Department of Internal Medicine and the Botnar Center for Clinical Research, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
2 UMR CNRS-UPS 5018, IFR 31, Toulouse, France
3 Institute of Pharmacology and Toxicology, University of Lausanne, Lausanne, Switzerland

Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endothelial NO synthase (eNOS) null mice. Extrapolation of these findings to humans is difficult, however, because eNOS gene deficiency has not been reported. eNOS gene polymorphism and impaired NO synthesis, however, have been reported in several cardiovascular disease states and could predispose to insulin resistance. High-fat diet induces insulin resistance and arterial hypertension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pressure in eNOS+/– mice. When fed a normal diet, these mice had normal insulin sensitivity and were normotensive. When fed a high-fat diet, however, eNOS+/– mice developed exaggerated arterial hypertension and had fasting hyperinsulinemia and a 35% lower insulin-stimulated glucose utilization than control mice. The partial deletion of the eNOS gene does not alter insulin sensitivity or blood pressure in mice. When challenged with nutritional stress, however, partial eNOS deficiency facilitates the development of insulin resistance and arterial hypertension, providing further evidence for the importance of this gene in linking metabolic and cardiovascular disease.

Address correspondence and reprint requests to Rémy Burcelin, PhD, CNRS-UMR 5018, Paul Sabatier University, CHU Rangueil, 1 Avenue Jean Poulhes, 31403 Toulouse, France. E-mail: burcelin{at}toulouse.inserm.fr. Urs Scherrer, MD, Department of Internal Medicine, BH 10.642, Centre Hospitalier Universitaire Vaudois, CH-1011 Lausanne, Switzerland. E-mail: urs.scherrer{at}hospvd.ch


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