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

Nitric oxide (NO) plays a major role in the regulation of cardiovascular and metabolic homeostasis, as evidenced by insulin resistance and arterial hypertension in endo-thelial 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 hyper-tension in normal mice. To test whether partial eNOS deficiency facilitates the development of insulin resis-tance and arterial hypertension during metabolic stress, we examined effects of an 8-week high-fat diet on insulin sensitivity (euglycemic clamp) and arterial pres