Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase

Background - Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNO S) is expressed in skeletal muscle, where it may govern metabolic processes , and in the vascular endothelium, where it regulates arterial pressure. Methods and Results - To study the role of eNOS in the control of the metab olic action of insulin, we assessed insulin sensitivity in conscious mice w ith disruption of the gene encoding for eNOS. eNOS(-/-) mice were hypertens ive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insul in-stimulated glucose uptake than control mice. Insulin resistance in eNOS( -/-) mice was related specifically to impaired NO synthesis, because in equ ally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertensio n), insulin-stimulated glucose uptake was normal. Conclusions - These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabo lic and cardiovascular disease.