Insulin resistance and cardiovascular disease

Cardiovascular risk factors cluster in obese individuals. Insulin resistanc e emerges as a common pathogenetic denominator underlying the risk factor c luster. Defects in nonesterified fatty acids metabolism have been implicate d in the abnormal lipid and glucose metabolism which characterize the clust er. Other evidence also leads to the adipocyte as an important contributor to the risk factor cluster and cardiovascular complications through effects not only on fatty acids but also on leptin, plasminogen activator inhibito r-1, and angiotensinogen, to name a few. Fatty acids are elevated among abd ominally obese individuals, are more resistant to suppression by insulin, a nd may contribute to hypertension. Fatty acids may affect blood pressure by inhibiting endothelial nitric oxide synthase activity and impairing endoth elium-dependent vasodilation. Fatty acids increase alpha (1)-adrenoceptor-m ediated vascular reactivity and enhance the proliferation and migration of cultured vascular smooth-muscle cells. Several effects of fatty acids are m ediated through oxidative stress. Fatty acids can also interact with other facets of cluster, including increased angiotensin II, to accentuate oxidat ive stress. Oxidative stress, in turn, is implicated in the pathogenesis of insulin resistance, hypertension, vascular remodeling, and vascular compli cations. A clearer delineation of the key reactive oxygen signaling pathway s and the impact of various interventions on these pathways could facilitat e a rationale approach to antioxidant therapy and improved outcomes among t he rapidly growing number of high-risk, insulin-resistant, obese individual s. Am J Hypertens 2001;14:116S-125S (C) 2001 American Journal of Hypertensi on, Ltd.