Insulin resistance and endothelial dysfunction in atherosclerosis: implications and interventions.

Current research suggests that insulin resistance is associated with endothelial dysfunction, which is considered an early but significant step in the pathogenesis of atherosclerosis. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Insulin-sensitizing agents--specifically, thiazolidinediones (TZDs)--may be useful for preventing or mitigating endothelial dysfunction. In vitro and clinical data show that TZDs can limit thrombotic, inflammatory, and oxidative changes that contribute to endothelial dysfunction. For example, TZDs have been shown to lower blood levels of plasminogen activator inhibitor-1, a prothrombotic substance, in patients with diabetes or insulin resistance. In obese patients, TZD treatment can improve vascular reactivity and reduce monocyte expression of nuclear factor kappa-B, a transcription factor that contributes to inflammation and oxidative damage. In patients with overt diabetes or insulin resistance, TZD treatment can lower blood levels of C-reactive protein and interleukin-6, markers of inflammation and cardiovascular risk. These beneficial effects of TZDs may help to decrease the risk of vascular damage and atherosclerosis in patients with insulin resistance or diabetes.