ABSTRACT
Under normal physiology, insulin exerts vasodilatory and pro-survival actions via the phosphati dylinositol 3-kinase (PI3-kinase) pathway and vasoconstrictive and mitogenic actions via the mitogen-activated protein kinase (MAPK) pathway in the vasculature. In the insulin resistant states, insulin signals through the PI3-kinase pathway are blunted but its signals through the MAPK cascade remain intact. This imbalance predisposes insulin resistant patients to hypertension and atherosclerosis. The renin-angiotensin system (RAS) is expressed both systemically and locally in the cardiovascular system. Insulin resistance up-regulates the local RAS which contributes to the pathogenesis of hypertension, heart failure, and atherosclerosis. Angiotensin Ⅱ impairs insulin signaling, induces inflammation via the NF-κB pathway, reduces nitric oxide availability and facilitates vasoconstriction,leading to insulin resistance and endothelial dysfunction. Thus the RAS, insulin resistance and inflammation perpetuate each other and coordinately contribute to endothelial dysfunction, vascular injury and atherosclerosis. RAS inhibition decreases cardiovascular and renal morbidity and mortality and the incidence of new onset Type 2 diabetes.