6 8. Vascular Dysfunction in Insulin Resistance and Metabolic Syndrome Hyperinsulinemia and IR are established metabolic features of obesity. Vasodilator actions of insulin to stimulate produc- tion of nitric oxide (NO) from vascular endothelium lead to increased blood ﬂow that further enhances glucose uptake in skeletal muscle [135, 136]. Insulin binding to its cognate receptor activates two major branches of insulin signal transduction network. Metabolic actions of insulin tend to be mediated by phosphatidylinositol 3-kinase- (PI3K-) dependent signaling pathways, whereas the nonmetabolic insulin signalling pathways (MAPK-dependent insulin sig- naling pathways) typically regulate growth, mitogenesis, and diﬀerentiation [137, 138] and also regulate the secretion of the vasoconstrictor endothelin-1 (ET-1) from endothelium. The PI3K-dependent metabolic actions of insulin directly promote glucose uptake in skeletal muscle by stimulating translocation of insulin responsive glucose trans- porters (GLUT4). At the same time, PI3K-dependent vascu- lar actions of insulin to increase blood ﬂow and capillary recruitment substantially contribute to promoting glucose disposal under healthy conditions [3]. ET-1, a potent vasoconstrictor synthesized and secreted by vascular endothelium, plays an important role in endothe- lial dysfunction. In humans, insulin-stimulated ET-1 production may inﬂuence skeletal muscle glucose disposal, and ET-1 infusion induces peripheral insulin resistance. NO, however, is known to inhibit ET-1 production and action [139]. Consequently, under healthy conditions, the eﬀects of insulin-stimulated ET-1 on the metabolic actions of insulin are likely to be oﬀset by insulin-stimulated production of NO [140]. IR is characterized by selective impairment in PI3K- dependent signalling in both metabolic and vascular insulin target tissues, and the diminished sensitivity to the actions of insulin in vascular endothelium contributes importantly to the clinical phenotype of this condition [3]. In insulin-resistant states, the insulin-mediated ET-1 secretion is augmented, and blockade of ET-1 receptors signiﬁcantly improves insulin sensitivity and peripheral glucose uptake in the context of IR [141, 142]. Another important mechanism of insulin action is the increased microvascular perfusion of skeletal muscle leading to increased muscle blood ﬂow and glucose uptake. While the majority of previous studies have focused on the endothelium-dependent eﬀect of insulin, we have suggested that the blunted vasodilator responsiveness to the exogenous NO seen in obese patients during hyperinsuline- mia could be related to the facilitatory action physiologically exerted by insulin on vasorelaxation within VSMCs. Indeed, insulin enhances vasodilator responsiveness by reducing Ca2+ concentration in VSMCs, via activation of the Na+, K+- ATPase pump [143]. Similarly, in human VSMCs, insulin inactivates the small GTPase RhoA and its target, Rho- kinase, thereby leading to decreased phosphorylation of myosin light chain and subsequent vasodilation [144]. In a recent study, we have demonstrated that insulin exerts a facilitatory eﬀect on vascular reactivity to a variety of Cardiology Research and Practice vasoactive molecules (acetylcholine, sodium nitroprusside, and verapamil) by the increased delivery of substrates in skeletal muscle of healthy subjects, but in contrast with the results obtained in healthy subjects, the responsiveness of these vasodilators was not enhanced during hyperinsuline- mia in the group of patients with the metabolic syndrome due to increased oxidative stress [145]. 9. Conclusion The rapid growth of obesity is contributing to an “epidemic” in Mets and diabetes and related renal and cardiovascular complications. Adipose tissue is an endocrine organ which produces a variety of “adipokines.” Clinical management should be aimed to reduce risk factors by encouraging lifestyle modiﬁcations such as diet, aerobic exercise, and healthy eating as well as pharmacologic intervention to improve insulin sensitivity, dyslipidemia, and blood pressure control and protect the kidney from further injury. At the present time, there are few drugs available to produce signiﬁcant long-term weight loss. Weight loss of about 10% can improve insulin sensitivity and lower blood pressure, reduce serum lipid levels, decrease plasma inﬂammatory cytokines, and increase circulating AND [97, 146]. Finally, an emerging area of interest is the potential role of the podocyte- speciﬁc drugs. Further research on adipokines action on renal cells is needed and will lead to novel treatment strategies aimed to ﬁght the increased incidence of obesity- related chronic kidney and cardiovascular diseases. 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