The union of vascular and metabolic actions of insulin in sickness and in health.

Disorders of metabolic homeostasis including type 2 diabetes, obesity, and dyslipidemias are characterized by both insulin resistance and endothelial dysfunction.1 Insulin resistance and endothelial dysfunction are also prominent features of important cardiovascular disorders including hypertension, coronary artery disease, and atherosclerosis.2 Indeed, insulin resistance is thought to be the tie that binds metabolic and cardiovascular disorders together in an unhappy union called the metabolic syndrome (aka the insulin resistance syndrome).3,4 Although these associations are well established, molecular mechanisms explaining the underlying pathophysiology are not completely understood. Interestingly, inflammation mediated by innate immune signaling pathways has been implicated in both metabolic insulin resistance and vascular endothelial dysfunction.1,5,6 In this issue of Arteriosclerosis, Thrombosis, and Vascular Biology, Kim et al demonstrate that treatment of vascular endothelial cells with the free fatty acid (FFA) palmitate activates IKK (a proinflammatory signaling molecule), impairs insulin signaling, and decreases insulin-stimulated production of nitric oxide (NO).7 Importantly, inhibitory effects of FFA treatment on insulin signaling and NO production are blocked by overexpression of a dominant inhibitory mutant of IKK . Moreover, deleterious effects of FFA treatment are recapitulated by overexpression of wildtype IKK . Thus, Kim et al have uncovered an additional link between metabolic and vascular pathophysiology that helps to explain mechanisms underlying the metabolic syndrome and related cardiovascular diseases. To understand the importance of these findings it is useful to review the mechanisms coupling vascular and metabolic physiology, the role of inflammation in insulin resistance, and the role of insulin resistance to couple vascular and metabolic pathophysiology (Figure).