The Union of Vascular and Metabolic Actions of Insulin in Sickness and in Health

J.-a Kim
2005 Arteriosclerosis, Thrombosis and Vascular Biology  
D isorders 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
more » ... n 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) . See page 989 Coupling of Hemodynamic and Metabolic Physiology Through Insulin Action Regulation of hemodynamic and metabolic homeostasis may be coupled by physiological actions of insulin in the vascular endothelium to stimulate production of NO. 4 The metabolic action of insulin to promote glucose uptake in skeletal muscle and adipose tissue is initiated by activation of the insulin receptor tyrosine kinase, subsequent phosphorylation of IRS-1, binding and activation of PI 3-kinase, activation of the serine kinase PDK-1, that in turn phosphorylates and activates Akt and PKC-, leading to recruitment of GLUT4 glucose transporters to the cell surface. 8 A similar pathway exists in vascular endothelium involving the insulin receptor, IRS-1, PI 3-kinase, PDK-1, and Akt that leads to phosphorylation and activation of eNOS by Akt with a resultant increase in production of NO. 9 -12 Insulin-stimulated production of NO leads to capillary recruitment, vasodilation, and increased blood flow to skeletal muscle that improves delivery of glucose and insulin to skeletal muscle. 4 Indeed, insulin-stimulated increases in capillary recruitment and total limb blood flow per se may account for up to 40% of insulin-mediated glucose disposal. 13-15 Thus, insulin signaling pathways that are shared in common in distinct tissues with vascular or metabolic functions may help to tightly couple regulation of vascular function with glucose metabolism. Insulin Resistance, Endothelial Dysfunction, and Inflammation Metabolic insulin resistance has both genetic and acquired causes. The causes for acquired insulin resistance related to diabetes and obesity include glucotoxicity and lipotoxicity resulting from hyperglycemica and elevated FFA levels. 16 Elevated levels of glucose and lipids increase oxidative stress, advanced glycation end products, flux through the hexosamine biosynthetic pathway, activation of PKC, and activation of proinflammatory pathways in skeletal muscle and adipose tissue leading to insulin resistance. Of note, these same mechanisms also participate in endothelial dysfunction. 17,18 With respect to inflammation, elevations in FFA associated with obesity and diabetes are linked to activation of IKK␤. 5 This leads to cross-talk between inflammatory signaling and insulin signaling that impairs IRS-1/PI 3-kinase function and causes metabolic insulin resistance. 19, 20 It is known that elevations in FFA also lead to endothelial dysfunction. 1 The study by Kim et al suggests that IKK␤ is mediating insulin resistance in endothelium in response to FFA resulting in endothelial dysfunction using a mechanism similar to that in metabolic targets of insulin. Thus IKK␤ may play an important role in both metabolic insulin resistance and vascular endothelial dysfunction.
doi:10.1161/01.atv.0000164044.42910.6b pmid:15863720 fatcat:cvpt7n3tijfvln42iwsjobp7ge