Mechanisms of Vascular Insulin Resistance

Insulin resistance is characterized by the diminished ability of insulin to initiate intracellular signaling. It is a common manifestation of obesity and a prelude to type 2 diabetes. The primary targets of insulin are skeletal muscle, adipose, and the liver. Impaired insulin signaling in these tissues reduces glucose uptake and promotes a metabolic syndrome that is characterized by elevated levels of insulin, inappropriate synthesis of glucose, and dyslipidemia.1 However, insulin receptors and insulin signaling are not exclusively restricted to metabolically active tissue and can be observed in most cell types including vascular cells. Individuals with insulin resistance have compromised endothelial cell function and increased frequency and severity of cardiovascular disease.2 Although it is clear that the metabolic consequences of insulin resistance are sufficient in themselves to induce cardiovascular dysfunction, the local actions of insulin on blood vessels are also thought to be of significance. Insulin directly stimulates nitric oxide (NO) release from the vascular endothelium in a phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the Akt-mediated phosphorylation of endothelial NO synthase (eNOS).3 Alternatively, insulin can stimulate the mitogenactivated protein kinase (MAPK) pathway to promote cellular proliferation.3 Selective or “pathway-specific” insulin resistance has also been described in blood vessels.4 This refers to the selective reduction in the ability of insulin to stimulate PI3K signaling while permitting or even enhancing MAPK activation (see the Figure). These effects are further magnified in insulin-resistant states where there is increased pancreatic secretion of insulin and by angiotensin II, which promotes MAPK signaling at the expense of the PI3K pathway. The reduction in PI3K signaling is proposed to attenuate eNOS activity and thus diminish the buffering and antiinflammatory actions of NO, and these events in conjunction with increased MAPK activity set the stage for increased vascular disease.5 Despite these observations, the local actions of insulin are not without controversy because insulin receptors are ubiquitous and insulin is a comparatively poor stimulus for both NO release and vasodilation. Direct evidence for a vascular role of insulin comes from genetic studies in which the insulin receptor has been selectively deleted from the endothelium. These mice (VENIRKO) have normal blood pressure and glucose tolerance but diminished eNOS and endothelin-1 mRNA, which predisposes them to atherosclerosis.6,7 However, the vascular phenotype of these mice, in particular alterations in the regulation of eNOS, does not exactly replicate that seen in mice with metabolic insulin resistance.8–10 In addition, the phenotypes of the muscle-specific (MIRKO), liver-specific (LIRKO), or fat-specific (FIRKO) insulin receptor knockout mice indicates that the severity or type of insulin resistance is unlikely to be uniform in different tissues.11–13 Therefore, the extent to which local insulin resistance contributes to the vascular dysfunction and cardiovascular disease observed in states of metabolic insulin resistance remains unclear. In this issue of Circulation Research, a study by Symons et al14 adds a new twist to what we know about roles of vascular insulin resistance and selective insulin resistance in cardiovascular function. To test whether vascular insulin receptors can modify endothelial and vascular function, Symons et al used a relatively novel insulin receptor–deficient mouse. The TTr-IR is a global insulin receptor knockout that normally results in perinatal lethality. However, these mice have been rescued by transgenic reexpression of the insulin receptor in the brain, pancreas, and liver, which results in mild metabolic insulin resistance, as evidenced by normoglycemia and hyperinsulinemia.15 Aside from the brain, pancreas, and liver, TTr-IR mice do not express the insulin receptor in other tissues including the endothelium and vascular smooth muscle. This is an important distinction from the VENIRKO mouse, which has intact insulin receptors in vascular smooth muscle and probably other vascular cells. Symons et al report that whereas the ability of insulin to induce vascular signaling and relaxation is impaired because of the loss of the insulin receptor, endothelial function in response to acetylcholine and mean blood pressure are unchanged in TTr-IR mice. The loss of insulin-dependent responses is not an unexpected finding, but the preservation of eNOS expression, endothelial function, and blood pressure is surprising. Although it can be argued that deletion of the insulin receptor would inhibit both arms of the opposing downstream PI3K and MAPK pathways to produce no net change in vascular function (see the Figure), results in mice with a more severe form of dietaryinduced insulin resistance suggest otherwise. In mice fed a high fat diet, Symons et al14 find that in contrast to the concept of pathway selective insulin resistance described above, both Erk1/2 and Akt phosphorylation are slightly diminished, whereas eNOS phosphorylation at S1177 is abolished. In addition, the high fat–fed mice have comproThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Department of Pharmacology and the Vascular Biology Center of the Medical College of Georgia, Augusta. Correspondence to David Fulton, Associate Professor, Medical College of Georgia, Vascular Biology and Pharmacology, 1459 Laney Walker Blvd, CB-3316, Augusta, GA 30912. E-mail [email protected] (Circ Res. 2009;104:1035-1037.) © 2009 American Heart Association, Inc.