Mechanisms of Vascular Insulin Resistance

Abstract

See related article, pages 1085–1094 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 mitogen-activated 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 …