Evidence Stacks Up That Endothelial Insulin Resistance Is a Culprit in Atherosclerosis

Type 2 diabetes mellitus and the metabolic syndrome greatly increase the risk of cardiovascular disease, manifested as myocardial infarction and stroke. Although it is well known that this risk is largely the result of increased atherosclerosis, the cellular and molecular events within the artery wall responsible for the worsening of atherosclerosis associated with type 2 diabetes mellitus and the metabolic syndrome are less clear. These states are frequently associated with several cardiovascular risk factors, including dyslipidemia, hypertension, obesity, hyperglycemia, and systemic insulin resistance, each of which may contribute to atherosclerosis.Article, see p 418Insulin resistance in now known to affect the vascular wall itself, in addition to the better-studied insulin target tissues liver, skeletal muscle, and adipose tissue. Vascular endothelial cells, which play critical roles in atherosclerosis by allowing monocytes and other immune cells to enter the atherosclerotic lesion and by producing proatherogenic and antiatherogenic molecules, develop insulin resistance in both humans and mice concomitant with dyslipidemia and systemic insulin resistance.1 Endothelial cells can also contribute to systemic insulin resistance.2Insulin has important biological effects in endothelial cells that affect atherosclerosis. Activation of the insulin receptor results in tyrosine phosphorylation of insulin receptor substrate 1 and 2 and subsequent activation of phosphoinositide 3-kinase (PI3K) and the serine/threonine protein kinase Akt. Akt has several targets in endothelial cells, one of which is endothelial nitric oxide (NO) synthase (eNOS). Insulin-induced activation of the PI3K-Akt-eNOS pathway causes increased production of NO, vasorelaxation,3 and suppressed expression of vascular cell adhesion molecule-1, an important adhesion molecule used by monocytes to invade the vessel wall. These actions of insulin are likely to be antiatherosclerotic (Figure) because both vascular cell adhesion molecule-1–deficient mice and eNOS-deficient mice exhibit reduced atherosclerosis4,5 (although …