Cardiovascular (CV) disease is the leading cause of morbidity and mortality and a major driver of health care costs in patients with type 2 diabetes. Observational studies suggest that insulin resistance and hyperglycemia independently predict atherosclerosis (1,2). However, recent clinical trials have been disappointing in that intensive glycemic control does not reduce the risk of CV events in individuals with diabetes (3). Consequently, it has been suggested that therapies targeting hyperinsulinemia and/or insulin resistance (e.g., metformin) may lead to CV risk reduction (2). In addition to its metabolic actions, insulin has important vascular actions that stimulate endothelial production of nitric oxide (NO), an anti-inflammatory and antiatheroslcerotic molecule (4). In turn, endothelial insulin resistance leads to diminished glucose disposal, endothelial dysfunction, and atherosclerosis. Strategies that ameliorate endothelial insulin resistance may simultaneously augment metabolic and vascular actions of insulin, thereby reducing CV risk. However, molecular mechanisms regulating endothelial insulin action are still unclear.
Elegant studies from various laboratories have elucidated insulin signaling pathways that regulate NO production in the endothelium (4). Insulin binding to its receptor increases receptor tyrosine kinase activity and results in phosphorylation of insulin receptor (IR) substrate (IRS)-1 and sequential activation of phosphatidylinositol 3-kinase (PI3K) and 3-phosphoinositide-dependent protein kinase (PDK)-1. PDK-1, in turn, activates Akt, which then directly phosphorylates endothelial NO synthase (eNOS) at Ser1177, resulting in increased eNOS activity and NO production (Fig. 1). Although less potent, IGF-1, like insulin, activates the PI3K-Akt-eNOS pathway and stimulates NO production in endothelial cells (5,6).