Insulin Keeps PYK-ing on eNOS: Enhanced Insulin Receptor Signaling Induces Endothelial Dysfunction

In healthy individuals, insulin is acutely released in response to food intake, a phenomenon linked with a decrease in systemic vascular resistance and that has been attributed to the generation and release of NO. The metabolic syndrome and the development of type 2 diabetes mellitus are associated with resistance to the effects of insulin and an impaired ability of metabolically active tissues such as skeletal muscle, adipose tissue, and the liver to take up glucose. Because the biological response to insulin is dampened, the β cells of the pancreas continue secreting insulin in an attempt to normalize the blood glucose levels, which results in increased circulating levels of the hormone and can ultimately result in β-cell apoptosis.1 In conditions associated with insulin resistance, vascular endothelial cells are exposed to high concentrations of insulin, which can affect vascular function. Indeed, hyperinsulinemia has been significantly associated with higher cardiovascular mortality in both men and women independently of other risk factors.2Article, see p 784 its target cells, insulin binds to the insulin receptor (IR), a tyrosine kinase receptor that recruits and phosphorylates numerous substrate adaptors such as the insulin receptor substrate (IRS) family of proteins. The tyrosine-phosphorylated IRS proteins, in turn, contain binding sites for numerous signaling molecules, resulting in the activation of multiple kinases, including the kinases phosphatidylinositol 3-kinase (PI 3-K) and its downstream target Akt (protein kinase B).1 On the contrary, the recruitment of the adaptor protein growth factor receptor–binding protein 2 to the IRS activates the mitogen-activated protein kinase pathway to promote cell proliferation.1 Given the number of pathways activated on IR stimulation, insulin resistance can be caused by alterations at many levels, including decreased receptor expression and kinase activity, decreased expression and phosphorylation of IRS, altered recruitment of downstream adaptor proteins, or increased …