Intracellular insulin pathway. Insulin (INS), upon binding to its receptor, activates the insulin receptor tyrosine kinase, inducing tyrosine phosphorylation of the insulin receptor substrate-1 (IRS1). Phosphorylated IRS1 binds and activates phosphoinositol 3-kinase (PI3K), leading to the activation of serine-kinase phosphoinositide-dependent kinase 1 (PDK1), which activates AKT1. AKT1 phosphorylates eNOS at Ser-1177, leading to increased activity of eNOS and production of NO, which induces vasodilatation and EC survival. This pathway is strongly compromised in insulin resistance and diabetes mellitus.