Effect of salicylates on insulin signaling during insulin resistance. (a) Normally, the occupied insulin receptor phosphorylates scaffold proteins, such as the IRS-1, on critical tyrosine residues. However, in insulin-resistant states, a number of agents, such as the cytokine TNF-α or circulating FFAs, lead through intermediary signaling pathways to the activation of IKK, which in turn indirectly increases the number of phosphorylated serine and threonine residues (indicated by blue circles) on IRS-1. This modification blocks the tyrosine phosphorylation and converts IRS-1 into an insulin receptor inhibitory protein. (b) In the presence of salicylates, IKK activity is inhibited, reducing the IRS-1 serine/threonine phosphorylation and allowing IRS-1 to be phosphorylated on tyrosine. These phosphorylated tyrosine residues (black squares) serve as binding sites for a number of signaling molecules, most importantly PI 3′-kinase, which initiate signaling pathways regulating metabolism. Aspirin (ASA) also inhibits cyclooxygensases (COX) to prevent the generation of inflammatory prostaglandins (PGE) from arachidonic acid (AA) in a pathway unrelated to the effects of the drug on insulin action.