Canonical IR signaling cascade. Insulin binds to the insulin receptor (IR), a receptor tyrosine kinase, which autophosphorylates and activates a cascade of phosphorylation events. IRS1 is phosphorylated on a tyrosine residue to activate further signaling, which ultimately leads to the translocation of glucose transporter 4 (GLUT4) to the membrane and uptake of glucose for energy in peripheral tissues. Solid arrows represent activation upon insulin stimulation. Blocked arrows represent inhibition. Glycogen synthase kinase 3 (GSK3) is serine phosphorylated and inhibited in response to insulin stimulation. Dashed arrows represent downstream effectors that have been found to phosphorylate IRS1 on a serine residue (p(Ser)-IRS1), which is thought to lead to less activation of the signaling cascade through negative feedback (dashed blocked arrow). p(Ser)-IRS1 is a marker of insulin resistance.