Insulin receptor structure and signaling. (A) Insulin receptor monomer, composed of an α (yellow) and β subunit (pink) bridged by an intrinsic disulfide bond, which dimerizes with another insulin receptor monomer through extrinsic disulfide bonds to form a functional receptor. (Adapted and modified from .) (B) Ligand selectivity of the insulin receptor homodimer or heterodimer with the insulin-like growth factor (IGF)-1 receptor. Note that the homodimer of the splice variant IRa, the predominant form of inslulin receptor in the brain, binds specifically to insulin (INS), whereas the heterodimer with the IGF-1 receptor binds to not only INS but also IGF-1 and IGF-2. (Adapted and modified from .) (C) Insulin receptor signaling initiated by ligand binding activates tyrosine autophosphorylation in the β subunit, which stimulates two major downstream pathways, the phosphoinositide-3 kinase (PI3K)/Akt and Ras/mitogen-activated protein kinase (MAPK) cascades, through insulin receptor substrates (IRSs) and results in a diverse series of cellular processes in peripheral tissues. (Modified from .) GSK3, glycogen synthase kinase 3.