Role of IRS2 in insulin signaling. Insulin binds to its receptor in target cells, leading to the activation of an intrinsic tyrosine kinase located in the β subunit. The resulting autophosphorylation (P) of the insulin receptor on tyrosine (Tyr) residues increases the association of various signaling molecules, including IRS2. Insulin receptor directly phosphorylates IRS2 on multiple tyrosine residues, which, in turn, initiates a variety of second messenger cascades. Recent work has demonstrated a critical role for IRS2 in the maintenance of peripheral insulin sensitivity, central leptin sensitivity, and proper β cell development in the islets of Langerhans (11, 12). Thus, IRS2 plays a central role in preserving insulin action in multiple cell types, while reduction of IRS expression and/or function may be a fundamental cause of the development of insulin resistance, obesity, β cell failure, and type 2 diabetes. S_S, disulphide bond.