FIGURE 1.

Proximal insulin signaling. Upon insulin binding, the insulin receptor (INSR) autophosphorylates and recruits diverse substrates. The two major arms of insulin signaling are mitogenic (initiated by GRB2 and SHC) and metabolic [initiated by insulin receptor substrate (IRS) proteins and SH2B2/APS]. Insulin signaling is also characterized by feedback mechanisms, both positive [GIV potentiation of phosphoinositide-3-kinase (PI3K)-AKT signaling, and phosphatase inhibition by NAD(P)H oxidase 4 (NOX4)-derived H₂O₂] and negative (stabilization and recruitment of GRB10 to the INSR, and activation of S6 kinase 1 (S6K1) to phosphorylate and inhibit IRS proteins). Green circles and arrows represent activating events; red circles and arrows represent inhibitory events.