Phenylarsine oxide inhibits insulin activation of phosphatidylinositol 3'-kinase.

Two early events downstream of insulin receptor autophosphorylation that are necessary for activation of glucose transport in adipocytes appear to be: (1) The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) which (2) recruits and activates phosphatidylinositol 3'-kinase (PI3'-K). Phenylarsine oxide (PAO) has long been known to inhibit glucose transport, without inhibiting insulin receptor auto- or substrate phosphorylation. However, the PAO-sensitive site downstream of these early regulatory eventshas not been identified. Here we provide evidence that exposure of 3T3-L1 adipocytes to PAO inhibits PI3'-K activation, but it does not decrease either IRS-1 tyrosine-phosphorylation or the recruitment of PI3'-K to IRS-1 after insulin stimulation. PAO is also shown to inhibit PI3'-K activity in vitro. Therefore, since PI3'-K activation is essential for insulin stimulation of glucose transport, our results demonstrate that PI3'-K is a PAO-sensitive target of the insulin signaling pathway regulating glucose transport.