Insulin is unique among growth factors and hormones in its ability to control metabolic functions such as the stimulation of glucose uptake and glucose transporter (GLUT4) translocation in physiological target tissues, such as muscle and adipose cells. Nonetheless, the mechanisms underlying this specificity have remained incompletely understood, particularly in view of the ability of some growth factors to mimic insulin-dependent early signaling events. In this study, we have probed the basis of insulin specificity by overexpressing in hormone-responsive 3T3-L1 adipocytes wild-type platelet-derived growth factor receptor (PDGFR-) and selected, informative mutant receptor proteins. We show that such adipocytes overexpressing wild-type PDGFR upon exposure to cognate growth factor activate glucose transport, GLUT4 translocation, and the serine-threonine protein kinase Akt/Protein kinase B to a degree comparable to that produced in response to insulin. In addition, PDGF elicits the robust generation of PIP₃ in vivo in PDGFR-overexpressing 3T3-L1 adipocytes. Expression of PDGFR- mutant proteins demonstrates that these responses require the presence of an intact PI3-Kinase binding site on the overexpressed PDGF receptor. Furthermore, PDGF stimulates these effects independent of insulin receptor substrate-1 (IRS-1) or insulin receptor substrate-2 (IRS-2) tyrosine phosphorylation or docking to activated PI3-Kinase. These data demonstrate that 1) the basis of insulin-specific glucose transport in cultured adipocytes is the low level of receptors for other growth factors and 2) in the presence of adequate receptors, PDGF is fully capable of activating glucose transport in a manner requiring PI3-Kinase and subsequent PIP₃ accumulation but independent of insulin, insulin receptor, and IRS proteins.