Soy glyceollins, induced during stress, have been shown to inhibit cancer cell growth in vitro and in vivo. In the present study, we used prediabetic rats to examine the glyceollins effect on blood glucose. During an oral glucose tolerance test (OGTT), the blood glucose excursion was significantly decreased in the rats treated with oral administration of either 30 or 90 mg/kg glyceollins. Plasma analysis demonstrated that glyceollins are absorbed after oral administration, and duration of exposure extends from 20 min to at least 4 h postadministration. Exposure of 3T3-L1 adipocytes to glyceollins significantly increased both insulin-stimulated and basal glucose uptake. Basal glucose uptake was increased 1.5-fold by exposure to 5 μM glyceollin in a dose-response manner. Coincubation with insulin significantly stimulated maximal glucose uptake above basal uptake levels and tended to increase glucose uptake beyond the levels of either stimulus alone. On a molecular level, polymerase chain reaction showed significantly increased levels of glucose transporter GLUT4 mRNA in 3T3-L1 adipocytes, especially when the cells were exposed to 5 μM glyceollins for 3 h in vitro. It correlated with elevated protein levels of GLUT4 detected in the 5 μM glyceollin-treated cells. Thus, the simulative effect of the glyceollins on adipocyte glucose uptake was attributed to up-regulation of glucose transporters. These findings indicate potential benefits of the glyceollins as an intervention in prediabetic conditions as well as a treatment for type 1 and type 2 diabetes by increasing both the insulin-mediated and the basal, insulin-independent, glucose uptake by adipocytes.