Technical Abstract: Glyceollins (glyceollin I, II, and III), isoflavone phytoalexins synthesized by soy in response to environmental stresses such as microbial infections. Glyceollins exhibited anti-cancer and anti-diabetes effects: previously we showed that glyceollins inhibited cancer cell growth in vitro and in vivo. In the present study we used pre-diabetic ZDSD rats to examine how the glyceollins’ regulate blood glucose. The blood glucose excursion during 2h following an oral glucose tolerance test (OGTT) significantly decreased in the rats treated with 30 mg/kg (n=8) or 90 mg/kg (n=8) glyceollins 1h prior to the glucose challenge compared to the vehicle treated animals (n=8). Exposure of the adipocytes to the glyceollins significantly (p<0.05) increased both insulin-stimulated and basal glucose uptake. Basal glucose uptake was increased 1.5-fold by exposure to 5µM glyceollin in a dose-response manner with an EC50 of 2.40 ± 0.43 µM and a maximal uptake of 2.04 ± 0.24–fold above basal glucose uptake (n=4). Co-incubation with insulin significantly (p<0.05) stimulated maximal glucose uptake but glyceollins did not alter the potency of insulin. Quantitative real-time PCR showed increased levels of both Glut1 and Glut4 glucose transporter genes in adipocytes treated with 5 µM to 10 µM glyceollins for 3h. Thus the stimulative effect of the glyceollins on adipocyte glucose uptake was attributed to up-regulation of the glucose transporters GLUT1 and GLUT4. These findings indicate potential benefits of the glyceollins for treating pre-diabetic conditions, type 1 and type 2 diabetes by increasing the insulin-mediated and basal, insulin-independent, glucose uptake by adipocytes.