The present study analyses the effect of two plant phenolic compounds, namely chlorogenic acid and ferulic acid, and a plant alkaloid, berberine, alone and also in combination with two commercial oral hypoglycemic drugs (OHD), namely metformin and 2,4-thiazolodinedione (THZ), on the uptake of 2-deoxyglucose (2DG) by L6 myotubes. 2-DG uptake is determined using an enzymatic assay. All the three natural products enhance the uptake of 2DG in time- and dose-dependent manner. A combination of different concentrations of chlorogenic acid and metformin or THZ, has a synergistic effect in the uptake of 2DG with a maximum of 5.0- and 5.3-times respectively, with reference to the base value (without the drugs or the natural products). Ferulic acid in combination with metformin or THZ has also shown a synergistic effect and the 2DG uptake increases by 4.98- and 5.11-fold when compared to the control respectively. Whereas, berberine, in combination with either metformin or THZ, has shown an additive effect with maximum 2DG uptake of 4.1- and 4.7-times from the base value, respectively. The synergistic interaction has been explained with the use of combination index and isobologram. Expression of GLUT4 and PPAR-γ gene were elevated in chlorogenic acid and berberine treated cells, whereas expression of GLUT4 and PI3K transcripts were significantly enhanced in ferulic acid treated cells. The studies indicate that chlorogenic acid enhances glucose uptake by increasing GLUT4 expression via PI3K independent pathway whereas ferulic acid increases glucose uptake by PI3K dependent pathway. The current findings suggest that the phytochemicals can replace the commercial drugs in part, which could lead to a reduction in toxicity and side effects of the later. © 2009 Elsevier GmbH. All rights reserved.