Although recent studies in vitro and in vivo indicate that the polyphenol resveratrol (RSV) has anti-diabetic properties, the exact mechanisms involved are not known. In the present study, we examined the effects of RSV and the mechanism of regulation of glucose uptake in skeletal muscle cells. In L6 myotubes RSV (100 mu M) induced maximum stimulation of glucose (2DG) uptake (201 +/- 8.90% of control, p < 0.001), an effect that was similar to insulin action. RSV-stimulated glucose uptake was abolished by AMPK inhibition. In the presence of the sirtuin inhibitor nicotinamide, RSV-stimulated 2DG uptake and AMPK phosphorylation were abolished. RSV did not stimulate significant translocation of GLUT4 or GLUT1 transporters. However, treatment with indinavir, a GLUT4 specific inhibitor, blocked RSV-stimulated glucose uptake. We propose that RSV elevates glucose uptake in muscle cells through a mechanism that involves sirtuins and AMPK and possibly stimulation of GLUT4 transporter intrinsic activity. (C) 2008 Elsevier Inc. All rights reserved.