Decreased insulin-mediated muscle glucose uptake is a characteristic feature of non-insulin-dependent diabetes mellitus and other insulin-resistant states. It has been suggested that an impairment in the ability of insulin to augment limb blood flow, resulting in diminished glucose delivery to muscle, may contribute to this abnormality. In this study, we used human insulin-like growth factor (IGF) I in conjunction with the forearm balance technique to determine whether forearm glucose uptake could be stimulated by increasing blood flow without directly stimulating the intrinsic ability of the muscle to extract glucose. IGF-I was infused intra-arterially in healthy controls at a rate of either 0.4 mu g.kg(-1).min(-1) (high IGF) or 0.04 mu g.kg(-1).min(-1) (low IGF) for 140 min. With high IGF, forearm blood flow increased approximately twofold (34 +/- 3 vs. 64 +/- 8 ml.min(-1).l forearm volume(-1), P < 0.01), and arteriovenous glucose concentration difference (a-v difference) increased modestly (0.19 +/- 0.05 vs. 0.31 +/- 0.08 mM, P = 0.32), resulting in an increased forearm glucose uptake (6.4 +/- 1.7 vs. 21.7 +/- 7.4 mu mol.min(-1).l forearm volume(-1), P = 0.09 vs. basal). With low IGF, forearm blood flow increased by 59% (29 +/- 4 vs. 46 +/- 9 ml.min(-1).l forearm volume(-1), P < 0.05) and was associated with a proportional decrease in the a-v difference (0.29 +/- 0.04 vs. 0.18 +/- 0.05 mM, P < 0.05). Forearm glucose uptake therefore was not significantly different from basal values (7.6 +/- 0.6 vs. 6.9 +/- 1.8 mu mol.min(-1).kg(-1)). These data demonstrate that increasing blood flow without increasing the intrinsic ability of the muscle to extract glucose does not increase forearm muscle glucose uptake.