The mechanisms by which healthy sedentary subjects with low insulin response (LIR; 5-min insulin response to glucose load within lowest quartile of healthy population) maintain a normal glucose tolerance are not clear. We studied glucose uptake and hepatic glucose production in LIR, in healthy subjects with high insulin response (HIR; two highest quartiles of insulin response) matched for weight and physical fitness, and in endurance-trained subjects (ET). For this purpose, we performed hyperinsulinemic euglycemic clamps using the "hot-GINF" method with high-pressure liquid chromatography purified [6-3H]glucose. All groups had a similar basal glucose appearance rate (Ra). During clamps, plasma insulin levels were doubled to 169 +/- 9 pmol/l, whereas Ra decreased similarly in all groups. Glucose utilization rate increased more in LIR and ET than in HIR (to 20.9 +/- 1.5 mumol.kg-1.min-1 in LIR, P < 0.001 vs. HIR; 27.4 +/- 3.6 in ET, P < 0.01 vs. HIR and LIR; and 14.3 +/- 0.6 in HIR). In conclusion, the present study demonstrates increased insulin sensitivity in LIR and ET with respect to glucose uptake but not glucose production.