To establish the relative importance of insulin sensitivity and glucose effectiveness during exercise using Bergman's minimal model, 12 nontrained healthy subjects were studied at rest and during 95 minutes of moderate exercise (50% maximum oxygen consumption [VO2max]). Each subject underwent two frequently sampled intravenous glucose tolerance tests (FSIGTs) for 90 minutes, at rest (FSIGTr) and during exercise (FSIGTe). Plasma glucose, insulin, and C-peptide were determined. Insulin sensitivity (S(I)), glucose effectiveness at basal insulin (S(G)), insulin action [X(t)], and first-phase (phi1) and second-phase (phi2) beta-cell responsiveness to glucose were estimated using both minimal models of glucose disposal (MMg) and insulin kinetics (MMi). Glucose effectiveness at zero insulin (GEZI), glucose tolerance index (K(G)), and the area under the insulin curve (AUC(0-90)) were also calculated. Intravenous glucose tolerance improved significantly during physical exercise. During exercise, S(I) (FSIGTr v FSIGTe: 8.5 +/- 1.0 v 25.5 +/- 7.2 x 10(-5) x min(-1) [pmol x L(-1)]-1, P < .01), S(G) (0.195 +/- 0.03 v 0.283 +/- 0.03 x 10(-1) x min(-1), P < .05), and GEZI (0.190 +/- 0.03 v 0.269 +/- 0.04 x 10(-1) x min(-1), P < .05) increased; however, no changes in phi1 and phi2 were found. Despite a significant decrease in the insulin response to glucose (AUC0-90, 21,000 +/- 2,008 v 14,340 +/- 2,596 pmol x L(-1) x min, P < .01), insulin action [X(t)] was significantly higher during the FSIGTe. These results show that physical exercise improves mainly insulin sensitivity, and to a lesser degree, glucose effectiveness. During exercise, the insulin response to glucose was lower than at rest, but beta-cell responsiveness to glucose did not change.