The minimal-model method allows for estimation of insulin sensitivity (S(I) = P(3)/P(2)) and glucose effectiveness (S(G) = P(1)) from the time course of glucose and insulin after a glucose bolus. We previously demonstrated that the minimal-model results in overestimates of S(G) in subjects with normal insulin secretory function. To determine whether overestimation of S(G) has an impact on estimation of S(I), we examined model estimation of S(I) when S(G) was constrained to levels below that found by the regular minimal-model fit. Fifty-six glucose tolerance tests from lean and obese women, with and without polycystic ovary syndrome, were used. S(I) ranged from 0.2-22.6 x 10(-4) min(-1)/(microU/mL), and S(G) ranged from 0.8-3.8 x 10(-2) min(-1) for the standard minimal-model fits. Constraining S(G) to as low as 40% of the unconstrained value resulted in a 4-fold increase in P2 and P3, but only a 3% reduction in S(I). We conclude that estimation of the insulin sensitivity index is independent of errors in minimal-model-derived estimates of glucose effectiveness.