The effects of the acute insulin response to glucose (AIRg), insulin sensitivity (SI), and glucose effectiveness at zero insulin (GEZI) on intravenous glucose tolerance were studied in 94 non elderly healthy subjects with a wide range of body mass index (BMI). Conrad's coefficient of glucose assimilation (KG) was calculated between 10 and 19 minutes of an intravenous glucose tolerance test. Both SI and GEZI were estimated using Bergman's minimal model. AIRg was calculated as the area under the insulin curve above basal between 0 and 10 minutes, and the suprabasal insulin effect was determined by the product of SI x AIRg. Stepwise multiple regression showed that the combined effect of SI x AIRg and GEZI explained 67% of the KG index variance. Division of the sample into tertiles according to KG shows that subjects with the lowest KG (KG < 1.32 min[-1]) had the lowest AIRg (2,832 +/- 1,362 v 6,510 +/- 4,410 [pmol x L(-1)] min, P = .0005), the lowest GEZI (0.092 +/- 0.06 v 0.179 +/- 0.09 min(-1), P = .0004), and the lowest SI x AIRg (0.014 +/- 0.008 v 0.022 +/- 0.01 min(-1), P = .00001), and were the oldest (41 +/- 10 v 31 +/- 10 years, P = .002) compared with subjects with the highest KG (KG > 1.8 min[-1]). However, no differences in SI (4.86 +/- 4.6 v 6.5 +/- 3.7 min(-1) [pmol x L(-1)],(-1) NS) or BMI (29.6 +/- 5.0 v 26.6 +/- 5.9 kg x m(-2), NS) were observed. These results did not vary when lean and obese subjects were analyzed separately. Age correlated significantly only with SI x AIRg. In conclusion, although the main factors that determine intravenous glucose tolerance are the suprabasal insulin effect and GEZI, worsening of the KG index depends on inadequate insulin secretion for the degree of insulin sensitivity and lower non-insulin-mediated glucose uptake. Age seems to be another factor in the worsening of intravenous glucose tolerance through a lower suprabasal insulin effect.