Glucose disposal occurs by both insulin-independent and insulin-dependent mechanisms, the latter being determined by the interaction of insulin sensitivity and insulin secretion. To determine the role of insulin-independent and insulin-dependent factors in glucose tolerance, we performed intravenous glucose tolerance tests on 93 young healthy subjects (55 male, 38 female; 18–44 years of age; body mass index, 19.5–52.2 kg/m2). From these tests, we determined glucose tolerance as the glucose disappearance constant (Kg), calculated β-cell function as the incremental insulin response to glucose for 19 min after an intravenous glucose bolus (IIR0-19), and derived an insulin sensitivity index (SI) and glucose effectiveness at basal insulin (SG) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on SG and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = SG [SI × basal insulin]). Insulin-dependent glucose uptake was estimated as SI × IIR0-19, because the relationship between SI and β-cell function has been shown to be hyperbolic. Using linear regression to determine the influence of these factors on glucose tolerance, we found that GEZI was significantly related to Kg (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, SI × IIR0-19 also correlated well with Kg (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with Kg (r = 0.35; P = 0.0005), SI did not (r = 0.18; P > 0.08). By multiple regression, 72% of the variance in Kg could be explained by GEZI and S1 × IIR0-19 (r = 0.85; P < 0.0001). We conclude that insulin-independent glucose uptake is a major determinant of intravenous glucose tolerance and that the interaction of insulin sensitivity and insulin levels are more important than either factor alone as a determinant of intravenous glucose tolerance.

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