The Contribution of Insulin-Dependent and Insulin-Independent Glucose Uptake to Intravenous Glucose Tolerance in Healthy Human Subjects

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 (K_g), 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 (S_I) and glucose effectiveness at basal insulin (S_G) using the minimal model of glucose kinetics. To eliminate the effect of basal insulin on S_G and estimate insulin-independent glucose uptake, we calculated glucose effectiveness at zero insulin (GEZI = S_G [S_I × basal insulin]). Insulin-dependent glucose uptake was estimated as S_I × IIR0-19, because the relationship between S_I 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 K_g (r = 0.70; P < 0.0001), suggesting a major contribution of insulin-independent glucose uptake to glucose disappearance. As expected, S_I × IIR0-19 also correlated well with K_g (r = 0.74; P < 0.0001), confirming the importance of insulin-dependent glucose uptake to glucose tolerance. Although IIR0-19 alone correlated with K_g (r = 0.35; P = 0.0005), S_I did not (r = 0.18; P > 0.08). By multiple regression, 72% of the variance in K_g 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.