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

Steven E Kahn; Ronald L Prigeon; David K McCulloch; Edward J Boyko; Richard N Bergman; Michael W Schwartz; James L Neifing; W Kenneth Ward; James C Beard; Jerry P Palmer

doi:10.2337/diab.43.4.587

Original Contributions

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

Steven E Kahn,
Ronald L Prigeon,
David K McCulloch,
Edward J Boyko ,
Richard N Bergman,
Michael W Schwartz,
James L Neifing,
W Kenneth Ward,
James C Beard and
Jerry P Palmer Jr

Divisions of Metabolism, Endocrinology, and Nutrition, University of Washington and Veterans Affairs Medical Center Seattle Washington
General Internal Medicine, University of Washington and Veterans Affairs Medical Center Seattle Washington
Department of Medicine, and Department of Epidemiology, University of Washington and Veterans Affairs Medical Center Seattle Washington
Department of Physiology and Biophysics, University of Southern California Los Angeles, California

Address correspondence and reprint requests to Dr. Steven E. Kahn, VA Medical Center (151L), 1660 South Columbian Way, Seattle WA 98108.

Diabetes 1994 Apr; 43(4): 587-592. https://doi.org/10.2337/diab.43.4.587

Abstract

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.