Reassessment of Glucose Effectiveness and Insulin Sensitivity From Minimal Model Analysis: A Theoretical Evaluation of the Single-Compartment Glucose Distribution Assumption

Abstract

Minimal model analysis with the frequently sampled intravenous glucose tolerance test provides an effective way to measure two important metabolic parameters in vivo under non-steady-state conditions: glucose effectiveness (SG) and insulin sensitivity (SI). Two questions regarding the validity of SG and SI have recently emerged. First, SG from the minimal model is suspected to be overestimated. Second, the occurrence of SI values indistinguishable from zero ("zero-SI") is not negligible in large clinical studies, and its physiological meaning is uncertain. In this study, we examined the significance of the assumed single-compartment glucose distribution embedded in the minimal model on the estimation of SG and SI. A more accurate two-compartment model was constructed by incorporating insulin action on hepatic glucose output and uptake into a previously validated construction. The two-compartment results were compared with the one-compartment minimal model results. It was shown that the one-compartment assumption contributes to a systematic deviation of SG (slope = 0.54, y-intercept = 0.014 min[-1]; n = 195 simulations). However, SG from the minimal model was linearly correlated to SG determined from the two-compartment model (r = 0.996). The one-compartment assumption also contributed to the occurrence of zero SI values for insulin-resistant subjects. A similar linear relationship was found between SI estimated by both the minimal model and the two-compartment model (slope = 0.58, y-intercept = -0.57 x 10[-4] min[-1] per pU/ml, r = 0.998). In conclusion, SG and SI from the minimal model are not necessarily equivalent to values emanating from the more accurate two-compartment model. However, the very high correlation between one- and two-compartment results suggests that the minimal model-derived SG and SI are dependable indexes of in vivo glucose effectiveness and insulin sensitivity. Minimal model analysis' advantages of simplicity, minimal invasiveness, reasonable reflection of non-steady-state glucose kinetics, and cost-effectiveness could in many cases outweigh the structural bias introduced by the model simplification.

Integrated model of hepatic and peripheral glucose regulation for estimation of endogenous glucose production during the hot IVGTT

“…Because we include endogenous glucose, which acts both to stimulate glucose disposal and inhibit glucose production, in the estimation of S G 2* , it is in fact imperative that we include a separate description of glucose's effect on EGP, since S G 2* only describes the ability of glucose to stimulate glucose disposal. Some concerns still remain regarding the estimation of glucose effectiveness, especially when comparing subjects with varying glucose tolerances (23) or under the assumptions of a two-compartment model (30,31), so future studies regarding this parameter and the best tactic to determine it should still be carried out. The glucose concentration causing half-maximal inhibition of EGP was not estimable, so we chose to set this value to be equal to the basal glucose concentration.…”

Insulin Sensitivity, Insulinemia, and Coronary Artery Disease

“…1, which were calculated using traditional S i values. This could be expected because S i estimates from the two-compartment model correlate perfectly with the one-compartment model S i estimates (38). Therefore, whereas the minimal model systematically underestimated insulin sensitivity, compared with the euglycemic clamp or a two-compartment model, it provided a dependable, cost-efficient, and minimally invasive way to measure insulin sensitivity in a large free-living population.…”

“…"Zero insulin sensitivity" is a difficult concept to accept; however, we have demonstrated that IRAS participants with S i ϭ 0 had more features of the metabolic syndrome than other insulin-resistant IRAS participants with S i Ͼ0 (37). The phenomenon has been recently explained (38) as an artifact of a single compartment glucose distribution assumption underlying the minimal model estimation of S i , which does not include insulin action on hepatic glucose metabolism. A more exact twocompartment modeling is not suitable for field studies due to complexity and use of a radiolabeled tracer.…”

Low Insulin Sensitivity (Si = 0) in Diabetic and Nondiabetic Subjects in the Insulin Resistance Atherosclerosis Study

“…The first is that these subjects are, indeed, very insulin resistant with insulin sensitivity not distinguishable from zero. A second possibility is that the use of a one-compartment model (25) may underestimate the S i , although this interpretation was not supported in other studies (26). Another possibility is that the FSIGTT may yield lower estimates of glucose disposal than the clamp because of the use of a short-acting bolus with its consequent high peak of insulin (27) rather than hyperinsulinemia of long duration, as with the clamp (28).…”