Glucose tolerance is determined by both insulin action and insulin-independent effects, or "glucose effectiveness," which includes glucose-mediated stimulation of glucose uptake (R d ) and suppression of hepatic glucose output (HGO). Despite its importance to tolerance, controversy surrounds accurate assessment of glucose effectiveness. Furthermore, the relative contributions of glucose's actions on R d and HGO under steady state and dynamic conditions are unclear. We performed hyperglycemic clamps and intravenous glucose tolerance tests in eight normal dogs, and assessed glucose effectiveness by two independent methods. During clamps, glucose was raised to three successive 90-min hyperglycemic plateaus by variable labeled glucose infusion rate; glucose effectiveness (GE) was quantified as the slope of the dose-response relationship between steady state glucose and glucose infusion rate (GE CLAMP (
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.
The results reported in this paper show that the current model of the red cell exhibits a self-consistent and stable steady state. However, the model is not very robust; the high parameter sensitivities associated with the synthesis of NADP and glutathione suggest that this portion of the model is illconditioned. Signals propagated from independent to dependent variables are attenuated in some cases and amplified in others. These influences exhibit large values, both negative as well as positive. The average influence on any given flux can be as high as 2/3, which is 27-fold greater than the value of 1/41 predicted on the basis of summation relationships [Kacser and Burns, 19811 and supports criticisms of this approach based on theoretical grounds [Savageau and Sorribas, 19891. The accuracy with which the theory predicts responses to a 10% variation of the independent variables is within 0.5% on the average.
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