Importance of Glucose Per Se to Intravenous Glucose Tolerance: Comparison of the Minimal-Model Prediction with Direct Measurements

Abstract

Glucose disappearance after an oral or intravenous challenge is a function of the effects of both endogenously secreted insulin and of glucose itself. We previously introduced the term “glucose effectiveness,” or SG, defined as the ability of glucose per se to enhance its own disappearance independent of an increment in plasma insulin. The present investigation, performed in conscious dogs, was undertaken to quantify this glucose effect by minimal-model-based analysis of insulin and glucose dynamics after a frequently sampled intravenous glucose tolerance test (FSIGT). The values from the standard FSIGT were then compared with direct measurementsobtained from experiments in which the dynamic insulin response to glucose was suppressed with somatostatin (SRIF). In addition, we examined SG values from the modified FSIGT protocol, which involves both glucose and tolbutamide injections. Protocol I (N = 9): FSIGTs were performed and the glucose and insulin data were analyzed by computer. KG was 2.65 ± 0.28 min−1, S1 was 4.09 ± 0.34 × 10−4 min−1/(μU/ml), and SG was 0.033 ± 0.004 min−1. Protocol II (N = 6): FSIGTs were performed on animals in which SRIF was infused (0.8 μg/min−1kg) to obliterate the dynamic insulin response to glucose injection. Before the FSIGT, insulin and glucagon were infused intraportally to reattain basal glycemia. Without dynamic insulin, KG was reduced to 0.96 ± 0.18 min−1 (P < 0.0001). However, SG, estimated from the exponential rate of fall of plasma glucose in the absence of dynamic insulin, was similar to the standard FSIGTs: 0.025 ± 0.004 (P > 0.25). Protocol III (N = 6): modified FSIGTs wereperformed using glucose and tolbutamide injections for a better estimate of model parameters. Model parameters S1 and SG, and the KGwere not different from standard FSIGTs (P > 0.3). In fact, the value of SG (0.028 ± 0.003 min−1) was nearly identical to the direct measure from protocol II. Therefore, the effect of glucose per se on glucose decline, estimated by modeling the standard and modified FSIGTs, was confirmed by a direct measurement with the endogenous insulin response suppressed with SRIF. Also, the time course of the insulin effect to enhance net glucose disappearance from plasma [leff(t)] was calculated from the data of protocol II, and was the same as the time coursepredicted by the model. These studies demonstrate the ability of the computer modeling approach to separate insulin-dependent and glucose-dependent glucose disappearance, and represent a direct confirmation of the minimal model. More important, they confirm that glucose per se, independent of the dynamic insulin response, is a very significant factor in the determination of glucose tolerance.