Use of [3H]glucose and a one-compartment model to determine glucose kinetics frequently underestimates the rate of glucose production (Ra). To assess to what extent an isotope effect, a tracer contaminant, or inadequacy of the model was responsible, we measured glucose Ra and forearm clearance of tracer and unlabeled glucose at various concentrations of plasma insulin (∼50, ∼160, and ∼1800 μU/ml) and plasma glucose (∼90, ∼160, ∼250, and ∼400 mg/dl) under steady-state and non-steady-state conditions. Under isotopic steady-state conditions, the clearances of tracer and unlabeled glucose across the forearm were identical, and exogenous glucose infusion rates did not differ significantly from the isotopically determined glucose Ra (10.0 ±1.3 vs. 10.5 ± 1.0 mg ⋅ kg−1 fat-free mass ⋅ min−1, respectively). However, under isotopic non-steady-state conditions, the isotopically determined Ra was significantly lower than the glucose infusion rate (11.5 ± 1.3 vs. 13.7 ± 1.5 mg ⋅ kg−1 fat-free mass ⋅ min−1, respectively, P < .001), and the underestimation was related to the deviation from the isotopic steady state. When [3H]glucose specific activity of plasma samples from experiments with the greatest underestimation of Ra was determined by high-performance liquid chromatography, <7% of the underestimation could be accounted for by a contaminant. These results indicate that inadequacy of the one-compartment model is responsible for underestimation of glucose Ra under non-steady-state conditions and that there is no detectable isotopic effect or appreciable contaminant of [3-3H]glucose. We conclude that under isotopic steady-state conditions, [3-3H]glucose is a reliable tracer for glucose kinetic studies in humans.

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