Experimental validation of measurements of glucose turnover in nonsteady state

J Radziuk, K H Norwich, M Vranic
1978 American Journal of Physiology. Endocrinology and Metabolism  
RADZIUK, J., K. H. NORWICH,AND M. VRANIC. Experimental validation of measurements of glucose turnover in nonsteady state. Am. J. Physiol. 234(l): E84-E93, 1978 or Am. J. Physiol.: Endocrinol. Metab. Gastrointest. Physiol. 3(l): E84-E93, 1978. -The aim of the present experiments is to validate, in conscious dogs, the tracer infusion methods of measuring nonsteady turnover rates. This was done in nine experiments performed in four normal dogs by infusing isotopically labeled glucose (2-3H, 6-3H,
more » ... ucose (2-3H, 6-3H, 1-14C) and monitoring the concentrations of both the labeled and unlabeled substances. The validation is based on the observation that a high exogenous infusion of glucose will suppress endo?enous glucose production and become the sole source of glucose in the body. I3y infusing glucose at a high, time-varying rate, calculating its rate of appearance, (R,) and comparing it to the infused rate, the method can be verified. The calculations were based on: a) a single-compartment model with a modified volume of distribution; b) a two-compartment model; and c) a generalized dispersion model. The absolute values of the areas of the deviations of the calculated from the infused curves were found to be, respectively, 9.5, 8.4, and 7.8% of the total area under the infused curve. It was concluded that the tracer infusion method can reliably measure R, of glucwe when it is changing rapidly, and the system is out of steady state. tracer methods; compartment models; dispersion models; glucose kinetics; glucose clearance; glucose production; insulin THIS STUDY WAS UNDERTAKEN in order to validate the measurement of time-varying turnover rates in the glucose system. This system is an example of nonlinear metabolic systems in which the measurement of these rates is necessary to elucidate the control mechanisms regulating the concentrations of metabolites because this control takes place at the sites of their production and of their removal. Impaired tolerance for a substance or the resetting of its chronic level results from dysfunction of these control mechanisms. An early indication of this dysfunction could therefore be observed in the adaptive responses of the rates of production and removal to various metabolic challenges because changes in these rates are not necessarily reflected by the metzibolite concentrations. For example, prolonged fasting (9), exercise (39), chronic administration of steroids (23), or growth hormone (1) cause a marked change in glucose turnover rates with only slight changes in its concentration. Arginine infusions do not induce any change in glucose concentration either in normal or in depancreatized insulin-infused dogs, but in the former glucose turnover increases due to increased secretion of insulin and glucagon (5), whereas in the latter it does not change because the supply of insulin and glucagon was unaltered (6, 37). Nonsteady glucose turnover has been measured most frequently by infusing labeled glucose at a constant rate; calculations were based on a modified single compartment model (36) , but their validity for the glucose system has not yet been ascertained, Validation can be accomplished by comparing a known infusion rate of a substance (if it is not produced endogenously or if its endogenous production has been suppressed), to rates calculated by using nonsteady-state equations and the measured concentrations of labeled and unlabeled substance. Using the polysaccharide, inulin, as a test substance, we have previously validated nonsteady turnover measurements based on a one-compartment, a two-compartment, and a more general dispersion model (25, 29). Glucose differs fundamentally from inulin in that it strongly influences its own clearance through feedback control based on insulin. Its behavior is thus nonlinear in contrast to the linear behavior of inulin. It was necessary therefore to determine the applicability of turnover calculations to the glucose system. Because glucose is produced endogenously, our approach to this validation was based on the observation that infusion of exogenous glucose, in normal dogs, suppresses endogenous glucose production (14, 19, 35). If we therefore infuse glucose at a sufficiently high rate, we may compare the calculated rate of production to the known rate of infusion. Although this experiment raises the levels of glucose appearance to the higher limits of those encountered physiologically, it will validate the calculations in general if the system remains nonlinear because the same feedback loops are operative as at lower rates of glucose production. As tracer we have used constant infusions of [6-3H]glucose, [2-3H]glucose, or [Li4C]glucose and have measured plasma concentrations of labeled glucose prior ti and during the period of exogenous glucose infusion. Our objectives were: a) to compare the magnitude of the errors in nonsteady turnover measurement based on the modified single-compartment, two-compartment, and dispersion models; b) to determine which radioactive label of glucose can be used under the conditions of E84
doi:10.1152/ajpendo.1978.234.1.e84 pmid:623255 fatcat:5i2x7ampffhabgwh2z45masvwa