AJP - Endocrinology and Metabolism, Vol 261, Issue 4 E539-E550, Copyright © 1991 by American Physiological Society

ARTICLES

Compartmental model of leucine kinetics in humans

C. Cobelli, M. P. Saccomani, P. Tessari, G. Biolo, L. Luzi and D. E. Matthews
Department of Electronics and Informatics, University of Padua, Italy.

The complexity of amino acid and protein metabolism has limited the development of comprehensive, accurate whole body kinetic models. For leucine, simplified approaches are in use to measure in vivo leucine fluxes, but their domain of validity is uncertain. We propose here a comprehensive compartmental model of the kinetics of leucine and alpha-ketoisocaproate (KIC) in humans. Data from a multiple-tracer administration were generated with a two-stage (I and II) experiment. Six normal subjects were studied. In experiment I, labeled leucine and KIC were simultaneously injected into plasma. Four plasma leucine and KIC tracer concentration curves and label in the expired CO2 were measured. In experiment II, labeled bicarbonate was injected into plasma, and labeled CO2 in the expired air was measured. Radioactive (L-[1-14C]leucine, [4,5-3H]KIC, [14C]bicarbonate) and stable isotope (L-[1-13C]leucine, [5,5,5-2H3]KIC, [13C]bicarbonate) tracers were employed. The input format was a bolus (impulse) dose in the radioactive case and a constant infusion in the stable isotope case. A number of physiologically based, linear time-invariant compartmental models were proposed and tested against the data. The model finally chosen for leucine-KIC kinetics has 10 compartments: 4 for leucine, 3 for KIC, and 3 for bicarbonate. The model is a priori uniquely identifiable, and its parameters were estimated with precision from the five curves of experiment I. The separate assessment of bicarbonate kinetics (experiment II) was shown to be unnecessary. The model defines masses and fluxes of leucine in the organism, in particular its intracellular appearance from protein breakdown, its oxidation, and its incorporation into proteins. An important feature of the model is its ability to estimate leucine oxidation by resolving the bicarbonate model in each individual subject. Finally, the model allows the assessment of the domain of validity of the simpler commonly used models.

This article has been cited by other articles:

				D. S. C. Raj, O. Adeniyi, E. A. Dominic, M. A. Boivin, S. McClelland, A. H. Tzamaloukas, N. Morgan, L. Gonzales, R. Wolfe, and A. Ferrando Amino acid repletion does not decrease muscle protein catabolism during hemodialysis Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1534 - E1542. [Abstract] [Full Text] [PDF]

				D. S. C. Raj, P. Zager, V. O. Shah, E. A. Dominic, O. Adeniyi, P. Blandon, R. Wolfe, and A. Ferrando Protein turnover and amino acid transport kinetics in end-stage renal disease Am J Physiol Endocrinol Metab, January 1, 2004; 286(1): E136 - E143. [Abstract] [Full Text]

				H. Hasegawa, T. Matsukawa, Y. Shinohara, and T. Hashimoto Kinetics of Sequential Metabolism from D-Leucine to L-Leucine via alpha -Ketoisocaproic Acid in Rat Drug Metab. Dispos., December 1, 2002; 30(12): 1436 - 1440. [Abstract] [Full Text] [PDF]

				A. Battezzati, A. Caumo, A. Fattorini, L. P. Sereni, J. Coppa, R. Romito, M. Ammatuna, E. Regalia, V. Mazzaferro, and L. Luzi Amino Acid Kinetics During the Anhepatic Phase of Liver Transplantation Diabetes, June 1, 2002; 51(6): 1690 - 1698. [Abstract] [Full Text] [PDF]

				L. Luzi, G. Perseghin, M. D. Brendel, I. Terruzzi, A. Battezzati, M. Eckhard, D. Brandhorst, H. Brandhorst, S. Friemann, C. Socci, et al. Metabolic Effects of Restoring Partial {beta}-Cell Function After Islet Allotransplantation in Type 1 Diabetic Patients Diabetes, February 1, 2001; 50(2): 277 - 282. [Abstract] [Full Text]

				H. Fouillet, C. Gaudichon, F. Mariotti, S. Mahe, P. Lescoat, J. F. Huneau, and D. Tome Compartmental modeling of postprandial dietary nitrogen distribution in humans Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E161 - E175. [Abstract] [Full Text] [PDF]

				R. Hovorka, P. V. Carroll, I. J. Gowrie, N. C. Jackson, D. L. Russell-Jones, and A. M. Umpleby A surrogate measure of whole body leucine transport across the cell membrane Am J Physiol Endocrinol Metab, March 1, 1999; 276(3): E573 - E579. [Abstract] [Full Text] [PDF]