AJP - Endocrinology and Metabolism, Vol 270, Issue 1 E170-E185, Copyright © 1996 by American Physiological Society

ARTICLES

A model to measure insulin effects on glucose transport and phosphorylation in muscle: a three-tracer study

M. P. Saccomani, R. C. Bonadonna, D. M. Bier, R. A. DeFronzo and C. Cobelli
Department of Electronics and Informatics, University of Padua, Italy.

We studied five healthy subjects with perfused forearm and euglycemic clamp techniques in combination with a three-tracer (D-[12C]mannitol, not transportable; 3-O-[14C]methyl-D-glucose, transportable but not metabolizable; D-[3-3H]glucose, transportable and metabolizable) intra-arterial pulse injection to assess transmembrane transport and intracellular phosphorylation of glucose in vivo in human muscle. The washout curves of the three tracers were analyzed with a multicompartmental model. A priori identifiability analysis of the tracer model shows that the rate constants of glucose transport into and out of the cells and of glucose phosphorylation are uniquely identifiable. Tracer model parameters were estimated by a nonlinear least-squares parameter estimation technique. We then solved for the tracee model and estimated bidirectional transmembrane transport glucose fluxes, glucose intracellular phosphorylation, extracellular and intracellular volumes of glucose distribution, and extracellular and intracellular glucose concentrations. Physiological hyperinsulinemia (473 +/- 22 pM) caused 2.7-fold (63.1 +/- 7.2 vs. 23.4 +/- 6.1 mumol.min-1.kg-1, P < 0.01) and 5.1-fold (42.5 +/- 5.8 vs. 8.4 +/- 2.2 mumol.min-1.kg-1, P < 0.01) increases in transmembrane influx and intracellular phosphorylation of glucose, respectively. Extracellular distribution volume and concentration of glucose were unchanged, whereas intracellular distribution volume of glucose was increased (approximately 2-fold) and intracellular glucose concentration was almost halved by hyperinsulinemia. In summary, 1) a multicompartment model of three-tracer kinetic data can quantify transmembrane glucose fluxes and intracellular glucose phosphorylation in human muscle; and 2) physiological hyperinsulinemia stimulates both transport and phosphorylation of glucose and, in doing so, amplifies the role of glucose transport as a rate-determining step of muscle glucose uptake.

This article has been cited by other articles:

				M. Pendergrass, A. Bertoldo, R. Bonadonna, G. Nucci, L. Mandarino, C. Cobelli, and R. A. DeFronzo Muscle glucose transport and phosphorylation in type 2 diabetic, obese nondiabetic, and genetically predisposed individuals Am J Physiol Endocrinol Metab, January 1, 2007; 292(1): E92 - E100. [Abstract] [Full Text] [PDF]

				H. A. Petersen, P. T. Fueger, D. P. Bracy, D. H. Wasserman, and A. E. Halseth Fiber type-specific determinants of Vmax for insulin-stimulated muscle glucose uptake in vivo Am J Physiol Endocrinol Metab, March 1, 2003; 284(3): E541 - E548. [Abstract] [Full Text] [PDF]

				M.R. Davids, S.-H. Lin, Y. Edoute, S. Cheema-Dhadli, and M.L. Halperin Hyponatraemia and hyperglycaemia during laproscopic surgery QJM, May 1, 2002; 95(5): 321 - 330. [Abstract] [Full Text] [PDF]

				A. Bertoldo, P. Peltoniemi, V. Oikonen, J. Knuuti, P. Nuutila, and C. Cobelli Kinetic modeling of [18F]FDG in skeletal muscle by PET: a four-compartment five-rate-constant model Am J Physiol Endocrinol Metab, September 1, 2001; 281(3): E524 - E536. [Abstract] [Full Text] [PDF]

				K. V. Williams, J. C. Price, and D. E. Kelley Interactions of Impaired Glucose Transport and Phosphorylation in Skeletal Muscle Insulin Resistance: A Dose-Response Assessment Using Positron Emission Tomography Diabetes, September 1, 2001; 50(9): 2069 - 2079. [Abstract] [Full Text] [PDF]

				K. Gottlob, N. Majewski, S. Kennedy, E. Kandel, R. B. Robey, and N. Hay Inhibition of early apoptotic events by Akt/PKB is dependent on the first committed step of glycolysis and mitochondrial hexokinase Genes & Dev., June 1, 2001; 15(11): 1406 - 1418. [Abstract] [Full Text] [PDF]

				T. Utriainen, S. Lovisatti, S. Makimattila, A. Bertoldo, S. Weintraub, R. DeFronzo, C. Cobelli, and H. Yki-Jarvinen Direct measurement of the lumped constant for 2-deoxy-[1-14C]glucose in vivo in human skeletal muscle Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E228 - E233. [Abstract] [Full Text] [PDF]

				S. Heikkinen, M. Pietila, M. Halmekyto, S. Suppola, E. Pirinen, S. S. Deeb, J. Janne, and M. Laakso Hexokinase II-deficient Mice. PRENATAL DEATH OF HOMOZYGOTES WITHOUT DISTURBANCES IN GLUCOSE TOLERANCE IN HETEROZYGOTES J. Biol. Chem., August 6, 1999; 274(32): 22517 - 22523. [Abstract] [Full Text] [PDF]

				D. E. Kelley, K. V. Williams, and J. C. Price Insulin regulation of glucose transport and phosphorylation in skeletal muscle assessed by PET Am J Physiol Endocrinol Metab, August 1, 1999; 277(2): E361 - E369. [Abstract] [Full Text] [PDF]

				G. W. Cline, K. F. Petersen, M. Krssak, J. Shen, R. S. Hundal, Z. Trajanoski, S. Inzucchi, A. Dresner, D. L. Rothman, and G. I. Shulman Impaired Glucose Transport as a Cause of Decreased Insulin-Stimulated Muscle Glycogen Synthesis in Type 2 Diabetes N. Engl. J. Med., July 22, 1999; 341(4): 240 - 246. [Abstract] [Full Text] [PDF]

				R. C. Bonadonna, M. P. Saccomani, S. Del Prato, E. Bonora, R. A. DeFronzo, and C. Cobelli Role of Tissue-Specific Blood Flow and Tissue Recruitment in Insulin-Mediated Glucose Uptake of Human Skeletal Muscle Circulation, July 21, 1998; 98(3): 234 - 241. [Abstract] [Full Text] [PDF]

				R. Roussel, P. G. Carlier, J.-J. Robert, G. Velho, and G. Bloch 13C/31P NMR studies of glucose transport in human skeletal muscle PNAS, February 3, 1998; 95(3): 1313 - 1318. [Abstract] [Full Text] [PDF]

				R. M. O'Doherty, A. E. Halseth, D. K. Granner, D. P. Bracy, and D. H. Wasserman Analysis of insulin-stimulated skeletal muscle glucose uptake in conscious rat using isotopic glucose analogs Am J Physiol Endocrinol Metab, February 1, 1998; 274(2): E287 - E296. [Abstract] [Full Text] [PDF]