TY - JOUR
T1 - A model to measure insulin effects on glucose transport and phosphorylation in muscle
T2 - A three-tracer study
AU - Saccomani, Maria Pia
AU - Bonadonna, Riccardo G.
AU - Bier, Dennis M.
AU - DeFronzo, Ralph A.
AU - Cobelli, Claudio
PY - 1996
Y1 - 1996
N2 - 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 μmol · min-1 · kg- 1, p < 0.01) and 5.1-fold (42.5 ± 5.8 vs. 8.4 ± 2.2 μmol · 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 (~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.
AB - 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 μmol · min-1 · kg- 1, p < 0.01) and 5.1-fold (42.5 ± 5.8 vs. 8.4 ± 2.2 μmol · 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 (~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.
KW - glucose metabolism
KW - mathematical model
KW - multiple tracer technique
KW - parameter estimation
KW - tracer kinetics
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M3 - Article
C2 - 8772490
AN - SCOPUS:0030025032
SN - 0193-1849
VL - 270
SP - E170-E185
JO - American Journal of Physiology - Endocrinology and Metabolism
JF - American Journal of Physiology - Endocrinology and Metabolism
IS - 1 33-1
ER -