A compartmental model to measure the effects of insulin on glucose
transport and phosphorylation in human skeletal muscle. a triple
tracer study.
Saccomani, Maria Pia, Riccardo C. Bonadonna, Dennis M. Bier, Ralph A.
Defronzo, Claudio Cobelli.
Department of Electronics and Informatics, University of Padua,
Padua, Italy; Division of Metabolic Diseases, University of Verona
School of Medicine and Ospedale Civile Maggiore, Verona, Italy;
Division of Diabetes, University of Texas Health Science Center, San
Antonio, TX, USA; Children's Nutrition Research Center at Baylor
College of Medicine, Houston, TX, USA
APStracts 2:0152E, 1995.
We studied 5 healthy subjects with the perfused forearm and euglycemic
clamp techniques in combination with a triple tracer (12C-D-mannitol,
not transportable; 3-O-14C-methyl-D-glucose, transportable but not
metabolizable; 3-3H-D-glucose, transportable and metabolizable)
intraarterial 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. Physiologic
hyperinsulinemia (473+/-22 pM) caused 2.7 fold (63.1+/-7.2 vs 23.4+/
-6.1 [mu]mol min-1 kg-1, p<0.01) and 5.1 fold (42.5+/-5.8 vs
8.4+/-2.2 [mu]mol 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 triple tracer kinetic data can quantify transmembrane glucose
fluxes and intracellular glucose phosphorylation in human muscle; 2)
physiologic 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.
Received 4 November 1994; accepted in final form 11 July 1995.
APS Manuscript Number E454-4.
Article publication pending Am. J. Physiol. (Endocrinol. Metab.).
ISSN 1080-4757 Copyright 1995 The American Physiological Society.
Published in APStracts on 30 July 1995.