J Appl Physiol 101: 1811, 2006.
First published October 5, 2006; doi:10.1152/japplphysiol.01083.2006
8750-7587/06 $8.00
Last Word: Point:Counterpoint authors respond to the commentaries on "Glucose phosphorylation is/is not a significant barrier to glucose uptake by the working muscle" that appear in this issue
Thorkil Ploug and
Jørgen Vinten
Copenhagen Muscle Research Centre
Department of Medical Physiology
The Panum Institute
University of Copenhagen
Denmark
e-mail: tp{at}mfi.ku.dk
The present debate, precipitated by our restatement of E. Lundsgaard’s claim that phosphorylation of glucose is not rate limiting for glucose utilization in muscle, has proved very instructive. It seems presently unchallenged that glucose phosphorylation is hardly rate limiting during insulin stimulation at rest or during moderate exercise stimulation at basal insulin concentrations. In further support of this, muscle glucose uptake increases during moderate intensity contractions in vitro (2) or in vivo (3), when extracellular glucose levels are raised beyond normal physiological levels in the absence of any change in insulin concentrations. This clearly demonstrates that at moderate intensity exercise the hexokinase is not saturated at euglycemic conditions, which means that the free intracellular glucose concentration must be below two to three times the Km value of the hexokinase. In human skeletal muscle, where hexokinase I accounts for three-fourths of total hexokinase activity (4) this translates into a free intracellular glucose concentration below 0.3 mM during moderate intensity exercise. Considering that the extracellular glucose concentration is around 5 mM during moderate intensity exercise, this shows that glucose phosphorylation contributes less than 10% to the overall resistance to glucose uptake by the working muscle.
When it comes to strenuous exercise, glucose transport is limiting for uptake for at least the first few minutes, where appreciable GLUT4 translocation has not yet occurred. When maximum GLUT4 translocation has taken place, glucose uptake is limited by glycogen breakdown. This is so, because during strenuous exercise more than 80% of energy production in human muscle is provided by this intracellular process (1), which mainly produces glucose 1-phosphate. This is in turn converted to glucose 6-phosphate by an isomerase, and thus bypasses phosphorylation by the hexokinase. In this situation, glucose 6-phosphate inhibition of hexokinase is increased. However, during such circumstances it does not make much sense to claim that muscle glucose metabolism is limited by phosphorylation by the hexokinase, when the need for carbohydrate fuel is so amply provided by an intracellular fuel store accumulated under control of glucose transport during more quiet periods (e.g., resting periods or alternating recruitment of motor units), where phosphorylation is unlikely to be rate limiting.
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Copyright © 2006 by the American Physiological Society.
