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POINT-COUNTERPOINT COMMENTS
Copenhagen Muscle Research Centre
University of Copenhagen
Copenhagen, Denmark
The following letters are in response to the Point:Counterpoint series "Glucose phosphorylation is/is not a significant barrier to muscle glucose uptake by the working muscle" that appears in this issue.
To the Editor: The Point:Counterpoint debate (4, 6) provides important insights into the complexity of determining the precise sites of regulation of skeletal muscle glucose uptake. In particular, the argument of Ploug and Vinten (4) that the Km for glucose uptake during exercise does not reflect contribution from hexokinase is quite convincing. On the other hand, the elegant work of Wasserman and colleagues (see Ref. 6) shows that, in mice, glucose phosphorylation is limiting under conditions of high glucose flux in vivo. In the debate only minor attention was paid to the reality that research based on mice may give results that are not always applicable to humans, and as physiologists we should keep the relevance to humans in mind. Mice have 
10-fold lower muscle glycogen content than humans [50 (3) vs. 500 (2) µmol/kg dry wt] and appear to rely more on extramuscular glucose than glycogen for fuel during exercise. This is exemplified by mice that do not express muscle glycogen synthase and consequently have virtually no muscle glycogen, but still have normal running endurance capacity (3). Our view (see Ref. 5) regarding exercise in humans is that glucose transport limits glucose uptake in most exercise conditions, but when uptake rates are high and accompanied by a high glycogenolytic rate, glucose phosphorylation may become limiting. This is exemplified by accumulation of unphosphorylated glucose in muscle during intense exercise, whereas this is not found during lower intensity exercise (1).
REFERENCES
Karolinska Institutet
Department of Physiology and Pharmacology
171 77 Stockholm, Sweden
To the Editor: Whether glucose transport or phosphorylation limits glucose utilization during exercise is a question that has been debated for decades and continues to be debated (4, 6). Methodological difficulties and differences in experimental designs have precluded a definitive conclusion. For example, overexpression of the GLUT1 transport protein in mouse skeletal muscle has led to the conclusion that transport is limiting for glucose utilization (5). However, studies where glycogen synthase and hexokinase are overexpressed do not support this idea (1, 6). During intense short-term exercise and during the initial phase of submaximal steady-state exercise in humans, phosphorylation limits glucose utilization (3). In contrast, the data in support of the idea that transport is limiting are not definitive. Thus Ploug and Vinten cited the finding that, following euglycemic hyperinsulinemia in humans, there is no detectable increase in the concentration of free glucose in muscle biopsies to support the conclusion that transport limits glucose utilization (4). It should be noted, however, that in the original report the authors concluded that there was no "appreciable" accumulation of intracellular glucose and they carefully discussed the potential pitfalls of the method used to estimate intracellular glucose. Moreover, they stated that if free glucose was sufficiently low in the basal state, then a several-fold increase in free glucose following hyperinsulinemia could still escape detection (2). Thus there appears to be good evidence that phosphorylation limits glucose utilization during some forms of exercise, whereas the evidence that transport is limiting is not as solidly established.
REFERENCES
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