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J Appl Physiol 101: 1807-1808, 2006; doi:10.1152/japplphysiol.00817d.2006
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POINT-COUNTERPOINT

REBUTTAL FROM DRS. PLOUG AND VINTEN

Wasserman and Fueger (8) put forward two arguments in support of the notion that "Glucose phosphorylation is a significant barrier to glucose uptake by the working muscle."

The first argument is based on a series of five papers by Wasserman and coworkers, where an increase in the transmembrane steady-state distribution ratio for 3-O-methylglucose (Si/So) on stimulation of glucose transport was used to estimate free intracellular glucose using a kinetic model for GLUT4-mediated transport. This clever approach is unfortunately dependent on knowledge of the kinetics for all transporters and for all glucose derivatives involved, and thus susceptible to deviations from the implicit assumptions that GLUT4 transport is symmetrical and equally rapid under exchange and net transport conditions and that basal and stimulated glucose transport are both mediated solely by GLUT4.

Concerning the assumed kinetics of GLUT4-mediated transport, deviations from simple kinetics in insulin-stimulated fat cells, where GLUT4, as in stimulated muscle, is the major glucose transporter, have been demonstrated (7, 9). Furthermore, a contribution to basal glucose transport by glucose transporters with kinetic characteristics different from those of GLUT4 could invalidate calculations of free intracellular glucose based on stimulation-induced changes in the Si/So ratio for 3-O-methylglucose. At least seven facilitative hexose transporters are expressed in skeletal muscle (6). Whereas the number of GLUT4 in the muscle plasma membrane is increased at least 15-fold by exercise (4), there are no reports that this should be the case for any of the other transporters. Thus reported stimulation-induced changes in kinetics of transport (2, 3) are well compatible with a stimulation-induced increase in the contribution by GLUT4.

The second argument is based on genetically modified mouse models of GLUT4 and hexokinase II expression in skeletal muscle. First of all, hexokinase I with kinetic parameters very different from hexokinase II accounts for three-fourth of all hexokinase activity in human skeletal muscle (5). So, at best, the findings only apply to rodent skeletal muscle. However, even in rodent muscle the arguments probably do not hold because of the underlying too simplistic assumption that it is possible to modify the expression of a single gene without any compensatory adjustments in the expression patterns of other genes. Thus it has recently been shown that in mice with muscle-specific knockout of GLUT4, hexokinase II expression is compensatory increased around fivefold together with alterations in multiple other regulatory steps in glycogen metabolism (1).

REFERENCES

  1. Kim YB, Peroni OD, Aschenbach WG, Minokoshi Y, Kotani K, Zisman A, Kahn CR, Goodyear LJ, and Kahn BB. Muscle-specific deletion of the Glut4 glucose transporter alters multiple regulatory steps in glycogen metabolism. Mol Cell Biol 25: 9713–9723, 2005.[Abstract/Free Full Text]
  2. Ploug T, Galbo H, Ohkuwa T, Tranum-Jensen J, and Vinten J. Kinetics of glucose transport in rat skeletal muscle membrane vesicles: effects of insulin and contractions. Am J Physiol Endocrinol Metab 262: E700–E711, 1992.[Abstract/Free Full Text]
  3. Ploug T, Galbo H, Vinten J, Jorgensen M, and Richter EA. Kinetics of glucose transport in rat muscle: effects of insulin and contractions. Am J Physiol Endocrinol Metab 253: E12–E20, 1987.[Abstract/Free Full Text]
  4. Ploug T, van Deurs B, Ai H, Cushman SW, and Ralston E. Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions. J Cell Biol 142: 1429–1446, 1998.[Abstract/Free Full Text]
  5. Ritov VB and Kelley DE. Hexokinase isozyme distribution in human skeletal muscle. Diabetes 50: 1253–1262, 2001.[Abstract/Free Full Text]
  6. Stuart CA, Yin D, Howell ME, Dykes RJ, Laffan JJ, and Ferrando AA. Hexose transporter mRNAs for GLUT4, GLUT5, and GLUT12 predominate in human muscle. Am J Physiol Endocrinol Metab. In press.
  7. Vinten J. Accelerated net efflux of 3-O-[14C]methylglucose in isolated fat cells. Biochim Biophys Acta 772: 244–250, 1984.[Medline]
  8. Wasserman DH and Fueger PT. Point: Glucose phosphorylation is a significant barrier to muscle glucose uptake by the working muscle. J Appl Physiol. In press.
  9. Wheeler TJ. Accelerated net efflux of 3-O-methylglucose from rat adipocytes: a reevaluation. Biochim Biophys Acta 1190: 345–354, 1994.[Medline]




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