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POINT-COUNTERPOINT

REBUTTAL FROM DRS. WASSERMAN AND FUEGER

1) Expression of GLUT4 ... maximum transport capacity.   This is correct, but irrelevant to the argument at hand. GLUT4 is undoubtedly important for muscle glucose uptake (MGU). This does not preclude that glucose phosphorylation by hexokinase is a barrier. Figure 1 of our Point statement illustrates the relationship between GLUT4 and removal of 2-deoxyglucose (2-DG) by exercising mouse muscle and that this relationship is amplified by increased hexokinase.

2) Uptake rate of 2-deoxyglucose ... with time.   Constant 2-DG uptake over time in perfused rat hindlimbs is not incongruous with a phosphorylation barrier for MGU. In any case, these studies are difficult to interpret with regard to balance between transport and phosphorylation because muscle free and phosphorylated 2-DG was not distinguished. The difference in 3-O-methylglucose and 2-DG kinetics occurs because no 3-O-methylglucose is phosphorylated. Substantial 2-DG is still phosphorylated, even when phosphorylation is a barrier to MGU.

3) There is no significant accumulation ... during contractions.   This is inaccurate. The references cited in the Counterpoint show marked increases in muscle glucose during exercise (5, 7). This overwhelmingly supports, and is, in fact, the linchpin for our position. The increase in muscle glucose observed in these papers suggests that glucose phosphorylation is a bottleneck.

4) K_m for glucose ... from hexokinase.   The function used to obtain the kinetic parameters in the review cited by Dr. Ploug and Dr. Vinten does not fit the data well (8). The K_m for MGU appears to be 5 mM and not 10 mM. A K_m of 5 mM agrees with other data (10). If one assumes that the K_m for GLUT4-mediated transport is closer to the high end of estimates (see Counterpoint), an influence of hexokinase on the K_m for MGU is evident. Nevertheless, K_m measured in vivo is determined not by glucose transport and phosphorylation alone, but by glucose delivery to the sarcolemma as well (9).

5) Prevention of exercise training-induced ... in MGU.   The argument made in response to the summary point 1 equally applies here.

In conclusion, the paradigm where MGU is controlled by transport as a rate-limiting step is inaccurate. MGU is under distributed control. Studies conducted in rodents (1–3) and humans (4, 5, 7) show that control shifts with exercise from glucose transport to glucose phosphorylation in vivo. At the same time it should be recognized that the magnitude shift in control of MGU likely depends on many factors such as exercise duration and intensity.

REFERENCES

1. Fueger PT, Bracy DP, Malabanan CM, Pencek RR, and Wasserman DH. Distributed control of glucose uptake by working muscles of conscious mice: roles of transport and phosphorylation. Am J Physiol Endocrinol Metab 286: E77–E84, 2004.[Abstract/Free Full Text]
2. Fueger PT, Heikkinen S, Bracy DP, Malabanan CM, Pencek RR, Laakso M, and Wasserman DH. Hexokinase II partial knockout impairs exercise-stimulated glucose uptake in oxidative muscles of mice. Am J Physiol Endocrinol Metab 285: E958–E963, 2003.[Abstract/Free Full Text]
3. Halseth AE, Bracy DP, and Wasserman DH. Limitations to exercise- and maximal insulin-stimulated muscle glucose uptake. J Appl Physiol 85: 2305–2313, 1998.[Abstract/Free Full Text]
4. Katz A, Broberg S, Sahlin K, and Wahren J. Leg glucose uptake during maximal dynamic exercise in humans. Am J Physiol Endocrinol Metab 251: E65–E70, 1986.[Abstract/Free Full Text]
5. Katz A, Sahlin K, and Broberg S. Regulation of glucose utilization in human skeletal muscle during moderate dynamic exercise. Am J Physiol Endocrinol Metab 260: E411–E415, 1991.[Abstract/Free Full Text]
6. Ploug T. Counterpoint: Glucose phosphorylation is not a significant barrier to glucose uptake by the working muscle. J Appl Physiol. In press.
7. Richter EA, Jensen P, Kiens B, and Kristiansen S. Sarcolemmal glucose transport and GLUT-4 translocation during exercise are diminished by endurance training. Am J Physiol Endocrinol Metab 274: E89–E95, 1998.[Abstract/Free Full Text]
8. Rose AJ and Richter EA. Skeletal muscle glucose uptake during exercise: how is it regulated? Physiology 20: 260–270, 2005.[Abstract/Free Full Text]
9. Wasserman DH and Halseth AE. An overview of muscle glucose uptake during exercise. Sites of regulation. Adv Exp Med Biol 441: 1–16, 1998.[Web of Science][Medline]
10. Zinker BA, Lacy DB, Bracy D, Jacobs J, and Wasserman DH. Regulation of glucose uptake and metabolism by working muscle. An in vivo analysis. Diabetes 42: 956–965, 1993.[Abstract]

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