Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Aug 1;100(3):671–677. doi: 10.1172/JCI119579

Muscle-specific transgenic complementation of GLUT4-deficient mice. Effects on glucose but not lipid metabolism.

T S Tsao 1, A E Stenbit 1, J Li 1, K L Houseknecht 1, J R Zierath 1, E B Katz 1, M J Charron 1
PMCID: PMC508236  PMID: 9239415

Abstract

We have taken the approach of introducing the muscle-specific myosin light chain (MLC)-GLUT4 transgene into the GLUT4-null background to assess the relative role of muscle and adipose tissue GLUT4 in the etiology of the GLUT4-null phenotype. The resulting MLC-GLUT4-null mice express GLUT4 predominantly in the fast-twitch extensor digitorum longus (EDL) muscle. GLUT4 is nearly absent in female white adipose tissue (WAT) and slow-twitch soleus muscle of both sexes of MLC-GLUT4-null mice. GLUT4 content in male MLC-GLUT4-null WAT is 20% of that in control mice. In transgenically complemented EDL muscle, 2-deoxyglucose (2-DOG) uptake was restored to normal (male) or above normal (female) levels. In contrast, 2-DOG uptake in slow-twitch soleus muscle of MLC-GLUT4-null mice was not normalized. With the normalization of glucose uptake in fast-twitch skeletal muscle, whole body insulin action was restored in MLC-GLUT4-null mice, as shown by the results of the insulin tolerance test. These results demonstrate that skeletal muscle GLUT4 is a major regulator of skeletal muscle and whole body glucose metabolism. Despite normal skeletal muscle glucose uptake and insulin action, the MLC-GLUT4-null mice exhibited decreased adipose tissue deposits, adipocyte size, and fed plasma FFA levels that are characteristic of GLUT4-null mice. Together these results indicate that the defects in skeletal muscle and whole body glucose metabolism and adipose tissue in GLUT4-null mice arise independently.

Full Text

The Full Text of this article is available as a PDF (279.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aghayan M., Rao L. V., Smith R. M., Jarett L., Charron M. J., Thorens B., Heyner S. Developmental expression and cellular localization of glucose transporter molecules during mouse preimplantation development. Development. 1992 May;115(1):305–312. doi: 10.1242/dev.115.1.305. [DOI] [PubMed] [Google Scholar]
  2. Ariano M. A., Armstrong R. B., Edgerton V. R. Hindlimb muscle fiber populations of five mammals. J Histochem Cytochem. 1973 Jan;21(1):51–55. doi: 10.1177/21.1.51. [DOI] [PubMed] [Google Scholar]
  3. Armstrong R. B., Phelps R. O. Muscle fiber type composition of the rat hindlimb. Am J Anat. 1984 Nov;171(3):259–272. doi: 10.1002/aja.1001710303. [DOI] [PubMed] [Google Scholar]
  4. Baldini G., Hohman R., Charron M. J., Lodish H. F. Insulin and nonhydrolyzable GTP analogs induce translocation of GLUT 4 to the plasma membrane in alpha-toxin-permeabilized rat adipose cells. J Biol Chem. 1991 Mar 5;266(7):4037–4040. [PubMed] [Google Scholar]
  5. Baron A. D., Brechtel G., Wallace P., Edelman S. V. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans. Am J Physiol. 1988 Dec;255(6 Pt 1):E769–E774. doi: 10.1152/ajpendo.1988.255.6.E769. [DOI] [PubMed] [Google Scholar]
  6. Burcelin R., Printz R. L., Kande J., Assan R., Granner D. K., Girard J. Regulation of glucose transporter and hexokinase II expression in tissues of diabetic rats. Am J Physiol. 1993 Sep;265(3 Pt 1):E392–E401. doi: 10.1152/ajpendo.1993.265.3.E392. [DOI] [PubMed] [Google Scholar]
  7. Chang P. Y., Benecke H., Le Marchand-Brustel Y., Lawitts J., Moller D. E. Expression of a dominant-negative mutant human insulin receptor in the muscle of transgenic mice. J Biol Chem. 1994 Jun 10;269(23):16034–16040. [PubMed] [Google Scholar]
  8. Chang P. Y., Le Marchand-Brustel Y., Cheatham L. A., Moller D. E. Insulin stimulation of mitogen-activated protein kinase, p90rsk, and p70 S6 kinase in skeletal muscle of normal and insulin-resistant mice. Implications for the regulation of glycogen synthase. J Biol Chem. 1995 Dec 15;270(50):29928–29935. doi: 10.1074/jbc.270.50.29928. [DOI] [PubMed] [Google Scholar]
  9. Charron M. J., Brosius F. C., 3rd, Alper S. L., Lodish H. F. A glucose transport protein expressed predominately in insulin-responsive tissues. Proc Natl Acad Sci U S A. 1989 Apr;86(8):2535–2539. doi: 10.1073/pnas.86.8.2535. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Cushman S. W., Salans L. B. Determinations of adipose cell size and number in suspensions of isolated rat and human adipose cells. J Lipid Res. 1978 Feb;19(2):269–273. [PubMed] [Google Scholar]
  11. DeFronzo R. A. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667–687. doi: 10.2337/diab.37.6.667. [DOI] [PubMed] [Google Scholar]
  12. Donoghue M. J., Alvarez J. D., Merlie J. P., Sanes J. R. Fiber type- and position-dependent expression of a myosin light chain-CAT transgene detected with a novel histochemical stain for CAT. J Cell Biol. 1991 Oct;115(2):423–434. doi: 10.1083/jcb.115.2.423. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hansen P., Gulve E., Gao J., Schluter J., Mueckler M., Holloszy J. Kinetics of 2-deoxyglucose transport in skeletal muscle: effects of insulin and contractions. Am J Physiol. 1995 Jan;268(1 Pt 1):C30–C35. doi: 10.1152/ajpcell.1995.268.1.C30. [DOI] [PubMed] [Google Scholar]
  14. Hirsch J., Gallian E. Methods for the determination of adipose cell size in man and animals. J Lipid Res. 1968 Jan;9(1):110–119. [PubMed] [Google Scholar]
  15. Houseknecht K. L., Zhu A. X., Gnudi L., Hamann A., Zierath J. R., Tozzo E., Flier J. S., Kahn B. B. Overexpression of Ha-ras selectively in adipose tissue of transgenic mice. Evidence for enhanced sensitivity to insulin. J Biol Chem. 1996 May 10;271(19):11347–11355. doi: 10.1074/jbc.271.19.11347. [DOI] [PubMed] [Google Scholar]
  16. James D. E., Piper R. C. Insulin resistance, diabetes, and the insulin-regulated trafficking of GLUT-4. J Cell Biol. 1994 Sep;126(5):1123–1126. doi: 10.1083/jcb.126.5.1123. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Kahn B. B. Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes. J Clin Invest. 1992 May;89(5):1367–1374. doi: 10.1172/JCI115724. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Kahn B. B., Rossetti L., Lodish H. F., Charron M. J. Decreased in vivo glucose uptake but normal expression of GLUT1 and GLUT4 in skeletal muscle of diabetic rats. J Clin Invest. 1991 Jun;87(6):2197–2206. doi: 10.1172/JCI115254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Katz E. B., Stenbit A. E., Hatton K., DePinho R., Charron M. J. Cardiac and adipose tissue abnormalities but not diabetes in mice deficient in GLUT4. Nature. 1995 Sep 14;377(6545):151–155. doi: 10.1038/377151a0. [DOI] [PubMed] [Google Scholar]
  20. King P. A., Horton E. D., Hirshman M. F., Horton E. S. Insulin resistance in obese Zucker rat (fa/fa) skeletal muscle is associated with a failure of glucose transporter translocation. J Clin Invest. 1992 Oct;90(4):1568–1575. doi: 10.1172/JCI116025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Lathe R. Mice, gene targeting and behaviour: more than just genetic background. Trends Neurosci. 1996 May;19(5):183–189. doi: 10.1016/s0166-2236(96)20022-0. [DOI] [PubMed] [Google Scholar]
  22. Le Marchand-Brustel Y., Olichon-Berthe C., Grémeaux T., Tanti J. F., Rochet N., Van Obberghen E. Glucose transporter in insulin sensitive tissues of lean and obese mice. Effect of the thermogenic agent BRL 26830A. Endocrinology. 1990 Dec;127(6):2687–2695. doi: 10.1210/endo-127-6-2687. [DOI] [PubMed] [Google Scholar]
  23. Marette A., Burdett E., Douen A., Vranic M., Klip A. Insulin induces the translocation of GLUT4 from a unique intracellular organelle to transverse tubules in rat skeletal muscle. Diabetes. 1992 Dec;41(12):1562–1569. doi: 10.2337/diab.41.12.1562. [DOI] [PubMed] [Google Scholar]
  24. McGarry J. D. What if Minkowski had been ageusic? An alternative angle on diabetes. Science. 1992 Oct 30;258(5083):766–770. doi: 10.1126/science.1439783. [DOI] [PubMed] [Google Scholar]
  25. Mueckler M. Facilitative glucose transporters. Eur J Biochem. 1994 Feb 1;219(3):713–725. doi: 10.1111/j.1432-1033.1994.tb18550.x. [DOI] [PubMed] [Google Scholar]
  26. Pedersen O., Bak J. F., Andersen P. H., Lund S., Moller D. E., Flier J. S., Kahn B. B. Evidence against altered expression of GLUT1 or GLUT4 in skeletal muscle of patients with obesity or NIDDM. Diabetes. 1990 Jul;39(7):865–870. doi: 10.2337/diab.39.7.865. [DOI] [PubMed] [Google Scholar]
  27. Ren J. M., Marshall B. A., Mueckler M. M., McCaleb M., Amatruda J. M., Shulman G. I. Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice. J Clin Invest. 1995 Jan;95(1):429–432. doi: 10.1172/JCI117673. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Rosenthal N., Kornhauser J. M., Donoghue M., Rosen K. M., Merlie J. P. Myosin light chain enhancer activates muscle-specific, developmentally regulated gene expression in transgenic mice. Proc Natl Acad Sci U S A. 1989 Oct;86(20):7780–7784. doi: 10.1073/pnas.86.20.7780. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Shepherd P. R., Gnudi L., Tozzo E., Yang H., Leach F., Kahn B. B. Adipose cell hyperplasia and enhanced glucose disposal in transgenic mice overexpressing GLUT4 selectively in adipose tissue. J Biol Chem. 1993 Oct 25;268(30):22243–22246. [PubMed] [Google Scholar]
  30. Stenbit A. E., Burcelin R., Katz E. B., Tsao T. S., Gautier N., Charron M. J., Le Marchand-Brustel Y. Diverse effects of Glut 4 ablation on glucose uptake and glycogen synthesis in red and white skeletal muscle. J Clin Invest. 1996 Aug 1;98(3):629–634. doi: 10.1172/JCI118833. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Tozzo E., Shepherd P. R., Gnudi L., Kahn B. B. Transgenic GLUT-4 overexpression in fat enhances glucose metabolism: preferential effect on fatty acid synthesis. Am J Physiol. 1995 May;268(5 Pt 1):E956–E964. doi: 10.1152/ajpendo.1995.268.5.E956. [DOI] [PubMed] [Google Scholar]
  32. Tsao T. S., Burcelin R., Katz E. B., Huang L., Charron M. J. Enhanced insulin action due to targeted GLUT4 overexpression exclusively in muscle. Diabetes. 1996 Jan;45(1):28–36. doi: 10.2337/diab.45.1.28. [DOI] [PubMed] [Google Scholar]
  33. Zierath J. R. In vitro studies of human skeletal muscle: hormonal and metabolic regulation of glucose transport. Acta Physiol Scand Suppl. 1995;626:1–96. [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES