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. 1995 Jan;95(1):429–432. doi: 10.1172/JCI117673

Overexpression of Glut4 protein in muscle increases basal and insulin-stimulated whole body glucose disposal in conscious mice.

J M Ren 1, B A Marshall 1, M M Mueckler 1, M McCaleb 1, J M Amatruda 1, G I Shulman 1
PMCID: PMC295454  PMID: 7814644

Abstract

The effect of increased Glut4 protein expression in muscle and fat on the whole body glucose metabolism has been evaluated by the euglycemic hyperinsulinemic clamp technique in conscious mice. Fed and fasting plasma glucose concentrations were 172 +/- 7 and 78 +/- 7 mg/dl, respectively, in transgenic mice, and were significantly lower than that of nontransgenic littermates (208 +/- 5 mg/dl in fed; 102 +/- 5 mg/dl in fasting state). Plasma lactate concentrations were higher in transgenic mice, (6.5 +/- 0.7 mM in the fed and 5.8 +/- 1.0 mM in fasting state) compared with that of non-transgenic littermates (4.7 +/- 0.3 mM in the fed and 4.2 +/- 0.5 mM in fasting state). In the fed state, the rate of whole body glucose disposal was 70% higher in transgenic mice in the basal state, 81 and 54% higher during submaximal and maximal insulin stimulation. In the fasting state, insulin-stimulated whole body glucose disposal was also higher in the transgenic mice. Hepatic glucose production after an overnight fast was 24.8 +/- 0.7 mg/kg per min in transgenic mice, and 25.4 +/- 2.7 mg/kg per min in nontransgenic mice. Our data demonstrate that overexpression of Glut4 protein in muscle increases basal as well as insulin-stimulated whole body glucose disposal. These results suggest that skeletal muscle glucose transport is rate-limiting for whole body glucose disposal and that the Glut4 protein is a potential target for pharmacological or genetic manipulation for treatment of patients with non-insulin-dependent diabetes mellitus.

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Selected References

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  1. Bailey C. J. Biguanides and NIDDM. Diabetes Care. 1992 Jun;15(6):755–772. doi: 10.2337/diacare.15.6.755. [DOI] [PubMed] [Google Scholar]
  2. Bonadonna R. C., Del Prato S., Saccomani M. P., Bonora E., Gulli G., Ferrannini E., Bier D., Cobelli C., DeFronzo R. A. Transmembrane glucose transport in skeletal muscle of patients with non-insulin-dependent diabetes. J Clin Invest. 1993 Jul;92(1):486–494. doi: 10.1172/JCI116592. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Burant C. F., Sivitz W. I., Fukumoto H., Kayano T., Nagamatsu S., Seino S., Pessin J. E., Bell G. I. Mammalian glucose transporters: structure and molecular regulation. Recent Prog Horm Res. 1991;47:349–388. doi: 10.1016/b978-0-12-571147-0.50015-9. [DOI] [PubMed] [Google Scholar]
  4. Damsbo P., Vaag A., Hother-Nielsen O., Beck-Nielsen H. Reduced glycogen synthase activity in skeletal muscle from obese patients with and without type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia. 1991 Apr;34(4):239–245. doi: 10.1007/BF00405082. [DOI] [PubMed] [Google Scholar]
  5. Devaskar S. U., Mueckler M. M. The mammalian glucose transporters. Pediatr Res. 1992 Jan;31(1):1–13. doi: 10.1203/00006450-199201000-00001. [DOI] [PubMed] [Google Scholar]
  6. Douen A. G., Ramlal T., Klip A., Young D. A., Cartee G. D., Holloszy J. O. Exercise-induced increase in glucose transporters in plasma membranes of rat skeletal muscle. Endocrinology. 1989 Jan;124(1):449–454. doi: 10.1210/endo-124-1-449. [DOI] [PubMed] [Google Scholar]
  7. Eriksson J., Franssila-Kallunki A., Ekstrand A., Saloranta C., Widén E., Schalin C., Groop L. Early metabolic defects in persons at increased risk for non-insulin-dependent diabetes mellitus. N Engl J Med. 1989 Aug 10;321(6):337–343. doi: 10.1056/NEJM198908103210601. [DOI] [PubMed] [Google Scholar]
  8. Gulve E. A., Ren J. M., Marshall B. A., Gao J., Hansen P. A., Holloszy J. O., Mueckler M. Glucose transport activity in skeletal muscles from transgenic mice overexpressing GLUT1. Increased basal transport is associated with a defective response to diverse stimuli that activate GLUT4. J Biol Chem. 1994 Jul 15;269(28):18366–18370. [PubMed] [Google Scholar]
  9. Hirshman M. F., Goodyear L. J., Wardzala L. J., Horton E. D., Horton E. S. Identification of an intracellular pool of glucose transporters from basal and insulin-stimulated rat skeletal muscle. J Biol Chem. 1990 Jan 15;265(2):987–991. [PubMed] [Google Scholar]
  10. James D. E., Strube M., Mueckler M. Molecular cloning and characterization of an insulin-regulatable glucose transporter. Nature. 1989 Mar 2;338(6210):83–87. doi: 10.1038/338083a0. [DOI] [PubMed] [Google Scholar]
  11. Liu M. L., Gibbs E. M., McCoid S. C., Milici A. J., Stukenbrok H. A., McPherson R. K., Treadway J. L., Pessin J. E. Transgenic mice expressing the human GLUT4/muscle-fat facilitative glucose transporter protein exhibit efficient glycemic control. Proc Natl Acad Sci U S A. 1993 Dec 1;90(23):11346–11350. doi: 10.1073/pnas.90.23.11346. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Mueckler M. Family of glucose-transporter genes. Implications for glucose homeostasis and diabetes. Diabetes. 1990 Jan;39(1):6–11. doi: 10.2337/diacare.39.1.6. [DOI] [PubMed] [Google Scholar]
  13. Olson A. L., Liu M. L., Moye-Rowley W. S., Buse J. B., Bell G. I., Pessin J. E. Hormonal/metabolic regulation of the human GLUT4/muscle-fat facilitative glucose transporter gene in transgenic mice. J Biol Chem. 1993 May 5;268(13):9839–9846. [PubMed] [Google Scholar]
  14. 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]
  15. RANDLE P. J., GARLAND P. B., HALES C. N., NEWSHOLME E. A. The glucose fatty-acid cycle. Its role in insulin sensitivity and the metabolic disturbances of diabetes mellitus. Lancet. 1963 Apr 13;1(7285):785–789. doi: 10.1016/s0140-6736(63)91500-9. [DOI] [PubMed] [Google Scholar]
  16. Ren J. M., Marshall B. A., Gulve E. A., Gao J., Johnson D. W., Holloszy J. O., Mueckler M. Evidence from transgenic mice that glucose transport is rate-limiting for glycogen deposition and glycolysis in skeletal muscle. J Biol Chem. 1993 Aug 5;268(22):16113–16115. [PubMed] [Google Scholar]
  17. Ren J. M., Semenkovich C. F., Gulve E. A., Gao J., Holloszy J. O. Exercise induces rapid increases in GLUT4 expression, glucose transport capacity, and insulin-stimulated glycogen storage in muscle. J Biol Chem. 1994 May 20;269(20):14396–14401. [PubMed] [Google Scholar]
  18. Rossetti L., Smith D., Shulman G. I., Papachristou D., DeFronzo R. A. Correction of hyperglycemia with phlorizin normalizes tissue sensitivity to insulin in diabetic rats. J Clin Invest. 1987 May;79(5):1510–1515. doi: 10.1172/JCI112981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Rothman D. L., Shulman R. G., Shulman G. I. 31P nuclear magnetic resonance measurements of muscle glucose-6-phosphate. Evidence for reduced insulin-dependent muscle glucose transport or phosphorylation activity in non-insulin-dependent diabetes mellitus. J Clin Invest. 1992 Apr;89(4):1069–1075. doi: 10.1172/JCI115686. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. 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]
  21. Yki-Järvinen H., Sahlin K., Ren J. M., Koivisto V. A. Localization of rate-limiting defect for glucose disposal in skeletal muscle of insulin-resistant type I diabetic patients. Diabetes. 1990 Feb;39(2):157–167. doi: 10.2337/diab.39.2.157. [DOI] [PubMed] [Google Scholar]

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