Skip to main content
NCBI home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Mar 1;97(5):1235–1241. doi: 10.1172/JCI118538

Glutamine:fructose-6-phosphate amidotransferase activity in cultured human skeletal muscle cells: relationship to glucose disposal rate in control and non-insulin-dependent diabetes mellitus subjects and regulation by glucose and insulin.

M C Daniels 1, T P Ciaraldi 1, S Nikoulina 1, R R Henry 1, D A McClain 1
PMCID: PMC507176  PMID: 8636435

Abstract

We examined the activity of the rate-limiting enzyme for hexosamine biosynthesis, glutamine:fructose-6-phosphate amidotransferase (GFA) in human skeletal muscle cultures (HSMC), from 17 nondiabetic control and 13 subjects with non-insulin-dependent diabetes. GFA activity was assayed from HSMC treated with low (5 mM) or high (20 mM) glucose and low (22 pM) or high (30 microM) concentrations of insulin. In control subjects GFA activity decreased with increasing glucose disposal rate (r = -0.68, P < 0.025). In contrast, a positive correlation existed between GFA and glucose disposal in the diabetics (r = 0.86, P < 0.005). Increased GFA activity was also correlated with body mass index in controls but not diabetics. GFA activity was significantly stimulated by high glucose (22%), high insulin (43%), and their combination (61%). GFA activity and its regulation by glucose and insulin were not significantly different in diabetic HSMC. We conclude that glucose and insulin regulate GFA activity in skeletal muscle. More importantly, our results are consistent with a regulatory role for the hexosamine pathway in human glucose homeostasis. This relationship between hexosamine biosynthesis and the regulation of glucose metabolism is altered in non-insulin-dependent diabetes.

Full Text

The Full Text of this article is available as a PDF (420.6 KB).

Selected References

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

  1. Adler A. J. Glutamine fructose-6-phosphate aminotransferase and glycoprotein synthesis in the developing chick eye. Curr Eye Res. 1984 Feb;3(2):351–362. doi: 10.3109/02713688408997220. [DOI] [PubMed] [Google Scholar]
  2. Balkan B., Dunning B. E. Glucosamine inhibits glucokinase in vitro and produces a glucose-specific impairment of in vivo insulin secretion in rats. Diabetes. 1994 Oct;43(10):1173–1179. doi: 10.2337/diab.43.10.1173. [DOI] [PubMed] [Google Scholar]
  3. Ciaraldi T. P., Abrams L., Nikoulina S., Mudaliar S., Henry R. R. Glucose transport in cultured human skeletal muscle cells. Regulation by insulin and glucose in nondiabetic and non-insulin-dependent diabetes mellitus subjects. J Clin Invest. 1995 Dec;96(6):2820–2827. doi: 10.1172/JCI118352. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Crook E. D., Daniels M. C., Smith T. M., McClain D. A. Regulation of insulin-stimulated glycogen synthase activity by overexpression of glutamine: fructose-6-phosphate amidotransferase in rat-1 fibroblasts. Diabetes. 1993 Sep;42(9):1289–1296. doi: 10.2337/diab.42.9.1289. [DOI] [PubMed] [Google Scholar]
  5. Crook E. D., Zhou J., Daniels M., Neidigh J. L., McClain D. A. Regulation of glycogen synthase by glucose, glucosamine, and glutamine:fructose-6-phosphate amidotransferase. Diabetes. 1995 Mar;44(3):314–320. doi: 10.2337/diab.44.3.314. [DOI] [PubMed] [Google Scholar]
  6. Daniels M. C., Kansal P., Smith T. M., Paterson A. J., Kudlow J. E., McClain D. A. Glucose regulation of transforming growth factor-alpha expression is mediated by products of the hexosamine biosynthesis pathway. Mol Endocrinol. 1993 Aug;7(8):1041–1048. doi: 10.1210/mend.7.8.8232303. [DOI] [PubMed] [Google Scholar]
  7. Henry R. R., Abrams L., Nikoulina S., Ciaraldi T. P. Insulin action and glucose metabolism in nondiabetic control and NIDDM subjects. Comparison using human skeletal muscle cell cultures. Diabetes. 1995 Aug;44(8):936–946. doi: 10.2337/diab.44.8.936. [DOI] [PubMed] [Google Scholar]
  8. Kornfeld R. Studies on L-glutamine D-fructose 6-phosphate amidotransferase. I. Feedback inhibition by uridine diphosphate-N-acetylglucosamine. J Biol Chem. 1967 Jul 10;242(13):3135–3141. [PubMed] [Google Scholar]
  9. Marshall S., Bacote V., Traxinger R. R. Discovery of a metabolic pathway mediating glucose-induced desensitization of the glucose transport system. Role of hexosamine biosynthesis in the induction of insulin resistance. J Biol Chem. 1991 Mar 15;266(8):4706–4712. [PubMed] [Google Scholar]
  10. McClain D. A., Paterson A. J., Roos M. D., Wei X., Kudlow J. E. Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells. Proc Natl Acad Sci U S A. 1992 Sep 1;89(17):8150–8154. doi: 10.1073/pnas.89.17.8150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. McKnight G. L., Mudri S. L., Mathewes S. L., Traxinger R. R., Marshall S., Sheppard P. O., O'Hara P. J. Molecular cloning, cDNA sequence, and bacterial expression of human glutamine:fructose-6-phosphate amidotransferase. J Biol Chem. 1992 Dec 15;267(35):25208–25212. [PubMed] [Google Scholar]
  12. 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]
  13. Richards T. C., Greengard O. Distribution of glutamine hexosephosphate aminotransferase in rat tissues; changes with state of differentiation. Biochim Biophys Acta. 1973 May 28;304(3):842–850. doi: 10.1016/0304-4165(73)90231-6. [DOI] [PubMed] [Google Scholar]
  14. Robinson K. A., Sens D. A., Buse M. G. Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. Diabetes. 1993 Sep;42(9):1333–1346. doi: 10.2337/diab.42.9.1333. [DOI] [PubMed] [Google Scholar]
  15. Sarabia V., Ramlal T., Klip A. Glucose uptake in human and animal muscle cells in culture. Biochem Cell Biol. 1990 Feb;68(2):536–542. doi: 10.1139/o90-076. [DOI] [PubMed] [Google Scholar]
  16. Thorburn A. W., Gumbiner B., Bulacan F., Wallace P., Henry R. R. Intracellular glucose oxidation and glycogen synthase activity are reduced in non-insulin-dependent (type II) diabetes independent of impaired glucose uptake. J Clin Invest. 1990 Feb;85(2):522–529. doi: 10.1172/JCI114468. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Traxinger R. R., Marshall S. Coordinated regulation of glutamine:fructose-6-phosphate amidotransferase activity by insulin, glucose, and glutamine. Role of hexosamine biosynthesis in enzyme regulation. J Biol Chem. 1991 Jun 5;266(16):10148–10154. [PubMed] [Google Scholar]
  18. Traxinger R. R., Marshall S. Insulin regulation of pyruvate kinase activity in isolated adipocytes. Crucial role of glucose and the hexosamine biosynthesis pathway in the expression of insulin action. J Biol Chem. 1992 May 15;267(14):9718–9723. [PubMed] [Google Scholar]
  19. Tsuiki S., Miyagi T. Neoplastic alterations of glucosamine 6-phosphate synthase in rat liver. Adv Enzyme Regul. 1976;15:35–52. doi: 10.1016/0065-2571(77)90008-5. [DOI] [PubMed] [Google Scholar]
  20. Unger R. H. Diabetic hyperglycemia: link to impaired glucose transport in pancreatic beta cells. Science. 1991 Mar 8;251(4998):1200–1205. doi: 10.1126/science.2006409. [DOI] [PubMed] [Google Scholar]
  21. Winterburn P. J., Phelps C. F. Purification and some kinetic properties of rat liver glucosamine synthetase. Biochem J. 1971 Feb;121(4):701–709. doi: 10.1042/bj1210701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Yki-Järvinen H. Glucose toxicity. Endocr Rev. 1992 Aug;13(3):415–431. doi: 10.1210/edrv-13-3-415. [DOI] [PubMed] [Google Scholar]
  23. Zhou J., Neidigh J. L., Espinosa R., 3rd, LeBeau M. M., McClain D. A. Human glutamine: fructose-6-phosphate amidotransferase: characterization of mRNA and chromosomal assignment to 2p13. Hum Genet. 1995 Jul;96(1):99–101. doi: 10.1007/BF00214194. [DOI] [PubMed] [Google Scholar]

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

RESOURCES