Skip to main content
NCBI home page
Biochemical Journal logoLink to Biochemical Journal
. 1996 Mar 15;314(Pt 3):903–909. doi: 10.1042/bj3140903

Requirement of glucose metabolism for regulation of glucose transporter type 2 (GLUT2) gene expression in liver.

F Rencurel 1, G Waeber 1, B Antoine 1, F Rocchiccioli 1, P Maulard 1, J Girard 1, A Leturque 1
PMCID: PMC1217142  PMID: 8615787

Abstract

Previous studies have shown that glucose increases the glucose transporter (GLUT2) mRNA expression in the liver in vivo and in vitro. Here we report an analysis of the effects of glucose metabolism on GLUT2 gene expression. GLUT2 mRNA accumulation by glucose was not due to stabilization of its transcript but rather was a direct effect on gene transcription. A proximal fragment of the 5' regulatory region of the mouse GLUT2 gene linked to a reporter gene was transiently transfected into liver GLUT2-expressing cells. Glucose stimulated reporter gene expression in these cells, suggesting that glucose-responsive elements were included within the proximal region of the promoter. A dose-dependent effect of glucose on GLUT2 expression was observed over 10 mM glucose irrespective of the hexokinase isozyme (glucokinase K(m) 16 mM; hexokinase I K(m) 0.01 mM) present in the cell type used. This suggests that the correlation between extracellular glucose and GLUT2 mRNA concentrations is simply a reflection of an activation of glucose metabolism. The mediators and the mechanism responsible for this response remain to be determined. In conclusion, glucose metabolism is required for the proper induction of the GLUT2 gene in the liver and this effect is transcriptionally regulated.

Full Text

The Full Text of this article is available as a PDF (334.3 KB).

Selected References

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

  1. Antoine B., Levrat F., Vallet V., Berbar T., Cartier N., Dubois N., Briand P., Kahn A. Gene expression in hepatocyte-like lines established by targeted carcinogenesis in transgenic mice. Exp Cell Res. 1992 May;200(1):175–185. doi: 10.1016/s0014-4827(05)80086-2. [DOI] [PubMed] [Google Scholar]
  2. Asano T., Katagiri H., Tsukuda K., Lin J. L., Ishihara H., Yazaki Y., Oka Y. Upregulation of GLUT2 mRNA by glucose, mannose, and fructose in isolated rat hepatocytes. Diabetes. 1992 Jan;41(1):22–25. doi: 10.2337/diab.41.1.22. [DOI] [PubMed] [Google Scholar]
  3. Bonny C., Thompson N., Nicod P., Waeber G. Pancreatic-specific expression of the glucose transporter type 2 gene: identification of cis-elements and islet-specific trans-acting factors. Mol Endocrinol. 1995 Oct;9(10):1413–1426. doi: 10.1210/mend.9.10.8544849. [DOI] [PubMed] [Google Scholar]
  4. Bontemps F., Hue L., Hers H. G. Phosphorylation of glucose in isolated rat hepatocytes. Sigmoidal kinetics explained by the activity of glucokinase alone. Biochem J. 1978 Aug 15;174(2):603–611. doi: 10.1042/bj1740603. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Brichard S. M., Desbuquois B., Girard J. Vanadate treatment of diabetic rats reverses the impaired expression of genes involved in hepatic glucose metabolism: effects on glycolytic and gluconeogenic enzymes, and on glucose transporter GLUT2. Mol Cell Endocrinol. 1993 Feb;91(1-2):91–97. doi: 10.1016/0303-7207(93)90259-m. [DOI] [PubMed] [Google Scholar]
  6. Brichard S. M., Henquin J. C., Girard J. Phlorizin treatment of diabetic rats partially reverses the abnormal expression of genes involved in hepatic glucose metabolism. Diabetologia. 1993 Apr;36(4):292–298. doi: 10.1007/BF00400230. [DOI] [PubMed] [Google Scholar]
  7. Burcelin R., Eddouks M., Kande J., Assan R., Girard J. Evidence that GLUT-2 mRNA and protein concentrations are decreased by hyperinsulinaemia and increased by hyperglycaemia in liver of diabetic rats. Biochem J. 1992 Dec 1;288(Pt 2):675–679. doi: 10.1042/bj2880675. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Decaux J. F., Antoine B., Kahn A. Regulation of the expression of the L-type pyruvate kinase gene in adult rat hepatocytes in primary culture. J Biol Chem. 1989 Jul 15;264(20):11584–11590. [PubMed] [Google Scholar]
  11. Doiron B., Cuif M. H., Kahn A., Diaz-Guerra M. J. Respective roles of glucose, fructose, and insulin in the regulation of the liver-specific pyruvate kinase gene promoter. J Biol Chem. 1994 Apr 8;269(14):10213–10216. [PubMed] [Google Scholar]
  12. Ferrer J., Gomis R., Fernández Alvarez J., Casamitjana R., Vilardell E. Signals derived from glucose metabolism are required for glucose regulation of pancreatic islet GLUT2 mRNA and protein. Diabetes. 1993 Sep;42(9):1273–1280. doi: 10.2337/diab.42.9.1273. [DOI] [PubMed] [Google Scholar]
  13. Foufelle F., Gouhot B., Pégorier J. P., Perdereau D., Girard J., Ferré P. Glucose stimulation of lipogenic enzyme gene expression in cultured white adipose tissue. A role for glucose 6-phosphate. J Biol Chem. 1992 Oct 15;267(29):20543–20546. [PubMed] [Google Scholar]
  14. Giffhorn-Katz S., Katz N. R. Carbohydrate-dependent induction of fatty acid synthase in primary cultures of rat hepatocytes. Eur J Biochem. 1986 Sep 15;159(3):513–518. doi: 10.1111/j.1432-1033.1986.tb09916.x. [DOI] [PubMed] [Google Scholar]
  15. Gorman C. M., Moffat L. F., Howard B. H. Recombinant genomes which express chloramphenicol acetyltransferase in mammalian cells. Mol Cell Biol. 1982 Sep;2(9):1044–1051. doi: 10.1128/mcb.2.9.1044. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Jenkins A. B., Furler S. M., Kraegen E. W. 2-deoxy-D-glucose metabolism in individual tissues of the rat in vivo. Int J Biochem. 1986;18(4):311–318. doi: 10.1016/0020-711x(86)90036-4. [DOI] [PubMed] [Google Scholar]
  17. Lefrançois-Martinez A. M., Diaz-Guerra M. J., Vallet V., Kahn A., Antoine B. Glucose-dependent regulation of the L-pyruvate kinase gene in a hepatoma cell line is independent of insulin and cyclic AMP. FASEB J. 1994 Jan;8(1):89–96. doi: 10.1096/fasebj.8.1.8299894. [DOI] [PubMed] [Google Scholar]
  18. Lefrançois-Martinez A. M., Martinez A., Antoine B., Raymondjean M., Kahn A. Upstream stimulatory factor proteins are major components of the glucose response complex of the L-type pyruvate kinase gene promoter. J Biol Chem. 1995 Feb 10;270(6):2640–2643. doi: 10.1074/jbc.270.6.2640. [DOI] [PubMed] [Google Scholar]
  19. Leloup C., Arluison M., Lepetit N., Cartier N., Marfaing-Jallat P., Ferré P., Pénicaud L. Glucose transporter 2 (GLUT 2): expression in specific brain nuclei. Brain Res. 1994 Feb 28;638(1-2):221–226. doi: 10.1016/0006-8993(94)90653-x. [DOI] [PubMed] [Google Scholar]
  20. Levrat F., Vallet V., Berbar T., Miquerol L., Kahn A., Antoine B. Influence of the content in transcription factors on the phenotype of mouse hepatocyte-like cell lines (mhAT). Exp Cell Res. 1993 Dec;209(2):307–316. doi: 10.1006/excr.1993.1315. [DOI] [PubMed] [Google Scholar]
  21. Melloul D., Ben-Neriah Y., Cerasi E. Glucose modulates the binding of an islet-specific factor to a conserved sequence within the rat I and the human insulin promoters. Proc Natl Acad Sci U S A. 1993 May 1;90(9):3865–3869. doi: 10.1073/pnas.90.9.3865. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Ohneda M., Johnson J. H., Inman L. R., Chen L., Suzuki K., Goto Y., Alam T., Ravazzola M., Orci L., Unger R. H. GLUT2 expression and function in beta-cells of GK rats with NIDDM. Dissociation between reductions in glucose transport and glucose-stimulated insulin secretion. Diabetes. 1993 Jul;42(7):1065–1072. doi: 10.2337/diab.42.7.1065. [DOI] [PubMed] [Google Scholar]
  23. Orci L., Ravazzola M., Baetens D., Inman L., Amherdt M., Peterson R. G., Newgard C. B., Johnson J. H., Unger R. H. Evidence that down-regulation of beta-cell glucose transporters in non-insulin-dependent diabetes may be the cause of diabetic hyperglycemia. Proc Natl Acad Sci U S A. 1990 Dec;87(24):9953–9957. doi: 10.1073/pnas.87.24.9953. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Postic C., Burcelin R., Rencurel F., Pegorier J. P., Loizeau M., Girard J., Leturque A. Evidence for a transient inhibitory effect of insulin on GLUT2 expression in the liver: studies in vivo and in vitro. Biochem J. 1993 Jul 1;293(Pt 1):119–124. doi: 10.1042/bj2930119. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Postic C., Leturque A., Rencurel F., Printz R. L., Forest C., Granner D. K., Girard J. The effects of hyperinsulinemia and hyperglycemia on GLUT4 and hexokinase II mRNA and protein in rat skeletal muscle and adipose tissue. Diabetes. 1993 Jun;42(6):922–929. doi: 10.2337/diab.42.6.922. [DOI] [PubMed] [Google Scholar]
  26. Thorens B., Flier J. S., Lodish H. F., Kahn B. B. Differential regulation of two glucose transporters in rat liver by fasting and refeeding and by diabetes and insulin treatment. Diabetes. 1990 Jun;39(6):712–719. doi: 10.2337/diab.39.6.712. [DOI] [PubMed] [Google Scholar]
  27. Thorens B., Sarkar H. K., Kaback H. R., Lodish H. F. Cloning and functional expression in bacteria of a novel glucose transporter present in liver, intestine, kidney, and beta-pancreatic islet cells. Cell. 1988 Oct 21;55(2):281–290. doi: 10.1016/0092-8674(88)90051-7. [DOI] [PubMed] [Google Scholar]
  28. Thorens B., Weir G. C., Leahy J. L., Lodish H. F., Bonner-Weir S. Reduced expression of the liver/beta-cell glucose transporter isoform in glucose-insensitive pancreatic beta cells of diabetic rats. Proc Natl Acad Sci U S A. 1990 Sep;87(17):6492–6496. doi: 10.1073/pnas.87.17.6492. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Thorens B., Wu Y. J., Leahy J. L., Weir G. C. The loss of GLUT2 expression by glucose-unresponsive beta cells of db/db mice is reversible and is induced by the diabetic environment. J Clin Invest. 1992 Jul;90(1):77–85. doi: 10.1172/JCI115858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Vaulont S., Munnich A., Decaux J. F., Kahn A. Transcriptional and post-transcriptional regulation of L-type pyruvate kinase gene expression in rat liver. J Biol Chem. 1986 Jun 15;261(17):7621–7625. [PubMed] [Google Scholar]
  31. Waeber G., Pedrazzini T., Bonny O., Bonny C., Steinmann M., Nicod P., Haefliger J. A. A 338-bp proximal fragment of the glucose transporter type 2 (GLUT2) promoter drives reporter gene expression in the pancreatic islets of transgenic mice. Mol Cell Endocrinol. 1995 Oct 30;114(1-2):205–215. doi: 10.1016/0303-7207(95)96801-n. [DOI] [PubMed] [Google Scholar]
  32. Waeber G., Thompson N., Haefliger J. A., Nicod P. Characterization of the murine high Km glucose transporter GLUT2 gene and its transcriptional regulation by glucose in a differentiated insulin-secreting cell line. J Biol Chem. 1994 Oct 28;269(43):26912–26919. [PubMed] [Google Scholar]
  33. Walker D. G., Holland G. The development of hepatic glucokinase in the neonatal rat. Biochem J. 1965 Dec;97(3):845–854. doi: 10.1042/bj0970845. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Yasuda K., Yamada Y., Inagaki N., Yano H., Okamoto Y., Tsuji K., Fukumoto H., Imura H., Seino S., Seino Y. Expression of GLUT1 and GLUT2 glucose transporter isoforms in rat islets of Langerhans and their regulation by glucose. Diabetes. 1992 Jan;41(1):76–81. doi: 10.2337/diab.41.1.76. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES