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Gene Review

Gck  -  glucokinase

Mus musculus

Synonyms: GLK, Gk, Gls006, Glucokinase, HK IV, ...
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Disease relevance of Gck

  • This study has confirmed the results of a previous report that human subjects carrying mutations in Gck had reduced birth weights and has provided direct evidence for a link between insulin and fetal growth [1].
  • GLK-deficient mice die perinatally with severe hyperglycemia [2].
  • Patients with maturity-onset diabetes of the young (MODY) have heterozygous point mutations in the glucokinase gene that result in reduced enzymatic activity and decreased insulin secretion [3].
  • Glucokinase (GK) gene mutations cause diabetes mellitus in both humans and mouse models, but the pathophysiological basis is only partially defined [4].
  • These defects were not due to a decrease in glucokinase or insulin gene transcription. beta cell mass adjusted for body weight was not reduced in the (-/-) animals, although pancreatic insulin content adjusted for pancreas weight was slightly lower (0.06+/-0.01 vs. 0.10+/-0.01 microg/mg, P < 0.01) than in the (+/+) animals [5].

High impact information on Gck


Chemical compound and disease context of Gck


Biological context of Gck


Anatomical context of Gck

  • To determine whether the effect of SREBP-1c requires GK expression and subsequent glucose metabolism, a transcriptionally active form of SREBP-1c was overexpressed both in vivo and in primary cultures of control and hGK-KO hepatocytes [11].
  • Insulin regulates GK activity by modulating its association with secretory granules, although little is known about the mechanisms involved in regulating this association [13].
  • We used MIN6 insulin-secretory cells and organelle fractionation to determine the effects of glucose on the subcellular distribution of glucokinase [14].
  • A construct containing 1,000 bp of 5'-flanking DNA was efficiently expressed in HIT M2.2.2 cells, a beta-cell-derived line that makes both insulin and glucokinase, but not in NIH 3T3 cells, a heterologous cell line [15].
  • The present study was undertaken to test the hypothesis that exposure to high glucose concentrations enhances insulin secretion in pancreatic islets from glucokinase-deficient mice [16].

Associations of Gck with chemical compounds

  • Heterozygous mice with beta cell glucokinase (GK) gene knockout showed impaired glucose tolerance due to decreased insulin secretion to glucose [10].
  • Mutation of cysteine 371 to serine blocks S-nitrosylation of GK and causes GK to remain tightly bound to secretory granules [13].
  • We show here that overexpressing SREBP-1c specifically in the liver of diabetic mice induces GK and lipogenic enzyme gene expression and represses the expression of phosphoenolpyruvate carboxykinase, a key enzyme of the gluconeogenic pathway [17].
  • Positional candidate gene analyses revealed an A to T transversion mutation in exon 9 of the glucokinase gene, resulting in an isoleucine to phenylalanine change at amino acid 366 (I366F) [18].
  • GK-deficient islets isolated from homozygotes showed defective insulin secretion in response to glucose, while they responded to other secretagogues: almost normally to arginine and to some extent to sulfonylureas [19].

Physical interactions of Gck


Co-localisations of Gck

  • Subfractionation of the insulin granule components by hypotonic lysis followed by sucrose gradient centrifugation showed that glucokinase colocalized with the granule membrane marker phogrin and not with insulin [14].

Regulatory relationships of Gck


Other interactions of Gck

  • Inactivation of the hnf6 gene did not modify the pattern of deoxyribonuclease I hypersensitive sites but was associated with a decrease of liver glucokinase mRNA to half the control value [12].
  • BAD is required to assemble the complex in that Bad-deficient hepatocytes lack this complex, resulting in diminished mitochondria-based glucokinase activity and blunted mitochondrial respiration in response to glucose [23].
  • Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose [19].
  • Reduced islet glucokinase activity causes mildly elevated fasting blood glucose levels [3].
  • The plasma insulin concentration was also lower in the GK transgenic animals (232 +/- 79 pmol/l) than in the controls (595 +/- 77 pmol/l), but there was no difference in plasma glucagon concentrations [24].

Analytical, diagnostic and therapeutic context of Gck


  1. Insulin effect during embryogenesis determines fetal growth: a possible molecular link between birth weight and susceptibility to type 2 diabetes. Terauchi, Y., Kubota, N., Tamemoto, H., Sakura, H., Nagai, R., Akanuma, Y., Kimura, S., Kadowaki, T. Diabetes (2000) [Pubmed]
  2. Transgenic knockouts reveal a critical requirement for pancreatic beta cell glucokinase in maintaining glucose homeostasis. Grupe, A., Hultgren, B., Ryan, A., Ma, Y.H., Bauer, M., Stewart, T.A. Cell (1995) [Pubmed]
  3. Animal model for maturity-onset diabetes of the young generated by disruption of the mouse glucokinase gene. Bali, D., Svetlanov, A., Lee, H.W., Fusco-DeMane, D., Leiser, M., Li, B., Barzilai, N., Surana, M., Hou, H., Fleischer, N. J. Biol. Chem. (1995) [Pubmed]
  4. Dual roles for glucokinase in glucose homeostasis as determined by liver and pancreatic beta cell-specific gene knock-outs using Cre recombinase. Postic, C., Shiota, M., Niswender, K.D., Jetton, T.L., Chen, Y., Moates, J.M., Shelton, K.D., Lindner, J., Cherrington, A.D., Magnuson, M.A. J. Biol. Chem. (1999) [Pubmed]
  5. Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. Pontoglio, M., Sreenan, S., Roe, M., Pugh, W., Ostrega, D., Doyen, A., Pick, A.J., Baldwin, A., Velho, G., Froguel, P., Levisetti, M., Bonner-Weir, S., Bell, G.I., Yaniv, M., Polonsky, K.S. J. Clin. Invest. (1998) [Pubmed]
  6. NeuroD-betacellulin gene therapy induces islet neogenesis in the liver and reverses diabetes in mice. Kojima, H., Fujimiya, M., Matsumura, K., Younan, P., Imaeda, H., Maeda, M., Chan, L. Nat. Med. (2003) [Pubmed]
  7. A dominant role for glucose in beta cell compensation of insulin resistance. Weir, G.C., Bonner-Weir, S. J. Clin. Invest. (2007) [Pubmed]
  8. Disruption of hepatic C/EBPalpha results in impaired glucose tolerance and age-dependent hepatosteatosis. Inoue, Y., Inoue, J., Lambert, G., Yim, S.H., Gonzalez, F.J. J. Biol. Chem. (2004) [Pubmed]
  9. Systemic treatment with sympatholytic dopamine agonists improves aberrant beta-cell hyperplasia and GLUT2, glucokinase, and insulin immunoreactive levels in ob/ob mice. Jetton, T.L., Liang, Y., Cincotta, A.H. Metab. Clin. Exp. (2001) [Pubmed]
  10. Development of non-insulin-dependent diabetes mellitus in the double knockout mice with disruption of insulin receptor substrate-1 and beta cell glucokinase genes. Genetic reconstitution of diabetes as a polygenic disease. Terauchi, Y., Iwamoto, K., Tamemoto, H., Komeda, K., Ishii, C., Kanazawa, Y., Asanuma, N., Aizawa, T., Akanuma, Y., Yasuda, K., Kodama, T., Tobe, K., Yazaki, Y., Kadowaki, T. J. Clin. Invest. (1997) [Pubmed]
  11. Hepatic glucokinase is required for the synergistic action of ChREBP and SREBP-1c on glycolytic and lipogenic gene expression. Dentin, R., Pégorier, J.P., Benhamed, F., Foufelle, F., Ferré, P., Fauveau, V., Magnuson, M.A., Girard, J., Postic, C. J. Biol. Chem. (2004) [Pubmed]
  12. Liver glucokinase gene expression is controlled by the onecut transcription factor hepatocyte nuclear factor-6. Lannoy, V.J., Decaux, J.F., Pierreux, C.E., Lemaigre, F.P., Rousseau, G.G. Diabetologia (2002) [Pubmed]
  13. Regulation of beta cell glucokinase by S-nitrosylation and association with nitric oxide synthase. Rizzo, M.A., Piston, D.W. J. Cell Biol. (2003) [Pubmed]
  14. Glucokinase is an integral component of the insulin granules in glucose-responsive insulin secretory cells and does not translocate during glucose stimulation. Arden, C., Harbottle, A., Baltrusch, S., Tiedge, M., Agius, L. Diabetes (2004) [Pubmed]
  15. Multiple elements in the upstream glucokinase promoter contribute to transcription in insulinoma cells. Shelton, K.D., Franklin, A.J., Khoor, A., Beechem, J., Magnuson, M.A. Mol. Cell. Biol. (1992) [Pubmed]
  16. Adaptation to hyperglycemia enhances insulin secretion in glucokinase mutant mice. Sreenan, S.K., Cockburn, B.N., Baldwin, A.C., Ostrega, D.M., Levisetti, M., Grupe, A., Bell, G.I., Stewart, T.A., Roe, M.W., Polonsky, K.S. Diabetes (1998) [Pubmed]
  17. Adenovirus-mediated overexpression of sterol regulatory element binding protein-1c mimics insulin effects on hepatic gene expression and glucose homeostasis in diabetic mice. Bécard, D., Hainault, I., Azzout-Marniche, D., Bertry-Coussot, L., Ferré, P., Foufelle, F. Diabetes (2001) [Pubmed]
  18. A new mouse model of type 2 diabetes, produced by N-ethyl-nitrosourea mutagenesis, is the result of a missense mutation in the glucokinase gene. Toye, A.A., Moir, L., Hugill, A., Bentley, L., Quarterman, J., Mijat, V., Hough, T., Goldsworthy, M., Haynes, A., Hunter, A.J., Browne, M., Spurr, N., Cox, R.D. Diabetes (2004) [Pubmed]
  19. Pancreatic beta-cell-specific targeted disruption of glucokinase gene. Diabetes mellitus due to defective insulin secretion to glucose. Terauchi, Y., Sakura, H., Yasuda, K., Iwamoto, K., Takahashi, N., Ito, K., Kasai, H., Suzuki, H., Ueda, O., Kamada, N. J. Biol. Chem. (1995) [Pubmed]
  20. Inhibitory effects of streptozotocin, tumor necrosis factor-alpha, and interleukin-1beta on glucokinase activity in pancreatic islets and gene expression of GLUT2 and glucokinase. Park, C., Kim, J.R., Shim, J.K., Kang, B.S., Park, Y.G., Nam, K.S., Lee, Y.C., Kim, C.H. Arch. Biochem. Biophys. (1999) [Pubmed]
  21. Characterization of glucokinase regulatory protein-deficient mice. Grimsby, J., Coffey, J.W., Dvorozniak, M.T., Magram, J., Li, G., Matschinsky, F.M., Shiota, C., Kaur, S., Magnuson, M.A., Grippo, J.F. J. Biol. Chem. (2000) [Pubmed]
  22. Increasing fructose 2,6-bisphosphate overcomes hepatic insulin resistance of type 2 diabetes. Wu, C., Okar, D.A., Newgard, C.B., Lange, A.J. Am. J. Physiol. Endocrinol. Metab. (2002) [Pubmed]
  23. BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Danial, N.N., Gramm, C.F., Scorrano, L., Zhang, C.Y., Krauss, S., Ranger, A.M., Datta, S.R., Greenberg, M.E., Licklider, L.J., Lowell, B.B., Gygi, S.P., Korsmeyer, S.J. Nature (2003) [Pubmed]
  24. Glucokinase gene locus transgenic mice are resistant to the development of obesity-induced type 2 diabetes. Shiota, M., Postic, C., Fujimoto, Y., Jetton, T.L., Dixon, K., Pan, D., Grimsby, J., Grippo, J.F., Magnuson, M.A., Cherrington, A.D. Diabetes (2001) [Pubmed]
  25. Partial structure of the mouse glucokinase gene. Ishimura-Oka, K., Nakamuta, M., Chu, M.J., Sullivan, M., Chan, L., Oka, K. Genomics (1995) [Pubmed]
  26. Establishment of liver specific glucokinase gene knockout mice: a new animal model for screening anti-diabetic drugs. Zhang, Y.L., Tan, X.H., Xiao, M.F., Li, H., Mao, Y.Q., Yang, X., Tan, H.R. Acta Pharmacol. Sin. (2004) [Pubmed]
  27. A glucose sensor role for glucokinase in anterior pituitary cells. Zelent, D., Golson, M.L., Koeberlein, B., Quintens, R., van Lommel, L., Buettger, C., Weik-Collins, H., Taub, R., Grimsby, J., Schuit, F., Kaestner, K.H., Matschinsky, F.M. Diabetes (2006) [Pubmed]
  28. Reversal of type 1 diabetes by engineering a glucose sensor in skeletal muscle. Mas, A., Montané, J., Anguela, X.M., Muñoz, S., Douar, A.M., Riu, E., Otaegui, P., Bosch, F. Diabetes (2006) [Pubmed]
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