Skip to main content

Advertisement

SpringerLink
Log in

Glucokinase, glucose homeostasis, and diabetes mellitus

  • Published:
Current Diabetes Reports Aims and scope Submit manuscript

Abstract

The enzyme glucokinase (GK) regulates the rate of glucose metabolism in many tissues, including liver, the pancreatic â cells, certain neurons, enteroendocrine cells, and the pituitary, serving as a glucose sensor in many of these. Thus, GK plays a critical role in glucose homeostasis. Spontaneous mutants of GK in humans result in autosomaldominant hypo- and hyperglycemia syndromes described as "GK disease." GK activator drugs have been discovered that lower blood glucose in normal and diabetic animals and promise to be useful in the treatment of type 2 diabetes mellitus. There is no question that the GK molecule and related issues will continue to be a fruitful topic for future research.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Cardenas ML, ed: Glucokinase: Its Regulation and Role in Liver Metabolism. Austin, TX: R. G. Landes; 1995.

    Google Scholar 

  2. Cornish-Bowden A, ed: Fundamentals of Enzyme Kinetics, edn 3. London: Portland Press; 2003.

    Google Scholar 

  3. Vandercammen A, Detheux M, Van Schaftingen E: Binding of sorbitol 6-phosphate and fructose 1-phosphate to the regulatory protein of liver glucokinase. Biochem J 1992, 286:253–256.

    PubMed  CAS  Google Scholar 

  4. Cardenas ML: Comparative biochemistry of glucokinase. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:31–41.

    Chapter  Google Scholar 

  5. Grimsby J, Sarabu R, Corbett WL, et al.: Allosteric activators of glucokinase: potential role in diabetes therapy. Science 2003, 301:370–373. First detailed report of GKA drugs, which have considerable promise as new antidiabetic agents.

    Article  PubMed  CAS  Google Scholar 

  6. Dunten P, Swain A, Kammlott U, et al.: Crystal structure of human liver glucokinase bound to a small molecule allosteric activator. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:145–154.

    Chapter  Google Scholar 

  7. Kamata K, Mitsuya M, Nishimura T, et al.: Structural basis for allosteric regulation of the monomeric allosteric enzyme human glucokinase. Structure 2004, 12:429–438. Crystallographic study showing two distinct structural forms of GK and providing a stimulating discussion of implications.

    Article  PubMed  CAS  Google Scholar 

  8. Cornish-Bowden A, Cardenas ML: Glucokinase: a monomeric enzyme with positive cooperativity. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:125–134.

    Chapter  Google Scholar 

  9. Baltrusch S, Wu C, Okar DA, et al.: Interaction of GK with the bifunctional enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (6PF2K/F26P2ase). In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:262–274.

    Chapter  Google Scholar 

  10. Danial NN, Gramm CF, Scorrano L, et al.: BAD and glucokinase reside in a mitochondrial complex that integrates glycolysis and apoptosis. Nature 2003, 424:952–956.

    Article  PubMed  CAS  Google Scholar 

  11. Magnuson MA, Matschinsky FM: Glucokinase as a glucose sensor: past, present and future. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:1–17.

    Chapter  Google Scholar 

  12. Niculescu L, Veiga-da-Cunha M, VanSchaftingenE: Investigation on the mechanism by which fructose, hexitols and other compounds regulate the translocation of glucokinase in rat hepatocytes. Biochem J 1997, 321:239–246.

    PubMed  CAS  Google Scholar 

  13. Toyoda Y, Tsuchida A, Iwami E, et al.: Regulation of hepatic glucose metabolism by translocation of glucokinase between the nucleus and the cytoplasm in hepatocytes. Horm Metab Res 2001, 33:329–336.

    Article  PubMed  CAS  Google Scholar 

  14. Miwa I, Toyoda Y, Yoshie S: Glucokinase in cell insulinsecretory granules. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:350–359.

    Chapter  Google Scholar 

  15. Noma Y, Bonner-Weir S, Latimer JB, et al.: Translocation of glucokinase in pancreatic beta-cells during acute and chronic hyperglycemia. Endocrinology 1996, 137:1485–1491.

    Article  PubMed  CAS  Google Scholar 

  16. Toyoda Y, Yoshie S, Shironoguchi H, Miwa I: Glucokinase is concentrated in insulin-secretory granules. Histochem Cell Biol 1999, 112:35–40.

    Article  PubMed  CAS  Google Scholar 

  17. Bedoya FJ, Matschinsky FM, Shimizu T, et al.: Differential regulation of glucokinase activity in pancreatic islets and liver of the rat. J Biol Chem 1986, 261:10760–10764.

    PubMed  CAS  Google Scholar 

  18. Magnuson MA, Shelton KD: An alternate promoter in the glucokinase gene is active in the pancreatic beta cell. J Biol Chem 1989, 264:15936–15942.

    PubMed  CAS  Google Scholar 

  19. Magnuson MA: Glucokinase gene structure. Functional implications of molecular genetic studies. Diabetes 1990, 39:523–527.

    Article  PubMed  CAS  Google Scholar 

  20. Liang Y, Jetton TL, Zimmerman EC, et al.: Effects of alternate RNA splicing on glucokinase isoform activities in the pancreatic islet, liver, and pituitary. J Biol Chem 1991, 266:6999–7007.

    PubMed  CAS  Google Scholar 

  21. Hughes SD, Quaade C, Milburn JL, et al.: Expression of normal and novel glucokinase mRNAs in anterior pituitary and islet cells. J Biol Chem 1991, 266:4521–4530.

    PubMed  CAS  Google Scholar 

  22. Zelent D, Collins H, Grimsby J, et al.: Rat pituitary contains the glucokinase glucose sensor: biological and pharmacological implications. Presented at the 65th Annual ADA Scientific Sessions. San Diego, CA: June 10-14, 2005.

  23. Liang Y, Najafi H, Matschinsky FM: Glucose regulates glucokinase activity in cultured islets from rat pancreas. J Biol Chem 1990, 265:16863–16866.

    PubMed  CAS  Google Scholar 

  24. Collins HW, Najafi H, Buettger C, et al.: Identification of glucose response in two biological models of beta-cell adaptation to chronic high glucose exposure. J Biol Chem 1992, 267:1357–1366.

    PubMed  CAS  Google Scholar 

  25. Iynedjian PB: Molecular biology of glucokinase regulation. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:155–168.

    Chapter  Google Scholar 

  26. Postic C, Decaux J-F, Girard J: Regulation of hepatic glucokinase gene expression. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:180–192.

    Chapter  Google Scholar 

  27. Leibiger B, Berggren P-O, Leibiger IB: Regulation of beta-cell GK gene transcription by insulin. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:249–261.

    Chapter  Google Scholar 

  28. Zelent D, Najafi H, Odili S, et al.: Glucokinase and glucose homeostasis: proven concepts and new ideas. Biochem Soc Trans 2005, 33:306–310. Report showing for the first time the sigmoidal glucose dependency of GK induction in pancreatic islets and discussing the GK glucose sensor concept in a new light.

    Article  PubMed  CAS  Google Scholar 

  29. Iynedjian PB, Pilot PR, Nouspikel T, et al.: Differential expression and regulation of the glucokinase gene in liver and islets of Langerhans. Proc Natl Acad Sci U S A 1989, 86:7838–7842.

    Article  PubMed  CAS  Google Scholar 

  30. Matschinsky FM: Banting Lecture 1995. A lesson in metabolic regulation inspired by the glucokinase glucose sensor paradigm. Diabetes 1996, 45:223–241.

    Article  PubMed  CAS  Google Scholar 

  31. Bell GI, Cuesta-Munoz A, Matschinsky FM: Glucokinase.In Wiley Encyclopedia of Molecular Medicine (5-volume set). Edited by Kazazian HH. Hoboken, NJ: John Wiley & Sons; 2002:1437–1441.

    Google Scholar 

  32. Matschinsky FM: Regulation of pancreatic beta-cell glucokinase from basics to therapeutics. Diabetes 2002, 51:S394-S404.

    Article  PubMed  CAS  Google Scholar 

  33. Levin BE, Routh V, Sanders N, et al.: Anatomy, physiology and regulation of glucokinase as a brain glucosensor. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:301–312.

    Chapter  Google Scholar 

  34. Gloyn AL: Glucokinase (GCK) mutations in hyper- and hypoglycemia: maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemia of infancy. Hum Mutat 2003, 22:253–362.

    Article  Google Scholar 

  35. Gloyn AL, Odili S, Buettger C, et al.: Glucokinase and the regulation of blood sugar. In Glucokinase and Glycemic Disease: From Basics to Novel Therapeutics. Front Diabetes, vol 16. Edited by Matschinsky FM, Magnuson MA. Basel: Karger; 2004:92–109. Most up-to-date description of the mathematical model of pancreatic glucose sensor function.

    Chapter  Google Scholar 

  36. Gloyn AL, Odili S, Zelent D, et al.: Insights into the structure and regulation of glucokinase from a novel mutation (V62M) which causes maturity-onset diabetes of the young. J Biol Chem 2005 Jan 25; [Epub ahead of print]. Latest and most detailed biochemical genetic study of a GK mutant that causes MODY but is, paradoxically, activating.

  37. Glaser B, Kesavan P, Heyman M, et al.: Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med 1998, 338:226–230.

    Article  PubMed  CAS  Google Scholar 

  38. Christesen H, Jacobsen B, Odili S, et al.: The second activating glucokinase mutation (A456V): implications for glucose homeostasis and diabetes therapy. Diabetes 2002, 51:1240–1246.

    Article  PubMed  CAS  Google Scholar 

  39. Gloyn AL, Noordam K, Willemsen MA, et al.: Insights into the biochemical and genetic basis of glucokinase activation from naturally occurring hypoglycemia mutations. Diabetes 2003, 52:2433–2440. Latest and most current report on the biochemical genetics of activating mutations causing hyperinsulinemic hypoglycemia.

    Article  PubMed  CAS  Google Scholar 

  40. Sayed S, Hughes N, Kwagh J, et al.: Two novel mutations of glucokinase that cause recurrent hyperinsulinemic hypoglycemia. Presented at the GCRC National Meeting. Washington, D.C.: April 28, 2005.

  41. Brocklehurst KJ, Payne VA, Davies RA, et al.: Stimulation of hepatocyte glucose metabolism by novel small molecule glucokinase activators. Diabetes 2004, 53:535–541.

    Article  PubMed  CAS  Google Scholar 

  42. Toye AA, Moir L, Hugill A, et al.: 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. Diabetes 2004, 53:1577–1583.

    Article  PubMed  CAS  Google Scholar 

  43. Inoue M, Sakuraba Y, Motegi H, et al.: A series of maturity onset diabetes of the young, type 2 (MODY2) mouse models generated by a large-scale ENU mutagenesis program. Hum Mol Genet 2004, 13:1147–1157.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Biophysics, University of Pennsylvania Medical School, 501 Stemmler Hall, 36th & Hamilton Walk, 19104, Philadelphia, PA, USA

    Franz M. Matschinsky MD

Authors
  1. Franz M. Matschinsky MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Matschinsky, F.M. Glucokinase, glucose homeostasis, and diabetes mellitus. Curr Diab Rep 5, 171–176 (2005). https://doi.org/10.1007/s11892-005-0005-4

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11892-005-0005-4

Keywords

Search

Navigation