|
 |
|
|||||||
|
|||||||||
Diabetes 53:535-541, 2004
© 2004 by the American Diabetes Association, Inc.
Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators
1 Cardiovascular and Gastrointestinal Department, AstraZeneca, Macclesfield, Cheshire, U.K
2 Department of Diabetes, School of Clinical Medical Sciences, University of Newcastle upon Tyne, Newcastle upon Tyne, U.K
Glucokinase (GK) has a major role in the control of blood glucose homeostasis and is a strong potential target for the pharmacological treatment of type 2 diabetes. We report here the mechanism of action of two novel and potent direct activators of GK: 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]nicotinic acid(GKA1) and 5-({3-isopropoxy-5-[2-(3-thienyl)ethoxy]benzoyl}amino)-1,3,4-thiadiazole-2-carboxylic acid(GKA2), which increase the affinity of GK for glucose by 4- and 11-fold, respectively. GKA1 increased the affinity of GK for the competitive inhibitor mannoheptulose but did not affect the affinity for the inhibitors palmitoyl-CoA and the endogenous 68-kDa regulator (GK regulatory protein [GKRP]), which bind to allosteric sites or to N-acetylglucosamine, which binds to the catalytic site. In hepatocytes, GKA1 and GKA2 stimulated glucose phosphorylation, glycolysis, and glycogen synthesis to a similar extent as sorbitol, a precursor of fructose 1-phosphate, which indirectly activates GK through promoting its dissociation from GKRP. Consistent with their effects on isolated GK, these compounds also increased the affinity of hepatocyte metabolism for glucose. GKA1 and GKA2 caused translocation of GK from the nucleus to the cytoplasm. This effect was additive with the effect of sorbitol and is best explained by a "glucose-like" effect of the GK activators in translocating GK to the cytoplasm. In conclusion, GK activators are potential antihyperglycemic agents for the treatment of type 2 diabetes through the stimulation of hepatic glucose metabolism by a mechanism independent of GKRP.
Address correspondence and reprint requests to Dr. Loranne Agius, University of Newcastle, Department of Diabetes, Medical School, Framlington Place, Newcastle upon Tyne, NE2 4HH, U.K. E-mail: loranne.agius{at}ncl.ac.uk
CiteULike 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  V. A. Payne, C. Arden, A. J. Lange, and L. Agius Contributions of glucokinase and phosphofructokinase-2/fructose bisphosphatase-2 to the elevated glycolysis in hepatocytes from Zucker fa/fa rats Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2007; 293(2): R618 - R625. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. Arden, A. Trainer, N. de la Iglesia, K. T. Scougall, A. L. Gloyn, A. J. Lange, J. A.M. Shaw, F. M. Matschinsky, and L. Agius Cell Biology Assessment of Glucokinase Mutations V62M and G72R in Pancreatic {beta}-Cells: Evidence for Cellular Instability of Catalytic Activity Diabetes, July 1, 2007; 56(7): 1773 - 1782. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Johnson, R. M. Shepherd, D. Gill, T. Gorman, D. M. Smith, and M. J. Dunne Glucose-Dependent Modulation of Insulin Secretion and Intracellular Calcium Ions by GKA50, a Glucokinase Activator Diabetes, June 1, 2007; 56(6): 1694 - 1702. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Lange For the ZDF rat, "Breaking Up Is Hard To Do": dissociation of the GK:GKRP complex Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2007; 292(4): R1379 - R1380. [Full Text] [PDF]
|
|
|
|
 |
|
 V. V. Heredia, T. J. Carlson, E. Garcia, and S. Sun Biochemical Basis of Glucokinase Activation and the Regulation by Glucokinase Regulatory Protein in Naturally Occurring Mutations J. Biol. Chem., December 29, 2006; 281(52): 40201 - 40207. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Futamura, H. Hosaka, A. Kadotani, H. Shimazaki, K. Sasaki, S. Ohyama, T. Nishimura, J.-i. Eiki, and Y. Nagata An Allosteric Activator of Glucokinase Impairs the Interaction of Glucokinase and Glucokinase Regulatory Protein and Regulates Glucose Metabolism J. Biol. Chem., December 8, 2006; 281(49): 37668 - 37674. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Baltrusch, S. Langer, L. Massa, M. Tiedge, and S. Lenzen Improved Metabolic Stimulus for Glucose-Induced Insulin Secretion through GK and PFK-2/FBPase-2 Coexpression in Insulin-Producing RINm5F Cells Endocrinology, December 1, 2006; 147(12): 5768 - 5776. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Baltrusch and M. Tiedge Glucokinase Regulatory Network in Pancreatic {beta}-Cells and Liver Diabetes, December 1, 2006; 55(Supplement_2): S55 - S64. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Zhang, C. Li, K. Chen, W. Zhu, X. Shen, and H. Jiang Conformational transition pathway in the allosteric process of human glucokinase PNAS, September 5, 2006; 103(36): 13368 - 13373. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. V. Sagen, S. Odili, L. Bjorkhaug, D. Zelent, C. Buettger, J. Kwagh, C. Stanley, K. Dahl-Jorgensen, C. de Beaufort, G. I. Bell, et al. From Clinicogenetic Studies of Maturity-Onset Diabetes of the Young to Unraveling Complex Mechanisms of Glucokinase Regulation Diabetes, June 1, 2006; 55(6): 1713 - 1722. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Guigas, L. Bertrand, N. Taleux, M. Foretz, N. Wiernsperger, D. Vertommen, F. Andreelli, B. Viollet, and L. Hue 5-Aminoimidazole-4-Carboxamide-1-{beta}-D-Ribofuranoside and Metformin Inhibit Hepatic Glucose Phosphorylation by an AMP-Activated Protein Kinase-Independent Effect on Glucokinase Translocation. Diabetes, April 1, 2006; 55(4): 865 - 874. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Baltrusch, F. Francini, S. Lenzen, and M. Tiedge Interaction of Glucokinase With the Liver Regulatory Protein Is Conferred by Leucine-Asparagine Motifs of the Enzyme Diabetes, October 1, 2005; 54(10): 2829 - 2837. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. L. Printz and D. K. Granner Tweaking the Glucose Sensor: Adjusting Glucokinase Activity with Activator Compounds Endocrinology, September 1, 2005; 146(9): 3693 - 3695. [Full Text] [PDF]
|
|
|
|
|
|
A. M. Efanov, D. G. Barrett, M. B. Brenner, S. L. Briggs, A. Delaunois, J. D. Durbin, U. Giese, H. Guo, M. Radloff, G. S. Gil, et al. A Novel Glucokinase Activator Modulates Pancreatic Islet and Hepatocyte Function Endocrinology, September 1, 2005; 146(9): 3696 - 3701. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Pedelini, M. A. Garcia-Gimeno, A. Marina, J. M. Gomez-Zumaquero, P. Rodriguez-Bada, S. Lopez-Enriquez, F. C. Soriguer, A. L. Cuesta-Munoz, and P. Sanz Structure--function analysis of the {alpha}5 and the {alpha}13 helices of human glucokinase: Description of two novel activating mutations Protein Sci., August 1, 2005; 14(8): 2080 - 2086. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. A. Payne, C. Arden, C. Wu, A. J. Lange, and L. Agius Dual Role of Phosphofructokinase-2/Fructose Bisphosphatase-2 in Regulating the Compartmentation and Expression of Glucokinase in Hepatocytes Diabetes, July 1, 2005; 54(7): 1949 - 1957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Gloyn, S. Odili, D. Zelent, C. Buettger, H. A. J. Castleden, A. M. Steele, A. Stride, C. Shiota, M. A. Magnuson, R. Lorini, 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., April 8, 2005; 280(14): 14105 - 14113. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. J. Hampson and L. Agius Increased Potency and Efficacy of Combined Phosphorylase Inactivation and Glucokinase Activation in Control of Hepatocyte Glycogen Metabolism Diabetes, March 1, 2005; 54(3): 617 - 623. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Diabetes | Diabetes Care | Clinical Diabetes | Diabetes Spectrum |