Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy
Abstract
Glucokinase (GK) plays a key role in whole-body glucose homeostasis by catalyzing the phosphorylation of glucose in cells that express this enzyme, such as pancreatic β cells and hepatocytes. We describe a class of antidiabetic agents that act as nonessential, mixed-type GK activators (GKAs) that increase the glucose affinity and maximum velocity (Vmax) of GK. GKAs augment both hepatic glucose metabolism and glucose-induced insulin secretion from isolated rodent pancreatic islets, consistent with the expression and function of GK in both cell types. In several rodent models of type 2 diabetes mellitus, GKAs lowered blood glucose levels, improved the results of glucose tolerance tests, and increased hepatic glucose uptake. These findings may lead to the development of new drug therapies for diabetes.
Get full access to this article
View all available purchase options and get full access to this article.
Supplementary Material
File (grimsby.som.pdf)
References and Notes
1
R. A. DeFronzo, Diabetes37, 667 (1988).
2
C. R. Kahn, Diabetes43, 1066 (1994).
3
N. Vionnetet al., Nature356, 721 (1992).
4
G. I. Bellet al., in Encyclopedia of Molecular Medicine, H. H. Kazazian et al., Eds. (Wiley, New York, 2002), pp. 1437–1442.
5
G. Velhoet al., J. Clin. Invest.98, 1755 (1996).
6
K. Clementet al., Diabetologia39, 82 (1996).
7
E. A. Daviset al., Diabetologia42, 1175 (1999).
8
Y. Lianget al., Biochem. J.309, 167 (1995).
9
J. Takedaet al., J. Biol. Chem.268, 15200 (1993).
10
M. Gidh-Jainet al., Proc. Natl. Acad. Sci. U.S.A.90, 1932 (1993).
11
S. P. Milleret al., Diabetes48, 1645 (1999).
12
B. Glaseret al., N. Engl. J. Med.338, 226 (1998).
13
H. B. Christesenet al., Diabetes51, 1240 (2002).
14
See supporting data on Science Online.
15
J. Grimsbyet al., unpublished data.
16
T. Ferre, A. Pujol, E. Riu, F. Bosch, A. Valera, Proc. Natl. Acad. Sci. U.S.A.93, 7225 (1996).
17
M. Shiotaet al., Diabetes50, 622 (2001).
18
U. J. Desaiet al., Diabetes50, 2287 (2001).
19
N. Morralet al., Hum. Gene Ther.13, 1561 (2002).
20
F. M. Matschinsky, Diabetes45, 223 (1996).
21
I. H. Segel, Enzyme Kinetics: Behavior and Analysis of Rapid Equilibrium and Steady-State Enzyme Systems (Wiley, New York, 1993), pp. 227–231.
22
I. R. Sweet, G. Li, H. Najafi, D. Berner, F. M. Matschinsky, Am. J. Physiol.271, E606 (1996).
23
We thank L. Ping, S. Tannu, D. Lucas-McGady, and A. Aglione for biological characterization; N. Doliba and M. Vatamaniuk for islet studies; and J. Sterner for editorial comments.
(0)eLetters
eLetters is an online forum for ongoing peer review. Submission of eLetters are open to all. eLetters are not edited, proofread, or indexed. Please read our Terms of Service before submitting your own eLetter.
Log In to Submit a ResponseNo eLetters have been published for this article yet.
Information & Authors
Information
Published In
Science
Volume 301 | Issue 5631
18 July 2003
18 July 2003
Copyright
American Association for the Advancement of Science.
Submission history
Received: 3 March 2003
Accepted: 13 June 2003
Published in print: 18 July 2003
Notes
Supporting Online Material
www.sciencemag.org/cgi/content/full/301/5631/370/DC1
Materials and Methods
Figs. S1 to S6
Table S1
References
Authors
Metrics & Citations
Metrics
Article Usage
Altmetrics
Citations
Export citation
Select the format you want to export the citation of this publication.
Cited by
- Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats, Science Translational Medicine, 14, 668, (2022)./doi/10.1126/scitranslmed.abh1316
- Energy Metabolism | Hexokinase/Glucokinase, Encyclopedia of Biological Chemistry III, (149-161), (2021).https://doi.org/10.1016/B978-0-12-819460-7.00034-7
- Glucokinase Inactivation Paradoxically Ameliorates Glucose Intolerance by Increasing β-Cell Mass in db/db Mice , Diabetes, 70, 4, (917-931), (2021).https://doi.org/10.2337/db20-0881
- Dual-specificity phosphatase 3 deletion promotes obesity, non-alcoholic steatohepatitis and hepatocellular carcinoma, Scientific Reports, 11, 1, (2021).https://doi.org/10.1038/s41598-021-85089-6
- Genetic activation of α-cell glucokinase in mice causes enhanced glucose-suppression of glucagon secretion during normal and diabetic states, Molecular Metabolism, 49, (101193), (2021).https://doi.org/10.1016/j.molmet.2021.101193
- Three‐Component Alkene Difunctionalization by Direct and Selective Activation of Aliphatic C−H Bonds, Angewandte Chemie International Edition, 60, 13, (7405-7411), (2021).https://doi.org/10.1002/anie.202014632
- Three‐Component Alkene Difunctionalization by Direct and Selective Activation of Aliphatic C−H Bonds, Angewandte Chemie, 133, 13, (7481-7487), (2021).https://doi.org/10.1002/ange.202014632
- Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure, Science, 331, 6023, (1439-1443), (2021)./doi/10.1126/science.1200113
- Glucokinase activation or inactivation: Which will lead to the treatment of type 2 diabetes?, Diabetes, Obesity and Metabolism, (2021).https://doi.org/10.1111/dom.14459
- The novel GCK variant p.Val455Leu associated with hyperinsulinism is susceptible to allosteric activation and is conducive to weight gain and the development of diabetes, Diabetologia, (2021).https://doi.org/10.1007/s00125-021-05553-w
- See more
Loading...
View Options
Check Access
Log in to view the full text
AAAS login provides access to Science for AAAS Members, and access to other journals in the Science family to users who have purchased individual subscriptions.
- Become a AAAS Member
- Activate your AAAS ID
- Purchase Access to Other Journals in the Science Family
- Account Help
Log in via OpenAthens.
Log in via Shibboleth.
More options
Purchase digital access to this article
Download and print this article for your personal scholarly, research, and educational use.
Buy a single issue of Science for just $15 USD.