Advertisement

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J. Grimsbyet al., unpublished data.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 Response

No eLetters have been published for this article yet.

Information & Authors

Information

Published In

Science
Volume 301 | Issue 5631
18 July 2003

Submission history

Received: 3 March 2003
Accepted: 13 June 2003
Published in print: 18 July 2003

Permissions

Request permissions for this article.

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

Affiliations

Joseph Grimsby
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Ramakanth Sarabu
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Wendy L. Corbett
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Nancy-Ellen Haynes
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Fred T. Bizzarro
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
John W. Coffey
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Kevin R. Guertin
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Darryl W. Hilliard*
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Robert F. Kester
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Paige E. Mahaney
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Linda Marcus
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Lida Qi
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Cheryl L. Spence
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
John Tengi
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Mark A. Magnuson
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Chang An Chu
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Mark T. Dvorozniak
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Franz M. Matschinsky
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.
Joseph F. Grippo
Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

Notes

To whom correspondence should be addressed. E-mail: [email protected]

Metrics & Citations

Metrics

Article Usage
Altmetrics

Citations

Export citation

Select the format you want to export the citation of this publication.

Cited by

  1. Chronotherapy with a glucokinase activator profoundly improves metabolism in obese Zucker rats, Science Translational Medicine, 14, 668, (2022)./doi/10.1126/scitranslmed.abh1316
    Abstract
  2. Energy Metabolism | Hexokinase/Glucokinase, Encyclopedia of Biological Chemistry III, (149-161), (2021).https://doi.org/10.1016/B978-0-12-819460-7.00034-7
    Crossref
  3. 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
    Crossref
  4. 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
    Crossref
  5. 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
    Crossref
  6. 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
    Crossref
  7. 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
    Crossref
  8. Cardiac Myosin Activation: A Potential Therapeutic Approach for Systolic Heart Failure, Science, 331, 6023, (1439-1443), (2021)./doi/10.1126/science.1200113
    Abstract
  9. 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
    Crossref
  10. 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
    Crossref
  11. See more
Loading...

View Options

Check Access

Log in to view the full text

AAAS ID LOGIN

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.

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.

Purchase this issue in print

Buy a single issue of Science for just $15 USD.

View options

PDF format

Download this article as a PDF file

Download PDF

Full Text

FULL TEXT

Media

Figures

Multimedia

Tables

Share

Share

Share article link

Share on social media