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Science 301 (5631): 370-373

Copyright © 2003 by the American Association for the Advancement of Science

Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy

Joseph Grimsby,1 Ramakanth Sarabu,1 Wendy L. Corbett,1 Nancy-Ellen Haynes,1 Fred T. Bizzarro,1 John W. Coffey,1 Kevin R. Guertin,1 Darryl W. Hilliard,1* Robert F. Kester,1 Paige E. Mahaney,1{dagger} Linda Marcus,1 Lida Qi,1 Cheryl L. Spence,1 John Tengi,1 Mark A. Magnuson,2 Chang An Chu,1 Mark T. Dvorozniak,1 Franz M. Matschinsky,3 Joseph F. Grippo1{ddagger}

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 ß 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.

1 Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. 2 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232, USA. 3 Department of Biochemistry and Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, USA.

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* Present address: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285, USA.

{dagger} Present address: Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA.

{ddagger} To whom correspondence should be addressed. E-mail: joseph.grippo{at}

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Diabetes 53, 1942-1948
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G(-30)A Polymorphism in the Pancreatic Promoter of the Glucokinase Gene Associated With Angiographic Coronary Artery Disease and Type 2 Diabetes Mellitus.
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Hepatic Glucokinase Is Required for the Synergistic Action of ChREBP and SREBP-1c on Glycolytic and Lipogenic Gene Expression.
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Diabetes 53, 1020-1029
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Stimulation of Hepatocyte Glucose Metabolism by Novel Small Molecule Glucokinase Activators.
K. J. Brocklehurst, V. A. Payne, R. A. Davies, D. Carroll, H. L. Vertigan, H. J. Wightman, S. Aiston, I. D. Waddell, B. Leighton, M. P. Coghlan, et al. (2004)
Diabetes 53, 535-541
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Permanent Neonatal Diabetes Caused by Glucokinase Deficiency: Inborn Error of the Glucose-Insulin Signaling Pathway.
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