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Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy
Joseph Grimsby,1Ramakanth Sarabu,1Wendy L. Corbett,1Nancy-Ellen Haynes,1Fred T. Bizzarro,1John W. Coffey,1Kevin R. Guertin,1Darryl W. Hilliard,1*Robert F. Kester,1Paige E. Mahaney,1Linda Marcus,1Lida Qi,1Cheryl L. Spence,1John Tengi,1Mark A. Magnuson,2Chang An Chu,1Mark T. Dvorozniak,1Franz M. Matschinsky,3Joseph F. Grippo1
Glucokinase (GK) plays a key role in whole-body glucose homeostasisby catalyzing the phosphorylation of glucose in cells that expressthis 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 affinityand maximum velocity (Vmax) of GK. GKAs augment both hepaticglucose metabolism and glucose-induced insulin secretion fromisolated rodent pancreatic islets, consistent with the expressionand function of GK in both cell types. In several rodent modelsof type 2 diabetes mellitus, GKAs lowered blood glucose levels,improved the results of glucose tolerance tests, and increasedhepatic glucose uptake. These findings may lead to the developmentof 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.
* Present address: Lilly Research Laboratories, Lilly CorporateCenter, Indianapolis, IN 46285, USA.
Present address: Chemical Sciences, Wyeth Research, 500 ArcolaRoad, Collegeville, PA 19426, USA.
To whom correspondence should be addressed. E-mail: joseph.grippo{at}roche.com
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Present address: Chemical Sciences, Wyeth Research, 500 Arcola Road, Collegeville, PA 19426, USA. 
To whom correspondence should be addressed. E-mail: 
