Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy-Reference-Cited by-同舟云学术

Allosteric Activators of Glucokinase: Potential Role in Diabetes Therapy

Published:2003-07-18 Issue:5631 Volume:301 Page:370-373
ISSN:0036-8075
Container-title:Science
language:en
Short-container-title:Science

Author:

Grimsby Joseph¹,Sarabu Ramakanth¹,Corbett Wendy L.¹,Haynes Nancy-Ellen¹,Bizzarro Fred T.¹,Coffey John W.¹,Guertin Kevin R.¹,Hilliard Darryl W.¹,Kester Robert F.¹,Mahaney Paige E.¹,Marcus Linda¹,Qi Lida¹,Spence Cheryl L.¹,Tengi John¹,Magnuson Mark A.¹,Chu Chang An¹,Dvorozniak Mark T.¹,Matschinsky Franz M.¹,Grippo Joseph F.¹

Affiliation:

1. 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.

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 ( V max ) 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.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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