Allosteric activators of glucokinase: potential role in diabetes therapy |
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| Authors: | Grimsby Joseph Sarabu Ramakanth Corbett Wendy L Haynes Nancy-Ellen Bizzarro Fred T Coffey John W Guertin Kevin R Hilliard Darryl W Kester Robert F Mahaney Paige E Marcus Linda Qi Lida Spence Cheryl L Tengi John Magnuson Mark A Chu Chang An Dvorozniak Mark T Matschinsky Franz M Grippo Joseph F |
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| Institution: | Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. |
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| 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 beta 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. |
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