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A Novel Glucokinase Activator Modulates Pancreatic Islet and Hepatocyte Function

Lilly Research Laboratories (A.M.E., D.G.B., M.B.B., U.G., M.R., G.S.G., S.S., A.W., A.Z., J.G.), 22419 Hamburg, Germany; Lilly Research Laboratories (S.L.B., J.D.D., H.G., Y.W.), Indianapolis, Indiana 46285; and Lilly Development Centre (A.D.), 1348 Mont-Saint-Guibert, Belgium

Address all correspondence and requests for reprints to: Dr. Alexander M. Efanov, Lilly Research Laboratories, Eli Lilly & Company, Essener Bogen 7, 22419 Hamburg, Germany. E-mail: efanov_alexander{at}lilly.com.

The glucose-sensing enzyme glucokinase (GK) plays a key role in glucose metabolism. We report here the effects of a novel glucokinase activator, LY2121260. The activator enhanced GK activity via binding to the allosteric site located in the hinge region of the enzyme. LY2121260 stimulated insulin secretion in a glucose-dependent manner in pancreatic ß-cells and increased glucose use in rat hepatocytes. In addition, incubation of ß-cells with the GK activator resulted in increased GK protein levels, suggesting that enhanced insulin secretion on chronic treatment with a GK activator may be due to not only changed enzyme kinetics but also elevated enzyme levels. Animals treated with LY2121260 showed an improved glucose tolerance after oral glucose challenge. These results support the concept that GK activators represent a new class of compounds that increase both insulin secretion and hepatic glucose use and in doing so may prove to be effective agents for the control of blood glucose levels in patients with type 2 diabetes.

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