title: A novel glucokinase activator modulates pancreatic islet and hepatocyte function.
abstract: 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 beta-cells and increased glucose use in rat hepatocytes. In addition, incubation of beta-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.
authors.affiliation: Lilly Research Laboratories, Eli Lilly & Company, Essener Bogen 7, 22419 Hamburg, Germany. efanov_alexander@lilly.com
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Efanov
authors.forename: David G
authors.initials: DG
authors.lastname: Barrett
authors.forename: Martin B
authors.initials: MB
authors.lastname: Brenner
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Briggs
authors.forename: Annie
authors.initials: A
authors.lastname: Delaunois
authors.forename: Jim D
authors.initials: JD
authors.lastname: Durbin
authors.forename: Ulrich
authors.initials: U
authors.lastname: Giese
authors.forename: Haihong
authors.initials: H
authors.lastname: Guo
authors.forename: Mark
authors.initials: M
authors.lastname: Radloff
authors.forename: Gema Sanz
authors.initials: GS
authors.lastname: Gil
authors.forename: Sabine
authors.initials: S
authors.lastname: Sewing
authors.forename: Yong
authors.initials: Y
authors.lastname: Wang
authors.forename: Andreas
authors.initials: A
authors.lastname: Weichert
authors.forename: Andrea
authors.initials: A
authors.lastname: Zaliani
authors.forename: Jesper
authors.initials: J
authors.lastname: Gromada
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D002478:Cells, Cultured; D003461:Crystallography; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D020536:Enzyme Activators / Q000494:pharmacology*; D005941:Glucokinase / Q000737:chemistry / Q000378:metabolism*; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D008297:Male; D017434:Protein Structure, Tertiary; D051381:Rats; D017208:Rats, Wistar; D013450:Sulfones / Q000737:chemistry / Q000494:pharmacology*; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C503863:2-cyclohexyl-1-(4-methanesulfonylphenyl)cyclopropanecarboxylic acid thiazol-2-ylamide; D001786:Blood Glucose; D020536:Enzyme Activators; D007328:Insulin; D013450:Sulfones; D013844:Thiazoles; D005941:Glucokinase