title: Characterization of a novel glucokinase activator in rat and mouse models.
abstract: Glucokinase (GK) is a hexokinase isozyme that catalyzes the phosphorylation of glucose to glucose-6-phosphate. Glucokinase activators are being investigated as potential diabetes therapies because of their effects on hepatic glucose output and/or insulin secretion. Here, we have examined the efficacy and mechanisms of action of a novel glucokinase activator, GKA23. In vitro, GKA23 increased the affinity of rat and mouse glucokinase for glucose, and increased glucose uptake in primary rat hepatocytes. In vivo, GKA23 treatment improved glucose homeostasis in rats by enhancing beta cell insulin secretion and suppressing hepatic glucose production. Sub-chronic GKA23 treatment of mice fed a high-fat diet resulted in improved glucose homeostasis and lipid profile.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Min
authors.initials: M
authors.lastname: Lu
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Gautam
authors.initials: G
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: William
authors.initials: W
authors.lastname: Lagakos
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Walter E
authors.initials: WE
authors.lastname: Dewolf
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Taylor
authors.initials: T
authors.lastname: Alford
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Mark Joseph
authors.initials: MJ
authors.lastname: Chicarelli
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Lance
authors.initials: L
authors.lastname: Williams
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Anderson
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Brian R
authors.initials: BR
authors.lastname: Baer
authors.affiliation: Array BioPharma Inc., Boulder, Colorado, United States of America.
authors.forename: Maralee
authors.initials: M
authors.lastname: McVean
authors.affiliation: Amgen Inc., South San Francisco, California, United States of America.
authors.forename: Marion
authors.initials: M
authors.lastname: Conn
authors.affiliation: Amgen Inc., Thousand Oaks, California, United States of America.
authors.forename: Murielle M
authors.initials: MM
authors.lastname: Véniant
authors.affiliation: Amgen Inc., South San Francisco, California, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Coward
mesh_terms: D000631:Aminopyridines / Q000737:chemistry*; D000818:Animals; D019540:Area Under Curve; D001786:Blood Glucose / Q000378:metabolism; D002384:Catalysis; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy; D020536:Enzyme Activators / Q000737:chemistry*; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D013830:Thiadiazoles / Q000737:chemistry*
chemical_list: C000594198:1-(5-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-ylamino)-1,2,4-thiadiazol-3-yl)ethane-1,2-diol; D000631:Aminopyridines; D001786:Blood Glucose; D020536:Enzyme Activators; D007328:Insulin; D013830:Thiadiazoles; D005941:Glucokinase; D005947:Glucose