title: Allosteric activators of glucokinase: potential role in diabetes therapy.
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.
authors.affiliation: Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Grimsby
authors.forename: Ramakanth
authors.initials: R
authors.lastname: Sarabu
authors.forename: Wendy L
authors.initials: WL
authors.lastname: Corbett
authors.forename: Nancy-Ellen
authors.initials: NE
authors.lastname: Haynes
authors.forename: Fred T
authors.initials: FT
authors.lastname: Bizzarro
authors.forename: John W
authors.initials: JW
authors.lastname: Coffey
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Guertin
authors.forename: Darryl W
authors.initials: DW
authors.lastname: Hilliard
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kester
authors.forename: Paige E
authors.initials: PE
authors.lastname: Mahaney
authors.forename: Linda
authors.initials: L
authors.lastname: Marcus
authors.forename: Lida
authors.initials: L
authors.lastname: Qi
authors.forename: Cheryl L
authors.initials: CL
authors.lastname: Spence
authors.forename: John
authors.initials: J
authors.lastname: Tengi
authors.forename: Mark A
authors.initials: MA
authors.lastname: Magnuson
authors.forename: Chang An
authors.initials: CA
authors.lastname: Chu
authors.forename: Mark T
authors.initials: MT
authors.lastname: Dvorozniak
authors.forename: Franz M
authors.initials: FM
authors.lastname: Matschinsky
authors.forename: Joseph F
authors.initials: JF
authors.lastname: Grippo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000494:Allosteric Regulation; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D002352:Carrier Proteins; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004789:Enzyme Activation; D020536:Enzyme Activators / Q000737:chemistry / Q000494:pharmacology; D005941:Glucokinase / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006706:Homeostasis; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000494:pharmacology; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D047908:Intracellular Signaling Peptides and Proteins; D007515:Islets of Langerhans / Q000187:drug effects* / Q000378:metabolism; D007651:Keto Acids / Q000378:metabolism; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008112:Liver Glycogen / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D011506:Proteins / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000378:metabolism; D013237:Stereoisomerism; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001786:Blood Glucose; D002352:Carrier Proteins; D020536:Enzyme Activators; C485100:GCKR protein, human; C499483:Gckr protein, mouse; C499484:Gckr protein, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D047908:Intracellular Signaling Peptides and Proteins; D007651:Keto Acids; D008112:Liver Glycogen; D011506:Proteins; C476008:RO-28-0450; D011994:Recombinant Proteins; D013844:Thiazoles; C080906:glucokinase regulatory protein; C013082:alpha-ketoisocaproic acid; D005941:Glucokinase; D005947:Glucose