title: An allosteric activator of glucokinase impairs the interaction of glucokinase and glucokinase regulatory protein and regulates glucose metabolism.
abstract: Glucokinase (GK) plays a key role in the control of blood glucose homeostasis. We identified a small molecule GK activator, compound A, that increased the glucose affinity and maximal velocity (V(max)) of GK. Compound A augmented insulin secretion from isolated rat islets and enhanced glucose utilization in primary cultured rat hepatocytes. In rat oral glucose tolerance tests, orally administrated compound A lowered plasma glucose elevation with a concomitant increase in plasma insulin and hepatic glycogen. In liver, GK activity is acutely controlled by its association to the glucokinase regulatory protein (GKRP). In order to decipher the molecular aspects of how GK activator affects the shuttling of GK between nucleus and cytoplasm, the effect of compound A on GK-GKRP interaction was further investigated. Compound A increased the level of cytoplasmic GK in both isolated rat primary hepatocytes and the liver tissues from rats. Experiments in a cell-free system revealed that compound A interacted with glucose-bound free GK, thereby impairing the association of GK and GKRP. On the other hand, compound A did not bind to glucose-unbound GK or GKRP-associated GK. Furthermore, we found that glucose-dependent GK-GKRP interaction also required ATP. Given the combined prominent role of GK on insulin secretion and hepatic glucose metabolism where the GK-GKRP mechanism is involved, activation of GK has a new therapeutic potential in the treatment of type 2 diabetes.
authors.affiliation: Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Tsukuba, Ibaraki 300-2611, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Futamura
authors.forename: Hideka
authors.initials: H
authors.lastname: Hosaka
authors.forename: Akito
authors.initials: A
authors.lastname: Kadotani
authors.forename: Hiroko
authors.initials: H
authors.lastname: Shimazaki
authors.forename: Kaori
authors.initials: K
authors.lastname: Sasaki
authors.forename: Sumika
authors.initials: S
authors.lastname: Ohyama
authors.forename: Teruyuki
authors.initials: T
authors.lastname: Nishimura
authors.forename: Jun-Ichi
authors.initials: J
authors.lastname: Eiki
authors.forename: Yasufumi
authors.initials: Y
authors.lastname: Nagata
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D001549:Benzamides / Q000737:chemistry / Q000494:pharmacology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002474:Cell-Free System; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism* / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D001549:Benzamides; D002352:Carrier Proteins; C485100:GCKR protein, human; D007328:Insulin; D011994:Recombinant Proteins; C080906:glucokinase regulatory protein; D000255:Adenosine Triphosphate; D005941:Glucokinase; D005947:Glucose