title: Chronic treatment with novel GPR40 agonists improve whole-body glucose metabolism based on the glucose-dependent insulin secretion.
abstract: GPR40 is a free fatty acid receptor that has been shown to regulate glucose-dependent insulin secretion. This study aimed to discover novel GPR40 agonists and investigate the whole-body effect on glucose metabolism of GPR40 activation using these novel GPR40 agonists. To identify novel GPR40-specific agonists, we conducted high-throughput chemical compound screening and evaluated glucose-dependent insulin secretion. To investigate the whole-body effect on glucose metabolism of GPR40 activation, we conducted repeat administration of the novel GPR40 agonists to diabetic model ob/ob mice and evaluated metabolic parameters. To characterize the effect of the novel GPR40 agonists more deeply, we conducted an insulin tolerance test and a euglycemic-hyperinsulinemic clamp test. As a result, we discovered the novel GPR40-specific agonists, including AS2034178 [bis{2-[(4-{[4'-(2-hydroxyethoxy)-2'-methyl[1,1'-biphenyl]-3-yl]methoxy}phenyl)methyl]-3,5-dioxo-1,2,4-oxadiazolidin-4-ide} tetrahydrate], and found that its exhibited glucose-dependent insulin secretion enhancement both in vitro and in vivo. In addition, the compounds also decreased plasma glucose and HbA1c levels after repeat administration to ob/ob mice, with favorable oral absorption and pharmacokinetics. Repeat administration of AS2034178 enhanced insulin sensitivity in an insulin tolerance test and a euglycemic-hyperinsulinemic clamp test. These results indicate that improvement of glucose-dependent insulin secretion leads the improvement of whole-body glucose metabolism chronically. In conclusion, AS2034178 and other GPR40 agonists may become useful therapeutics in the treatment of type 2 diabetes mellitus.
authors.affiliation: Pharmacology Research Laboratories, Drug Discovery Research, Astellas Pharma Inc, Tsukuba, Japan. hirotsugu.tanaka@jp.astellas.com
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tanaka
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Oshima
authors.forename: Hideaki
authors.initials: H
authors.lastname: Minoura
authors.forename: Kenji
authors.initials: K
authors.lastname: Negoro
authors.forename: Takao
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakuda
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Iwasaki
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Matsui
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000235:genetics / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D015309:Glucose Clamp Technique; D005951:Glucose Tolerance Test; D007328:Insulin / Q000378:metabolism*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D010069:Oxadiazoles / Q000494:pharmacology; D047495:PPAR gamma / Q000378:metabolism; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D001713:Biphenyl Compounds; D001786:Blood Glucose; C473036:Ffar1 protein, mouse; D007328:Insulin; D010069:Oxadiazoles; D047495:PPAR gamma; D043562:Receptors, G-Protein-Coupled; C584079:bis(2-((4-((4'-(2-hydroxyethoxy)-2'-methyl(1,1'-biphenyl)-3-yl)methoxy)phenyl)methyl)-3,5-dioxo-1,2,4-oxadiazolidine); D005947:Glucose; D002118:Calcium