RT Journal Article SR Electronic T1 Chronic Treatment with Novel GPR40 Agonists Improve Whole-Body Glucose Metabolism Based on the Glucose-Dependent Insulin Secretion JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 443 OP 452 DO 10.1124/jpet.113.206466 VO 346 IS 3 A1 Hirotsugu Tanaka A1 Shigeru Yoshida A1 Hiroyuki Oshima A1 Hideaki Minoura A1 Kenji Negoro A1 Takao Yamazaki A1 Shuichi Sakuda A1 Fumiyoshi Iwasaki A1 Tetsuo Matsui A1 Masayuki Shibasaki YR 2013 UL http://jpet.aspetjournals.org/content/346/3/443.abstract AB 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.