TY - JOUR 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 SP - 443 LP - 452 DO - 10.1124/jpet.113.206466 VL - 346 IS - 3 AU - Hirotsugu Tanaka AU - Shigeru Yoshida AU - Hiroyuki Oshima AU - Hideaki Minoura AU - Kenji Negoro AU - Takao Yamazaki AU - Shuichi Sakuda AU - Fumiyoshi Iwasaki AU - Tetsuo Matsui AU - Masayuki Shibasaki Y1 - 2013/09/01 UR - http://jpet.aspetjournals.org/content/346/3/443.abstract N2 - 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. ER -