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: Hirotsugu Tanaka, Shigeru Yoshida, Hiroyuki Oshima, Hideaki Minoura, Kenji Negoro, Takao Yamazaki, Shuichi Sakuda, Fumiyoshi Iwasaki, Tetsuo Matsui, Masayuki Shibasaki
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 346 Issue 3 Pg. 443-52 (Sep 2013) ISSN: 1521-0103 [Electronic] United States
• PMID: 23853170 (Publication Type: Journal Article)

Chemical References

• Biphenyl Compounds
• Blood Glucose
• Ffar1 protein, mouse
• Insulin
• Oxadiazoles
• PPAR gamma
• Receptors, G-Protein-Coupled
• bis(2-((4-((4'-(2-hydroxyethoxy)-2'-methyl(1,1'-biphenyl)-3-yl)methoxy)phenyl)methyl)-3,5-dioxo-1,2,4-oxadiazolidine)
• Glucose
• Calcium

Topics

• Animals
• Biphenyl Compounds (pharmacology)
• Blood Glucose (metabolism)
• CHO Cells
• Calcium (metabolism)
• Cricetinae
• Cricetulus
• Diabetes Mellitus (genetics, metabolism)
• Glucose (metabolism)
• Glucose Clamp Technique
• Glucose Tolerance Test
• Insulin (metabolism)
• Male
• Mice
• Mice, Inbred ICR
• Mice, Obese
• Oxadiazoles (pharmacology)
• PPAR gamma (metabolism)
• Rats
• Rats, Zucker
• Receptors, G-Protein-Coupled (agonists)
• Transcriptional Activation (drug effects)