title: Novel GPR40 agonist AS2575959 exhibits glucose metabolism improvement and synergistic effect with sitagliptin on insulin and incretin secretion.
abstract: OBJECTIVE
  GPR40 is a free fatty acid receptor that regulates glucose-dependent insulin secretion at pancreatic β-cells and glucagon-like peptide-1 (GLP-1), one of the major incretins, secretion at the endocrine cells of the gastrointestinal tract. We investigated the synergistic effect of AS2575959, a novel GPR40 agonist, in combination with sitagliptin, a major dipeptidyl peptidase-IV (DPP-IV) inhibitor, on glucose-dependent insulin secretion and GLP-1 secretion. In addition, we investigated the chronic effects of AS2575959 on whole-body glucose metabolism.
  
  
  METHODS
  We evaluated acute glucose metabolism on insulin and GLP-1 secretion using an oral glucose tolerance test (OGTT) as well as assessed the chronic glucose metabolism in diabetic ob/ob mice following the repeated administration of AS2575959.
  
  
  RESULTS
  We discovered the novel GPR40 agonist sodium [(3S)-6-({4'-[(3S)-3,4-dihydroxybutoxy]-2,2',6'-trimethyl[1,1'-biphenyl]-3-yl}methoxy)-3H-spiro[1-benzofuran-2,1'-cyclopropan]-3-yl]acetate (AS2575959) and found that the compound influenced glucose-dependent insulin secretion both in vitro pancreas β-cell-derived cells and in vivo mice OGTT. Further, we observed a synergistic effect of AS2575959 and DPP-IV inhibitor on insulin secretion and plasma GLP-1 level. In addition, we discovered the improvement in glucose metabolism on repeated administration of AS2575959.
  
  
  CONCLUSIONS
  To our knowledge, this study is the first to demonstrate the synergistic effect of a GPR40 agonist and DPP-IV inhibitor on the glucose-dependent insulin secretion and GLP-1 concentration increase. These findings suggest that GPR40 agonists may represent a promising therapeutic strategy for the treatment of type 2 diabetes mellitus, particularly when used in combination with DPP-IV inhibitors.
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. Electronic address: hirotsugu.tanaka@jp.astellas.com.
authors.forename: Hirotsugu
authors.initials: H
authors.lastname: Tanaka
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Hideaki
authors.initials: H
authors.lastname: Minoura
authors.affiliation: Chemistry Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Negoro
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Akiyoshi
authors.initials: A
authors.lastname: Shimaya
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Teruhiko
authors.initials: T
authors.lastname: Shimokawa
authors.affiliation: Pharmacology Research Labs, Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Shibasaki
mesh_terms: D000085:Acetates / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D052216:Glucagon-Like Peptide 1 / Q000097:blood; D005947:Glucose / Q000378:metabolism*; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000032:analysis; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D054795:Incretins / Q000378:metabolism*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D008820:Mice, Obese; D011719:Pyrazines / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D000068900:Sitagliptin Phosphate; D013141:Spiro Compounds / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
chemical_list: D000085:Acetates; D001786:Blood Glucose; D054873:Dipeptidyl-Peptidase IV Inhibitors; D052216:Glucagon-Like Peptide 1; D005947:Glucose; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D054795:Incretins; D007328:Insulin; D011719:Pyrazines; D043562:Receptors, G-Protein-Coupled; D000068900:Sitagliptin Phosphate; D013141:Spiro Compounds; D014230:Triazoles; C586830:(6-((4'-(3,4-dihydroxybutoxy)-2,2',6'-trimethyl(1,1'-biphenyl)-3-yl)methoxy)-3H-spiro(1-benzofuran-2,1'-cyclopropan)-3-yl)acetic acid; C473036:Ffar1 protein, mouse
keywords: Diabetes; GPR40; Insulin secretion; OGTT