title: Potentiation of insulin secretion and improvement of glucose intolerance by combining a novel G protein-coupled receptor 40 agonist DS-1558 with glucagon-like peptide-1 receptor agonists.
abstract: G protein-coupled receptor 40 (GPR40) is a Gq-coupled receptor for free fatty acids predominantly expressed in pancreatic β-cells. In recent years, GPR40 agonists have been investigated for use as novel therapeutic agents in the treatment of type 2 diabetes. We discovered a novel small molecule GPR40 agonist, (3S)-3-ethoxy-3-(4-{[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]oxy}phenyl)propanoic acid (DS-1558). The GPR40-mediated effects of DS-1558 on glucose-stimulated insulin secretion were evaluated in isolated islets from GPR40 knock-out and wild-type (littermate) mice. The GPR40-mediated effects on glucose tolerance and insulin secretion were also confirmed by an oral glucose tolerance test in these mice. Furthermore, oral administration of DS-1558 (0.03, 0.1 and 0.3mg/kg) significantly and dose-dependently improved hyperglycemia and increased insulin secretion during the oral glucose tolerance test in Zucker fatty rats, the model of insulin resistance and glucose intolerance. Next, we examined the combination effects of DS-1558 with glucagon like peptide-1 (GLP-1). DS-1558 not only increased the glucose-stimulated insulin secretion by GLP-1 but also potentiated the maximum insulinogenic effects of GLP-1 after an intravenous glucose injection in normal Sprague Dawley rats. Furthermore, the glucose lowering effects of exendin-4, a GLP-1 receptor agonist, were markedly potentiated by the DS-1558 (3mg/kg) add-on in diabetic db/db mice during an intraperitoneal glucose tolerance test. In conclusion, our results indicate that add-on GPR40 agonists to GLP-1 related agents might be a potential treatment compared to single administration of these compounds. Therefore the combinations of these agents are a novel therapeutic option for type 2 diabetes.
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan; Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan. Electronic address: nakashima.ryutaro.ia@daiichisankyo.co.jp.
authors.forename: Ryutaro
authors.initials: R
authors.lastname: Nakashima
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yano
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Junko
authors.initials: J
authors.lastname: Ogawa
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Naomi
authors.initials: N
authors.lastname: Tanaka
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Narihiro
authors.initials: N
authors.lastname: Toda
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Masao
authors.initials: M
authors.lastname: Yoshida
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Takano
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Masahiro
authors.initials: M
authors.lastname: Inoue
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Honda
authors.affiliation: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
authors.forename: Shoen
authors.initials: S
authors.lastname: Kume
authors.affiliation: R&D Division, Daiichi Sankyo Co., Ltd., Tokyo 140-8710, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Matsumoto
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D000077270:Exenatide; D055786:Gene Knockout Techniques; D052216:Glucagon-Like Peptide 1 / Q000494:pharmacology; D000067757:Glucagon-Like Peptide-1 Receptor; D018149:Glucose Intolerance / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D010455:Peptides / Q000494:pharmacology; D010666:Phenylpropionates / Q000494:pharmacology* / Q000627:therapeutic use; D011422:Propionates / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D043562:Receptors, G-Protein-Coupled / Q000819:agonists* / Q000172:deficiency / Q000235:genetics; D018027:Receptors, Glucagon / Q000819:agonists*; D014688:Venoms / Q000494:pharmacology
chemical_list: C000595179:3-ethoxy-3-(4-((4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl)oxy)phenyl)propanoic acid; D001786:Blood Glucose; C473034:FFAR1 protein, human; C473035:G-protein-coupled receptor 40, rat; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007189:Indans; D007328:Insulin; D010455:Peptides; D010666:Phenylpropionates; D011422:Propionates; D043562:Receptors, G-Protein-Coupled; D018027:Receptors, Glucagon; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide
keywords: Diabetes; GLP-1; GPR40; Insulin