title: Fasiglifam/TAK-875, a Selective GPR40 Agonist, Improves Hyperglycemia in Rats Unresponsive to Sulfonylureas and Acts Additively with Sulfonylureas.
abstract: Sulfonylureas (SUs) are widely used insulin secretagogues, but they have adverse effects including hypoglycemia and secondary failure. Fasiglifam/TAK-875, a selective GPR40 agonist, enhances glucose-stimulated insulin secretion and improves hyperglycemia. In the present study, we compared the in vivo glucose-lowering effects of fasiglifam with SUs. The risk of secondary failure of fasiglifam and the efficacy in rats desensitized to SUs were also evaluated. Moreover, we assessed whether fasiglifam was effective when combined with SUs. In diabetic neonatally streptozotocin-induced rats 1.5 days after birth (N-STZ-1.5), oral administrations of fasiglifam (3-30 mg/kg) dose dependently improved glucose tolerance; the effect was greater than that of glibenclamide at maximal effective doses (glucose AUC: fasiglifam, -37.6%; glibenclamide, -12.3%). Although the glucose-lowering effects of glibenclamide (10 mg/kg/day) were completely diminished in N-STZ-1.5 rats after 4 weeks of treatment, effects were maintained in rats receiving fasiglifam (10 mg/kg/day), even after 15 weeks. Fasiglifam (3-10 mg/kg) was still effective in two models desensitized to SUs: 15-week glibenclamide-treated N-STZ-1.5 rats and aged Zucker diabetic fatty (ZDF) rats. Acute administration of fasiglifam (3 mg/kg) and glimepiride (10 mg/kg) in combination additively decreased glucose AUC (fasiglifam, -25.3%; glimepiride, -20.0%; combination, -43.1%). Although glimepiride (10 mg/kg) decreased plasma glucose below normal in nonfasted control rats, fasiglifam (3 mg/kg) maintained normoglycemia, and no further exaggeration of hypoglycemia was observed with combination treatment. These results indicate that GPR40 agonists could be more effective and durable than SUs. Our results also provide new insights into GPR40 pharmacology and rationale for the use of GPR40 agonists in diabetic patients with SU failure.
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan ryo.ito@takeda.com.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Miyawaki
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Matsuda
authors.affiliation: Cardiovascular and Metabolic Drug Discovery Unit, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, Kanagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D004357:Drug Synergism; D005951:Glucose Tolerance Test; D005905:Glyburide / Q000627:therapeutic use; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011924:Rats, Zucker; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D013450:Sulfones / Q000494:pharmacology*; D013453:Sulfonylurea Compounds / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; C473035:G-protein-coupled receptor 40, rat; D007004:Hypoglycemic Agents; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; D013453:Sulfonylurea Compounds; C557331:TAK-875; C057619:glimepiride; D005905:Glyburide