title: TAK-875, an orally available G protein-coupled receptor 40/free fatty acid receptor 1 agonist, enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia in type 2 diabetic rats.
abstract: G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic β cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 μM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired β cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of β cell toxicity.
authors.affiliation: Metabolic Disease Drug Discovery Unit,Takeda Pharmaceutical Company Limited, Osaka, Japan. tsujihata_yoshiyuki@takeda.co.jp
authors.forename: Yoshiyuki
authors.initials: Y
authors.lastname: Tsujihata
authors.forename: Ryo
authors.initials: R
authors.lastname: Ito
authors.forename: Masami
authors.initials: M
authors.lastname: Suzuki
authors.forename: Ayako
authors.initials: A
authors.lastname: Harada
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Negoro
authors.forename: Tsuneo
authors.initials: T
authors.lastname: Yasuma
authors.forename: Yu
authors.initials: Y
authors.lastname: Momose
authors.forename: Koji
authors.initials: K
authors.lastname: Takeuchi
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000494:pharmacology*; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053179:Caspase 7 / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000188:drug therapy; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D005215:Fasting / Q000502:physiology; D005947:Glucose / Q000502:physiology*; D006943:Hyperglycemia / Q000097:blood / Q000188:drug therapy*; D007004:Hypoglycemic Agents; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism; D008297:Male; D019518:Postprandial Period / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043562:Receptors, G-Protein-Coupled / Q000819:agonists*; D015398:Signal Transduction / Q000187:drug effects; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D001572:Benzofurans; D001786:Blood Glucose; C473035:G-protein-coupled receptor 40, rat; D007004:Hypoglycemic Agents; D007328:Insulin; D043562:Receptors, G-Protein-Coupled; D013450:Sulfones; C557331:TAK-875; D053148:Caspase 3; D053179:Caspase 7; D005947:Glucose; D002118:Calcium