Metabolic Disease Drug Discovery Unit,Takeda Pharmaceutical Company Limited, Osaka, Japan.
J Pharmacol Exp Ther. 2011 Oct;339(1):228-37. doi: 10.1124/jpet.111.183772. Epub 2011 Jul 13.
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.
G 蛋白偶联受体 40/游离脂肪酸受体 1（GPR40/FFA1）在胰岛β细胞中高度表达，并介导游离脂肪酸诱导的胰岛素分泌。本研究考察了新型口服 GPR40 选择性激动剂 [(3S)-6-({2',6'-二甲基-4'-[3-(甲磺酰基)丙氧基]联苯-3-基}甲氧基)-2,3-二氢-1-苯并呋喃-3-基]乙酸半水合物（TAK-875）的药理学作用及其避免脂毒性的潜力。采用胰岛素瘤细胞系和原代大鼠胰岛评估 TAK-875 的体外作用。在 2 型糖尿病大鼠和正常大鼠中考察了 TAK-875 对餐后高血糖、空腹高血糖和正常血糖的体内作用。在大鼠胰岛素瘤 INS-1 833/15 细胞中，TAK-875 增加了细胞内肌醇单磷酸和钙浓度，与 Gqα 信号通路的激活一致。TAK-875（10 μM）在 INS-1 833/15 和原代大鼠胰岛中的胰岛素促分泌作用依赖于葡萄糖。在药理活性浓度下，用 TAK-875 对细胞因子敏感的 INS-1 832/13 进行长达 72 小时的延长暴露，并未改变葡萄糖刺激的胰岛素分泌、胰岛素含量或 caspase 3/7 活性，而长时间暴露于棕榈酸或油酸会损害β细胞功能和存活。在 2 型糖尿病 N-STZ-1.5 大鼠的口服葡萄糖耐量试验中，TAK-875（1-10 mg/kg，口服）显示出葡萄糖耐量的明显改善和胰岛素分泌的增加。此外，TAK-875（10 mg/kg，口服）显著增加了雄性 Zucker 糖尿病肥胖大鼠的血浆胰岛素水平并降低了空腹高血糖，而在禁食的正常 Sprague-Dawley 大鼠中，即使在 30 mg/kg 时，TAK-875 既没有增强胰岛素分泌，也没有引起低血糖。TAK-875 增强了葡萄糖依赖性胰岛素分泌，并改善了餐后和空腹高血糖，低血糖风险低，没有β细胞毒性的证据。
