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首页> 外文期刊>American Journal of Physiology >Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity
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Multiple mechanisms of GW-9508, a selective G protein-coupled receptor 40 agonist, in the regulation of glucose homeostasis and insulin sensitivity

机译：选择性G蛋白偶联受体40激动剂GW-9508调节葡萄糖稳态和胰岛素敏感性的多种机制

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Activation of G protein-coupled receptor 40 (GPR40) by agonists increases insulin release in isolated islets, whereas it is inconclusive whether GPR40 antagonists decrease blood glucose and increase insulin sensitivity. Although some clinical trials indicated that administration of a GPR40 agonist shows benefits in the regulation of blood glucose homeostasis, the pharmacological mechanisms of this receptor in the improvement of glycemic control remain unclear. Therefore, we used a selective GPR40 agonist, GW-9508, to clarify the role of GPR40 in the regulation of blood glucose. Bolus intraperitoneal injection of GW-9508 in mice showed a slight decrease in blood glucose, with an increase in plasma insulin levels under glucose stimuli. However, long-term treatment with low doses of GW-9508 in high-fat diet-induced (HFD) diabetic mice decreased blood glucose with decreased plasma insulin significantly and improved glucose intolerance and insulin resistance. Using small interfering ribonucleic acid to delete GPR40 in HepG2 cells, we demonstrated that GW-9508 reversed palmitate-induced insulin signaling impairment through a GPR40-dependent pathway. We also found that GW-9508 activates the Akt/GSK-3β pathway to increase glycogen levels in HepG2 cells. Furthermore, administration of GW-9508 decreased the hepatic expression of fetuin-A in HFD mice significantly and regulated highglucose- or palmitate-induced fetuin-A expression to increase insulin sensitivity through a GPR40/PLC/PKC pathway in HepG2 cells. Taken together, GW-9508 exerts a partial agonist effect to regulate blood glucose through multiple mechanisms. Investigation of chemicals that act on GPR40 might be a new strategy for the treatment of diabetes.
机译：激动剂对G蛋白偶联受体40（GPR40）的激活增加了离体胰岛中胰岛素的释放，而GPR40拮抗剂是否降低血糖并增加胰岛素敏感性尚无定论。尽管一些临床试验表明，施用GPR40激动剂在调节血糖稳态方面显示出益处，但该受体在改善血糖控制中的药理机制仍不清楚。因此，我们使用了选择性GPR40激动剂GW-9508来阐明GPR40在血糖调节中的作用。小鼠腹腔注射GW-9508的小丸显示血糖略有降低，在葡萄糖刺激下血浆胰岛素水平升高。但是，在高脂饮食诱导的（HFD）糖尿病小鼠中长期使用低剂量GW-9508进行治疗可降低血糖，显着降低血浆胰岛素，并改善葡萄糖耐量和胰岛素抵抗。使用小的干扰核糖核酸删除HepG2细胞中的GPR40，我们证明GW-9508通过GPR40依赖性途径逆转了棕榈酸酯诱导的胰岛素信号传导障碍。我们还发现GW-9508激活Akt /GSK-3β途径，以增加HepG2细胞中的糖原水平。此外，GW-9508的施用显着降低了HFD小鼠中胎球蛋白A的肝表达，并调节了高葡萄糖或棕榈酸酯诱导的胎球蛋白A的表达，从而通过GPR40 / PLC / PKC途径提高了HepG2细胞的胰岛素敏感性。综上所述，GW-9508通过多种机制发挥部分激动剂作用来调节血糖。研究作用于GPR40的化学物质可能是治疗糖尿病的新策略。

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