Full agonist-mediated activation of free fatty acid receptor 1 (FFAR1/GPR40) alleviates diabetes in rodents. Considering that diabetes is a chronic disease, assessment of treatment durability of chronic exposure to a GPR40 full agonist is pivotal for treating patients with diabetes. However, the physiologic significance of chronic in vitro and in vivo exposure to GPR40 full agonists is largely unclear. Here, we evaluated the in vitro and in vivo effects of chronic treatment with SCO-267, a GPR40 full agonist, on signal transduction and glucose control. In vitro experiments showed that SCO-267 is an allosteric full agonist for GPR40, which activates the Gα_q, Gα_s, and Gα_12/13 pathways and β-arrestin recruitment. The calcium signal response was largely sustained in GPR40-overexpressing CHO cells even after prolonged incubation with SCO-267. To evaluate the in vivo relevance of chronic exposure to GPR40 full agonists, SCO-267 (1 and 10 mg/kg) was administered once daily to neonatally streptozotocin-induced diabetic rats for 15–33 days, and glucose control was evaluated. After 15 days of dosing followed by the drug washout period, SCO-267 improved glucose tolerance, most likely by increasing insulin sensitivity in rats. After 33 days, repeated exposure to SCO-267 was highly effective in improving glucose tolerance in rats. Furthermore, chronic exposure to SCO-267 increased pancreatic insulin content. These results demonstrated that even after chronic exposure, SCO-267 effectively activates GPR40 in cells and rats, suggesting the clinical application of SCO-267 in treating chronic diseases including diabetes.

中文翻译：

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长期暴露于SCO-267（一种变构GPR40完全激动剂）可有效改善大鼠的血糖控制

完全激动剂介导的游离脂肪酸受体1（FFAR1 / GPR40）的活化可减轻啮齿类动物的糖尿病。考虑到糖尿病是一种慢性疾病，因此评估长期暴露于GPR40完全激动剂的治疗持久性对于治疗糖尿病患者至关重要。但是，长期体外和体内暴露于GPR40完全激动剂的生理学意义尚不清楚。在这里，我们评估了GPR40完全激动剂SCO-267对信号转导和葡萄糖控制的慢性治疗的体外和体内作用。在体外实验表明，SCO-267为GPR40变构完全激动剂，其激活对于g α _q，G α_小号和G α _12/13途径和β-arrestin招募。即使在与SCO-267长时间孵育后，钙信号反应仍在过表达GPR40的CHO细胞中得到很大程度的维持。为了评估慢性暴露于GPR40完全激动剂的体内相关性，每天对新生的链脲佐菌素诱导的糖尿病大鼠施用SCO-267（1和10 mg / kg）15-33天，并评估血糖控制。服药15天后再进行药物冲洗，SCO-267改善了葡萄糖耐量，这很可能是通过增加大鼠的胰岛素敏感性来实现的。33天后，反复接触SCO-267对改善大鼠的葡萄糖耐量非常有效。此外，长期暴露于SCO-267会增加胰腺胰岛素含量。这些结果表明，即使在长期暴露后，SCO-267仍能有效激活细胞和大鼠中的GPR40，