Guo Dan-yang, Li De-wen, Ning Meng-meng, Dang Xiang-yu, Zhang Li-na, Zeng Li-min, Hu You-hong, Leng Ying
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China.
Biochem Biophys Res Commun. 2015 Oct 30;466(4):740-7. doi: 10.1016/j.bbrc.2015.09.130. Epub 2015 Sep 28.
G protein-coupled receptor 40 (GPR40) is predominantly expressed in pancreatic β-cells and activated by long-chain fatty acids. GPR40 has drawn considerable interest as a potential therapeutic target for type 2 diabetes mellitus (T2DM) due to its important role in enhancing glucose-stimulated insulin secretion (GSIS). Encouragingly, GPR40 is also proven to be highly expressed in glucagon-like peptide-1 (GLP-1)-producing enteroendocrine cells afterwards, which opens a potential role of GPR40 in enhancing GLP-1 secretion to exert additional anti-diabetic efficacy. In the present study, we discovered a novel GPR40 agonist, yhhu4488, which is structurally different from other reported GPR40 agonists. Yhhu4488 showed potent agonist activity with EC50 of 49.96 nM, 70.83 nM and 58.68 nM in HEK293 cells stably expressing human, rat and mouse GPR40, respectively. Yhhu4488 stimulated GLP-1 secretion from fetal rat intestinal cells (FRIC) via triggering endogenous calcium store mobilization and extracellular calcium influx. The effect of yhhu4488 on GLP-1 secretion was further confirmed in type 2 diabetic db/db mice. Yhhu4488 exhibited satisfactory potency in in vivo studies. Single administration of yhhu4488 improved glucose tolerance in SD rats. Chronic administration of yhhu4488 effectively decreased fasting blood glucose level, improved β-cell function and lipid homeostasis in type 2 diabetic ob/ob mice. Taken together, yhhu4488 is a novel GPR40 agonist that enhances GLP-1 secretion, improves metabolic control and β-cell function, suggesting its promising potential for the treatment of type 2 diabetes.
G蛋白偶联受体40（GPR40）主要在胰腺β细胞中表达，并由长链脂肪酸激活。由于GPR40在增强葡萄糖刺激的胰岛素分泌（GSIS）中起重要作用，它作为2型糖尿病（T2DM）的潜在治疗靶点引起了广泛关注。令人鼓舞的是，GPR40后来也被证明在产生胰高血糖素样肽-1（GLP-1）的肠内分泌细胞中高表达，这揭示了GPR40在增强GLP-1分泌以发挥额外抗糖尿病功效方面的潜在作用。在本研究中，我们发现了一种新型GPR40激动剂yhhu4488，其结构与其他已报道的GPR40激动剂不同。Yhhu4488在稳定表达人、大鼠和小鼠GPR40的HEK293细胞中分别表现出强效激动剂活性，其EC50分别为49.96 nM、70.83 nM和58.68 nM。Yhhu4488通过触发内源性钙库动员和细胞外钙内流刺激胎鼠肠细胞（FRIC）分泌GLP-1。Yhhu4488对GLP-1分泌的影响在2型糖尿病db/db小鼠中得到进一步证实。Yhhu4488在体内研究中表现出令人满意的效力。单次给予yhhu4488可改善SD大鼠的糖耐量。长期给予yhhu4488可有效降低2型糖尿病ob/ob小鼠的空腹血糖水平，改善β细胞功能和脂质稳态。综上所述，yhhu4488是一种新型GPR40激动剂，可增强GLP-1分泌，改善代谢控制和β细胞功能，表明其在治疗2型糖尿病方面具有广阔的潜力。
