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首页> 外文期刊>Life sciences >Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice
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Novel GPR119 agonist AS1669058 potentiates insulin secretion from rat islets and has potent anti-diabetic effects in ICR and diabetic db/db mice

机译：新型GPR119激动剂AS1669058增强大鼠胰岛的胰岛素分泌，并在ICR和糖尿病db / db小鼠中具有有效的抗糖尿病作用

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Aims G-protein-coupled receptor 119 (GPR119), mainly expressed in pancreatic β-cells, represents a new target for treating type 2 diabetes. GPR119 agonist is known to induce insulin secretion in a glucose-dependent manner by elevating intracellular cAMP concentrations. This study mainly examined the anti-hyperglycemic effect of a novel candidate small-molecule GPR119 agonist AS1669058 2-(4-bromo-2,5-difluorophenyl)-6-methyl-N-[2-(1- oxidopyridin-3-yl)ethyl]pyrimidin-4-amine ethanedioate on ICR mice and diabetic db/db mice. Main methods We measured blood glucose, plasma insulin, and insulin content in the pancreas after repeated administration of AS1669058 to db/db mice twice daily for one week. Key findings Under high-concentration glucose conditions, AS1669058 induced insulin secretion in a dose-dependent manner in the hamster pancreatic β-cell line HIT-T15 and in rat pancreatic islets. In addition, AS1669058 increased human insulin promoter activity in NIT-1 cells. In in vivo studies, a single administration of AS1669058 (1 mg/kg) in ICR mice improved oral glucose tolerance based on insulin secretion. Further, 1-week repeated treatment (3 mg/kg, twice daily) in diabetic db/db mice significantly reduced blood glucose levels and tended to increase insulin content in the pancreas. Significance These results suggest that AS1669058 has promising potential as an extremely more effective anti-hyperglycemic agent than other compounds we previously reported as GPR119 agonists.
机译：目的主要在胰腺β细胞中表达的G蛋白偶联受体119（GPR119）代表了治疗2型糖尿病的新靶标。已知GPR119激动剂通过升高细胞内cAMP浓度以葡萄糖依赖性方式诱导胰岛素分泌。这项研究主要研究了新型候选小分子GPR119激动剂AS1669058 2-（4-bromo-2,5-difluorophenyl）-6-methyl-N- [2-（1-oxidopyridin-3-yl）的降血糖作用）乙基]嘧啶-4-胺乙二酸酯对ICR小鼠和糖尿病db / db小鼠的影响。主要方法我们每天两次向db / db小鼠重复给药AS1669058后，测量胰腺的血糖，血浆胰岛素和胰岛素含量。主要发现在高浓度葡萄糖条件下，AS1669058在仓鼠胰腺β细胞系HIT-T15和大鼠胰岛中以剂量依赖的方式诱导胰岛素分泌。另外，AS1669058增加了NIT-1细胞中人胰岛素启动子的活性。在体内研究中，在ICR小鼠中单次施用AS1669058（1 mg / kg）可改善基于胰岛素分泌的口服葡萄糖耐量。此外，在糖尿病db / db小鼠中进行1周的重复治疗（3 mg / kg，每天两次）可显着降低血糖水平，并倾向于增加胰腺中的胰岛素含量。意义这些结果表明，AS1669058作为一种极有效的抗降血糖药，比我们先前报道为GPR119激动剂的其他化合物具有广阔的前景。

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