Department of Medicine, University of Tennessee Health Science Center, Memphis, Tennessee 38163, USA.
Endocrinology. 2012 Oct;153(10):4608-15. doi: 10.1210/en.2012-1301. Epub 2012 Aug 7.
L-arginine (l-Arg) is an insulin secretagogue, but the molecular mechanism whereby it stimulates insulin secretion from β-cells is not known. The possibility that l-Arg regulates insulin secretion through a G protein-coupled receptor (GPCR)-mediated mechanism is suggested by the high expression of the nutrient receptor GPCR family C group 6 member A (GPRC6A) in the pancreas and TC-6 β-cells and the finding that Gprc6a(-/]minus]) mice have abnormalities in glucose homeostasis. To test the direct role of GPRC6A in regulating insulin secretion, we evaluated the response of pancreatic islets derived from Gprc6a(-/]minus]) mice to L-Arg. We found that the islet size and insulin content were decreased in pancreatic islets from Gprac6a(-/]minus]) mice. These alterations were selective for β-cells, because there were no abnormalities in serum glucagon levels or glucagon content of islets derived from Gprac6a(-/]minus]) mice. Significant reduction was observed in both the pancreatic ERK response to L-Arg administration to Gprc6a(-/]minus]) mice in vivo and L-Arg-induced insulin secretion and production ex vivo in islets isolated from Gprc6a(-/]minus]) mice. L-Arg stimulation of cAMP accumulation in isolated islets isolated from Gprc6a(-/]minus]) mice was also diminished. These findings suggest that l-Arg stimulation of insulin secretion in β-cells is mediated, at least in part, through GPRC6A activation of cAMP pathways.
精氨酸（l-Arg）是一种胰岛素促分泌剂，但它刺激β细胞分泌胰岛素的分子机制尚不清楚。高表达营养受体 G 蛋白偶联受体（GPCR）家族 C 组 6 成员 A（GPRC6A）表明，l-Arg 可能通过 G 蛋白偶联受体（GPCR）介导的机制调节胰岛素分泌，在胰腺和 TC-6β细胞中发现 Gprc6a（-/]minus]）小鼠的葡萄糖稳态存在异常。为了测试 GPRC6A 在调节胰岛素分泌中的直接作用，我们评估了来自 Gprc6a（-/]minus]）小鼠的胰岛对 l-Arg 的反应。我们发现，来自 Gprac6a（-/]minus]）小鼠的胰岛的胰岛大小和胰岛素含量降低。这些改变是β细胞选择性的，因为来自 Gprac6a（-/]minus]）小鼠的胰岛的血清胰高血糖素水平或胰高血糖素含量没有异常。在体内给予 Gprac6a（-/]minus]）小鼠 l-Arg 后，胰腺 ERK 对 l-Arg 的反应以及从 Gprac6a（-/]minus]）小鼠分离的胰岛中 l-Arg 诱导的胰岛素分泌和产生均显著减少。来自 Gprc6a（-/]minus]）小鼠的分离胰岛中 cAMP 积累对 l-Arg 的刺激也减弱。这些发现表明，l-Arg 刺激β细胞胰岛素分泌至少部分是通过 GPRC6A 激活 cAMP 途径介导的。
