Signaling axis of urotensin II, parasympathetic nerves, and nitric oxide on carbohydrate metabolism: A clinical

为了研究尾加压素II（Urotensin II，UTS 2）在胰岛素敏感性和葡萄糖耐量中的作用，我们建立了B6小鼠模型，研究了Urotensin II基因多态性对胰岛素敏感性和葡萄糖耐量的影响（UT 2-小鼠），其通过经由尾静脉施用含有UT 2的腺病毒载体在小鼠肝脏中过表达UT 2，并与B6小鼠比较，研究葡萄糖耐受不良和胰岛素敏感性通过应用含有LacZ的腺病毒载体，在肝脏中过表达LacZ的小鼠（LacZ-小鼠）。我们发现UT 2-小鼠的胰岛素敏感性和葡萄糖耐量显著改善，与LacZ小鼠相比。然后，我们开发了B6小鼠（GPR 14-mice），通过L型腺病毒载体的GPR 14在小鼠肝脏中过表达。我们还证实了胰岛素敏感性和葡萄糖耐量的显着改善UT 2小鼠，与LacZ小鼠相比。结论：肝内尿加压素II信号通路的激活有助于胰岛素敏感性和糖耐量的改善;越来越多的证据表明，副交感神经对NO的信号通路调节胰岛素信号通路对糖原合成、脂肪生成、脂肪生成和抗脂肪分解的作用。我们证实了UT 2-小鼠和GPR 14-小鼠的副交感神经对NO的信号通路增强，与LacZ-小鼠相比。因此，本研究清楚地表明，尾加压素II、副交感神经对NO的信号转导缺陷可能是胰岛素抵抗和糖尿病的发病机制之一。

We reported that genetic polymorphisms of urotensin II, UTS2, one of most potent vasoactive polypeptides, might be contributed to in vivo insulin sensitivity, resulting to the onset of diabetes.To elucidate possible roles of urotensin II on insulin sensitivity and glucose tolerance, we developed B6 mice (UT2-mice) that over-expressed UT2 in mice liver by the administration of adenovirus vector containing UT2 via tail veins, and investigate glucose intolerance and insulin sensitivity as compared with the B6 mice (LacZ-mice) that over-expressed LacZ in liver by the application of adenovirus vector containing LacZ.We found a significant improvement of insulin sensitivity and glucose tolerance in UT2-mice, as compared with LacZ-mice. Then, we developed B6 mice (GPR14-mice) that over-expressed GPR14 in mice liver by the Ladministration of adenovirus vector containing GPR14. We also confirmed a significant improvement of insulin sensitivity and glucose tolerance in UT2-mice, as compared with LacZ-mice. We concluded that the activation of urorensin II signaling in liver contributed to the improvement of insulin sensitivity and glucose tolerance.There were accumulating evidence suggesting that the signaling of parasympathetic nerve to NO regulates insulin signaling on glycogen synthesis, gluconeogenesis, lipogenesis and anti-lipolysis. We confirmed the enhanced signaling pathway of parasympathetic nerve to NO in UT2-mice and GPR14-mice, as compared with LacZ-mice. Thus, this investigation clearly demonstrated that signaling defects of urotensin II, parasympathetic nerve to NO might be one of pathogenic mechanisms of insulin resistance and diabetes.