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

我们报道了最有效的血管活性多肽之一尿紧张素II （UTS2）的遗传多态性可能与体内胰岛素敏感性有关，从而导致糖尿病的发生。为了阐明尿紧张素II对胰岛素敏感性和葡萄糖耐量的可能作用，我们通过尾静脉给药含有UT2的腺病毒载体在小鼠肝脏中过表达UT2的B6小鼠（UT2小鼠），并与使用含有LacZ的腺病毒载体在肝脏中过表达LacZ的B6小鼠（LacZ小鼠）比较，研究了葡萄糖耐受不良和胰岛素敏感性。我们发现，与lacz小鼠相比，ut2小鼠的胰岛素敏感性和葡萄糖耐量有显著改善。然后，我们通过给药含GPR14的腺病毒载体，在小鼠肝脏中培养了过表达GPR14的B6小鼠（GPR14-小鼠）。我们还证实，与lacz小鼠相比，ut2小鼠的胰岛素敏感性和葡萄糖耐量有显著改善。我们的结论是，肝脏中尿肾素II信号的激活有助于胰岛素敏感性和葡萄糖耐量的改善。越来越多的证据表明，副交感神经对NO的信号传导调节糖原合成、糖异生、脂肪生成和抗脂肪分解的胰岛素信号传导。与lacz小鼠相比，我们证实了ut2小鼠和gpr14小鼠副交感神经对NO的信号通路增强。因此，本研究清楚地表明，副交感神经对NO的信号缺陷可能是胰岛素抵抗和糖尿病的致病机制之一。

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.