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

尾加压素 II、副交感神经和一氧化氮对碳水化合物代谢的信号轴：临床

• 批准号: 17590912
• 负责人: TAMURA Akira
• 金额: $ 2.24万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17590912/
• 关键词: Diabetes; Urotensin II; Parasympatic nerve; Nitric Oxide; Insulin; Liver; Gene knockdown

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.

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。

项目成果

WRN gene 1367 Arg allele protects against development of type 2 diabetes mellitus

• DOI: 10.1016/j.diabres.2005.01.012
• 发表时间: 2005-09-01
• 期刊: DIABETES RESEARCH AND CLINICAL PRACTICE
• 影响因子: 5.1
• 作者: Hirai, M;Suzuki, S;Oka, Y
• 通讯作者: Oka, Y

Efficient and controlled gene expression in mouse pancreatic islets by arterial delivery of tetracycline-inducible adenoviral vectors

• DOI: 10.1677/jme.1.02189
• 发表时间: 2007-02-01
• 期刊: JOURNAL OF MOLECULAR ENDOCRINOLOGY
• 影响因子: 3.5
• 作者: Takahashi, Rui;Ishihara, Hisamitsu;Oka, Yoshitomo
• 通讯作者: Oka, Yoshitomo

WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells.

WFS1 缺乏会增加内质网应激，损害细胞周期进程并特别在胰腺 β 细胞中触发凋亡途径。

• 发表时间: 2006
• 期刊: Hum Mol Genet. 15・10
• 作者: Yamada T;Ishihara H;et al.
• 通讯作者: et al.

Cell type-specific activation of metabolism reveals that beta-cell secretion suppresses glucagon release from alpha-cells in rat pancreatic islets

细胞类型特异性代谢激活揭示β细胞分泌抑制大鼠胰岛α细胞释放胰高血糖素

• 发表时间: 2006
• 期刊: Am J Physiol Endocrinol Metab 290(2)
• 作者: Tsuji K;Shigeta Y;Takahashi R
• 通讯作者: Takahashi R

Disruption of the WFS1 gene in mice causes progressive beta-cell loss and impaired stimulus-secretion coupling in insulin secretion.

小鼠 WFS1 基因的破坏会导致进行性 β 细胞丧失，并损害胰岛素分泌中的刺激-分泌耦合。

• 发表时间: 2004
• 期刊: Hum Mol Genet 13
• 作者: Ishihara H;Takeda S;Tamura A;Takahashi R;Yamaguchi S;Takei D;Yamada T;Inoue H;Soga H;Katagiri H;Tanizawa Y;Oka Y.
• 通讯作者: Oka Y.