Elucidation of pathophysiological roles of Wnt5b gene susceptible to type 2 diabetes in glucose metabolism in liver

阐明易患2型糖尿病的Wnt5b基因在肝脏葡萄糖代谢中的病理生理作用

• 批准号: 18591002
• 负责人: KANAZAWA Akio
• 金额: $ 2.57万
• 依托单位: Juntendo University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591002/
• 关键词: Diabetes; Wnt; Hepatic glucose metabolism; 糖尿病学

Wnt/β-catenin signaling is reported to be associated with insulin secretion and adipocyte differentiation. However physiological roles in liver have remained unknown. Recently, it has been reported that Wnt5b gene, one of the Wnt family, is susceptible to type2 diabetes and regulates 9-catenin signaling negatively. In order to investigate some roles of Wnt/β-catenin signaling and Wnt5b gene in liver we examined whether activation of β-catenin signaling can affect glucose metabolism using primary rat hepatocytes. lithium chloride phosphorylated GSK-3f3 and reduced the gene expression levels of PEPCK and G6Pase that are associated with gluconeogenesis. Additionally, we did ipGTT in mice and examined the expression level of Wnt5b gene in liver of db/db mice. The result of ipGTT showed that the expression level of Wnt5b gene was transiently increased after glucose loading and Wnt5b gene expression in live of db/db mice was increased compared with control mice. From these results, it could be hypothesized that Wnt/β-catenin signaling has pathophyisological roles in hepatic glucose metabolism. Therefore, we overexpressed mouse Wnt5b gene in mouse liver using adenovirus vector However no remarkable changes in Wnt5b-overexpressed mice were found in both fasting glucose and after glucose loading compared with control mice and we did not find direct effects of Wnt5b gene on hepatic glucose metabolism in vivo model However, previous reports showed that Wnt/β-catenin signaling was associated with lipid metabolism in liver. Therefore Wnt/β-catenin signaling may have indirect effects on onset or/and progression of diabetes by regulating lipid metabolism and it is important to clear pathophyisological roles of Wnt5b gene in lipid metabolism.

据报道，Wnt/β-连环蛋白信号与胰岛素分泌和脂肪细胞分化有关，但最近有报道称，Wnt 家族之一的 Wnt5b 基因对 2 型糖尿病敏感并具有调节作用。 9-连环蛋白信号传导负向 为了研究 Wnt/β-连环蛋白信号传导和 Wnt5b 基因在肝脏中的某些作用，我们使用原代大鼠肝细胞锂来检查 β-连环蛋白信号传导的激活是否会影响葡萄糖代谢。氯化物磷酸化GSK-3f3并降低与糖异生相关的PEPCK和G6Pase基因表达水平。另外，我们对小鼠进行ipGTT并检测db/db小鼠肝脏中Wnt5b基因的表达水平。葡萄糖负荷后Wnt5b基因的表达水平短暂增加，并且与对照小鼠相比，db/db小鼠活体中Wnt5b基因的表达增加。从这些结果可以看出，Wnt/β-catenin信号在肝脏葡萄糖代谢中具有病理生理学作用，因此，我们使用腺病毒载体在小鼠肝脏中过表达小鼠Wnt5b基因，但在禁食期间没有发现Wnt5b过表达小鼠的显着变化。与对照小鼠相比，在葡萄糖负荷后和葡萄糖负荷后，我们没有发现Wnt5b基因对体内模型肝葡萄糖代谢的直接影响。然而，之前的报道表明Wnt/β-catenin信号传导是因此，Wnt/β-catenin 信号可能通过调节脂质代谢对糖尿病的发病或/和进展产生间接影响，明确 Wnt5b 基因在脂质代谢中的病理生理作用具有重要意义。