氧化三甲胺干扰胰岛素靶细胞胰岛素敏感性的作用和机制研究  

The effects and mechanisms of trimethylamine-N-oxide on insulin sensitivity in insulin target cells

作　　者：孔丽娟 姜晓静 李平平 KONG Li-juan;JIANG Xiao-jing;LI Ping-ping(State Key Laboratory of Bioactive Substance and Function of Natural Medicines,Institute of Materia Medica,Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China)

机构地区：[1]中国医学科学院、北京协和医学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050

出　　处：《药学学报》2023年第12期3637-3643,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81622010);北京高校卓越青年科学家计划项目(BJJWZYJH01201910023028);中国医学科学院医学与健康科技创新工程(2021-I2M-1-016);中国医学科学院中央级公益性科研院所基本科研业务费(2018PT350004)

摘　　要：肠源性菌群代谢物氧化三甲胺(trimethylamine-N-oxide,TMAO)与2型糖尿病(type 2 diabetes,T2DM)相关,胰岛素敏感性下降是T2DM的一个重要发病原因。脂肪细胞、肌肉细胞和肝细胞是胰岛素的三大靶细胞,本研究旨在探讨TMAO对这些靶细胞胰岛素敏感性的作用和机制。研究结果表明,在不同周龄db/db糖尿病小鼠中,血浆TMAO水平升高,TMAO显著抑制胰岛素三大靶细胞的胰岛素信号通路,降低3T3-L1脂肪细胞和L6肌肉细胞的葡萄糖摄取,下调小鼠原代肝细胞糖异生相关基因的水平。此外,对于胰岛素敏感性正常的小鼠,通过使用皮下微渗透泵将血浆TMAO水平升高至db/db小鼠水平,小鼠表现为糖耐量异常,诱发高胰岛素血症。所有动物实验操作均遵循中国医学科学院、北京协和医学院药物研究所实验动物伦理与动物福利委员会的规定。机制研究表明,TMAO处理增加三大胰岛素靶细胞内质网应激相关蛋白的水平。综上,TMAO直接减弱胰岛素三大靶细胞的胰岛素敏感性,其作用机制可能是通过增强内质网应激。Gut microbial metabolite trimethylamine-N-oxide(TMAO)is associated with type 2 diabetes(T2DM).Decreased insulin sensitivity is a significant etiological factor of T2DM.Adipocytes,myocytes,and hepatocytes are the three major target cells for insulin.This study aims to investigate the effects and mechanisms of TMAO on the insulin sensitivity of these target cells.Research results indicate that in different ages of dbldb diabetic mice,plasma TMAO levels were increased.TMAO significantly inhibits the insulin signaling pathways in these three major insulin target cells,reduces glucose uptake in 3T3-L1 adipocytes and L6 myocytes and downregulates genes related to gluconeogenesis in primary mouse hepatocytes.Furthermore,in mice with normal insulin sensitivity,elevating plasma TMAO levels to those seen in dbldb mice using a minipump results in impaired glucose tolerance and hyperinsulinemia.All animal experiments were carried out with approval of the Experimental Animal Welfare Ethics Committee of the Institute of Materia Medica(Chinese Academy of Medical Sciences and Peking Union Medical College).Mechanistic studies suggest that TMAO exposure increases the levels of endoplasmic reticulum stress-related proteins in these three major insulin target cells.In summary,TMAO directly attenuates insulin sensitivity in insulin target cells,and its mechanism of action may involve enhancing endoplasmic reticulum stress。

关 键 词：氧化三甲胺 胰岛素信号通路 葡萄糖摄取 糖异生 内质网应激 

分 类 号：R966[医药卫生—药理学]