内质网应激致肠-胰轴功能紊乱在2型糖尿病中的研究进展  

The role of endoplasmic reticulum stress in gut-pancreas axis dysfunction in type 2 diabetes

作　　者：雷丽冉 付雅馨 刘泉 翟佳羽 申竹芳 曹慧 刘率男 LEI Li-ran;FU Ya-xin;LIU Quan;ZHAI Jia-yu;SHEN Zhu-fang;CAO Hui;LIU Shuai-nan(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;Diabetes Research Center of Chinese Academy of Medical Sciences and Peking Union Medical College,Beijing 100050,China;Beijing Key Laboratory of Polymorphic Drugs,Beijing 100050,China)

机构地区：[1]中国医学科学院药物研究所,天然药物活性物质与功能国家重点实验室,北京100050 [2]中国医学科学院糖尿病研究中心,北京100050 [3]晶型药物研究北京市重点实验室,北京100050

出　　处：《药学学报》2024年第12期3189-3198,共10页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(82474243,82474136);中国医学科学院创新工程项目(2021-I2M-1-026);北京协和医院中央高水平医院临床科研专项(2022-PUMCH-B-121)。

摘　　要：2型糖尿病(type 2 diabetes mellitus,T2DM)是以高血糖、高血脂和胰岛素抵抗为主要特征的代谢性疾病。内质网应激(endoplasmic reticulum stress,ERS)是机体细胞的一种适应性调节反应。在T2DM发展过程中,长期高血糖会导致机体多种组织细胞持续发生ERS,进而引起蛋白质合成功能紊乱。其中,具有激素分泌功能的上皮细胞或内分泌细胞,更易受ERS影响而发生功能紊乱。肠-胰轴在调控机体代谢及T2DM发展过程中具有重要作用。肠道上皮L细胞作为肠道屏障的一部分,负责分泌肠道激素胰高血糖素样肽1 (glucagon-like peptide-1,GLP-1),其促胰岛β细胞分泌的胰岛素对糖代谢稳态维持具有重要意义。近年研究表明,ERS与肠-胰轴激素分泌及功能稳态密切相关。ERS通过影响肠道激素分泌、肠道屏障完整性以及β细胞的分泌功能和数量,参与T2DM的发生与发展。因此,本文将以肠-胰轴功能稳态为切入点,探讨ERS对肠-胰轴激素分泌功能与肠道屏障完整性的影响,并概述当前几类抗糖尿病药物通过调节肠-胰轴中ERS状态,进而改善糖脂代谢的作用及机制研究进展。Type 2 diabetes mellitus(T2DM) is a complex metabolic disorder characterized by chronic hyperglycemia,hyperlipidemia,and peripheral insulin resistance.Endoplasmic reticulum stress(ERS),a response to cellular stress,is activated across various tissues during the progression of T2DM,leading to disruptions in protein synthesis.Notably,epithelial and endocrine cells with hormone-secreting functions are particularly vulnerable to functional impairments induced by ERS.The gut-pancreas axis is essential for regulating metabolism and the progression of T2DM.Intestinal epithelial L cells,integral to the intestinal barrier,can secrete the glucagonlike peptide-1(GLP-1).This hormone promotes insulin secretion from pancreatic β-cells and plays a critical role in glucose metabolism.Importantly,ERS plays a critical role in regulating glucolipid-induced dysfunction of gut-pancreas axis.For instance,ERS is involved in regulating the intestinal barrier and the secretion of GLP-1 as well as insulin.Therefore,ERS can be a potential target for T2DM treatment.In this paper,we review the regulatory roles of ERS in the gut-pancreas axis during the development of T2DM,and summarize the therapeutic drugs and strategies targeting ERS for T2DM treatment.

关 键 词：内质网应激 肠-胰轴 肠道屏障 胰高血糖素样肽1 Β细胞 2型糖尿病 

分 类 号：R966[医药卫生—药理学]