{"title":"Trapα缺乏会损害胰岛素生物合成和葡萄糖稳态的早期事件。","authors":"Xin Li,Jingxin Hu,Yumeng Huang,Hai Zhang,Ning Xu,Yang Liu,Xuan Liu,Yuanyuan Ye,Xinxin Zhang,Xiaoxi Xu,Yuxin Fan,Ziyue Zhang,Weiping J Zhang,Shusen Wang,Wenli Feng,Peter Arvan,Ming Liu","doi":"10.1172/jci179845","DOIUrl":null,"url":null,"abstract":"Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"56 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.\",\"authors\":\"Xin Li,Jingxin Hu,Yumeng Huang,Hai Zhang,Ning Xu,Yang Liu,Xuan Liu,Yuanyuan Ye,Xinxin Zhang,Xiaoxi Xu,Yuxin Fan,Ziyue Zhang,Weiping J Zhang,Shusen Wang,Wenli Feng,Peter Arvan,Ming Liu\",\"doi\":\"10.1172/jci179845\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.\",\"PeriodicalId\":520097,\"journal\":{\"name\":\"The Journal of Clinical Investigation\",\"volume\":\"56 1\",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2025-05-20\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"The Journal of Clinical Investigation\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1172/jci179845\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"The Journal of Clinical Investigation","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1172/jci179845","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 0
摘要
胰岛素生物合成的早期缺陷,包括胰岛素前原(PPI)在内质网(ER)膜上的低效易位和胰岛素前(PI)在内质网中的错误折叠,可导致糖尿病。参与这些事件的细胞机制仍不清楚。基因编码trans - locon- associated Protein α (TRAPα)显示与人类血糖控制有关,尽管其病理生理作用尚不清楚。本研究发现,喂食鼠粮或高脂饮食(HFD)的β细胞特异性TRAPα敲除(TRAPα-β ko)小鼠表现出循环胰岛素减少,并伴有与年龄和饮食相关的葡萄糖耐受不良。多种独立的方法表明,TRAPα-βKO不仅导致PPI转运效率低下,还导致PI错误折叠和内质网应激,选择性地限制PI ER输出和β细胞代偿电位。重要的是,在高脂肪饮食的野生型小鼠和2型糖尿病(T2D)患者的胰岛中,TRAPα表达明显下降。此外,胰岛β细胞中TRAPα的表达与胰岛素含量呈正相关,TRAPα的降低与T2D胰岛PI成熟缺陷有关。总之,这些数据表明,胰腺β细胞中TRAPα缺乏会损害PPI易位、PI折叠、胰岛素产生和葡萄糖稳态,从而导致其与T2D的遗传联系。
Trapα deficiency impairs the early events of insulin biosynthesis and glucose homeostasis.
Defects in the early events of insulin biosynthesis, including inefficient preproinsulin (PPI) translocation across the membrane of the endoplasmic reticulum (ER) and proinsulin (PI) misfolding in the ER, can cause diabetes. Cellular machineries involved in these events remain poorly defined. Gene encoding TRanslocon-Associated Protein alpha (TRAPα) shows linkage to glycemic control in humans, although their pathophysiological role remains unknown. Here we found that β-cell specific TRAPα knockout (TRAPα-βKO) mice fed with chow diet or high fat diet (HFD) exhibit decreased circulating insulin, with age- and diet-related glucose intolerance. Multiple independent approaches revealed that TRAPα-βKO not only causes inefficient PPI translocation, but also leads to PI misfolding and ER stress, selectively limiting PI ER export and β-cell compensatory potential. Importantly, decreased TRAPα expression was evident in islets of wild-type mice fed with high fat diet and in patients with type 2 diabetes (T2D). Furthermore, TRAPα expression was positively correlated with insulin content in human islet β cells, and decreased TRAPα was associated with PI maturation defects in T2D islets. Together, these data demonstrate that TRAPα deficiency in pancreatic β-cells impairs PPI translocation, PI folding, insulin production, and glucose homeostasis, contributing to its genetic linkage to T2D.