胆固醇平衡失调是 2 型糖尿病特有的β细胞蛋白毒性的早期信号。

IF 2.5 4区 生物学 Q3 CELL BIOLOGY
Physiological genomics Pub Date : 2024-09-01 Epub Date: 2024-07-01 DOI:10.1152/physiolgenomics.00029.2024
Tatyana Gurlo, Ruoshui Liu, Zhongying Wang, Jonathan Hoang, Sergey Ryazantsev, Marie Daval, Alexandra E Butler, Xia Yang, Montgomery Blencowe, Peter C Butler
{"title":"胆固醇平衡失调是 2 型糖尿病特有的β细胞蛋白毒性的早期信号。","authors":"Tatyana Gurlo, Ruoshui Liu, Zhongying Wang, Jonathan Hoang, Sergey Ryazantsev, Marie Daval, Alexandra E Butler, Xia Yang, Montgomery Blencowe, Peter C Butler","doi":"10.1152/physiolgenomics.00029.2024","DOIUrl":null,"url":null,"abstract":"<p><p>Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.<b>NEW & NOTEWORTHY</b> β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.</p>","PeriodicalId":20129,"journal":{"name":"Physiological genomics","volume":null,"pages":null},"PeriodicalIF":2.5000,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Dysregulation of cholesterol homeostasis is an early signal of β-cell proteotoxicity characteristic of type 2 diabetes.\",\"authors\":\"Tatyana Gurlo, Ruoshui Liu, Zhongying Wang, Jonathan Hoang, Sergey Ryazantsev, Marie Daval, Alexandra E Butler, Xia Yang, Montgomery Blencowe, Peter C Butler\",\"doi\":\"10.1152/physiolgenomics.00029.2024\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.<b>NEW & NOTEWORTHY</b> β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.</p>\",\"PeriodicalId\":20129,\"journal\":{\"name\":\"Physiological genomics\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":2.5000,\"publicationDate\":\"2024-09-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Physiological genomics\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1152/physiolgenomics.00029.2024\",\"RegionNum\":4,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2024/7/1 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q3\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Physiological genomics","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1152/physiolgenomics.00029.2024","RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2024/7/1 0:00:00","PubModel":"Epub","JCR":"Q3","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
引用次数: 0

摘要

2 型糖尿病(T2D)是一种常见的代谢性疾病,是由于胰岛素抵抗导致胰岛β细胞胰岛素分泌不足引起的。胰岛分子病理学揭示了蛋白质错误折叠在β细胞功能障碍和丧失中的作用,胰岛淀粉样蛋白来自胰岛淀粉样多肽(IAPP),这是一种与胰岛素共同表达和分泌的蛋白质。折叠错误的 IAPP 最具毒性的形式是细胞内膜破坏性毒性低聚物,存在于 T2D 患者的β细胞和转基因人类 IAPP(hIAPP)小鼠的β细胞中。之前的研究发现,T2D 和糖尿病前期 9-10 周龄转基因 hIAPP 小鼠的胰岛转录变化高度重叠,大多数变化都是有利于生存的适应性变化,因此治疗指导意义有限。在这里,我们研究了更早年龄(6 周)的 hIAPP 转基因小鼠的胰岛,以筛选在促生存信号占主导地位之前的 hIAPP 毒性潜在介质。我们发现胆固醇合成和运输受到早期抑制,同时β细胞内胆固醇和脂质沉积异常,胆固醇向细胞膜的运输受损。这些发现与终末期糖尿病患者β细胞内出现的类似脂质沉积以及服用抑制胆固醇合成药物的人更容易患上终末期糖尿病的情况相吻合。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Dysregulation of cholesterol homeostasis is an early signal of β-cell proteotoxicity characteristic of type 2 diabetes.

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic β-cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in β-cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein coexpressed and cosecreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in β-cells in T2D and in β-cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and prediabetic 9- to 10-wk-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here, we investigated islets from hIAPP transgenic mice at an earlier age (6 wk) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-β-cell cholesterol and lipid deposits and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in β-cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.NEW & NOTEWORTHY β-Cell failure in type 2 diabetes (T2D) is characterized by β-cell misfolded protein stress due to the formation of toxic oligomers of islet amyloid polypeptide (IAPP). Most transcriptional changes in islets in T2D are pro-survival adaptations consistent with the slow progression of β-cell loss. In the present study, investigation of the islet transcriptional signatures in a mouse model of T2D expressing human IAPP revealed decreased cholesterol synthesis and trafficking as a plausible early mediator of IAPP toxicity.

求助全文
通过发布文献求助,成功后即可免费获取论文全文。 去求助
来源期刊
Physiological genomics
Physiological genomics 生物-生理学
CiteScore
6.10
自引率
0.00%
发文量
46
审稿时长
4-8 weeks
期刊介绍: The Physiological Genomics publishes original papers, reviews and rapid reports in a wide area of research focused on uncovering the links between genes and physiology at all levels of biological organization. Articles on topics ranging from single genes to the whole genome and their links to the physiology of humans, any model organism, organ, tissue or cell are welcome. Areas of interest include complex polygenic traits preferably of importance to human health and gene-function relationships of disease processes. Specifically, the Journal has dedicated Sections focused on genome-wide association studies (GWAS) to function, cardiovascular, renal, metabolic and neurological systems, exercise physiology, pharmacogenomics, clinical, translational and genomics for precision medicine, comparative and statistical genomics and databases. For further details on research themes covered within these Sections, please refer to the descriptions given under each Section.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
确定
请完成安全验证×
copy
已复制链接
快去分享给好友吧!
我知道了
右上角分享
点击右上角分享
0
联系我们:info@booksci.cn Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。 Copyright © 2023 布克学术 All rights reserved.
京ICP备2023020795号-1
ghs 京公网安备 11010802042870号
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术官方微信