Endoplasmic reticulum stress and forkhead box protein O1 inhibition mediate palmitic acid and high glucose-inducedβ-cell dedifferentiation  

作　　者：Li-Kun Wang Chu-Chu Kong Ting-Yan Yu Hui-Song Sun Lu Yang Ying Sun Ming-Yu Li Wei Wang 

机构地区：[1]Department of Endocrinology,Xiang’an Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen 361102,Fujian Province,China [2]Fujian Provincial Key Laboratory of Innovative Drug Target Research,School of Pharmaceutical Sciences,Xiamen University,Xiamen 361102,Fujian Province,China [3]Department of Equipment and Materials,Xiang’an Hospital of Xiamen University,School of Medicine,Xiamen University,Xiamen 361102,Fujian Province,China

出　　处：《World Journal of Diabetes》2025年第5期216-233,共18页世界糖尿病杂志(英文)

基　　金：Supported by the Natural Science Foundation of China,No.81471081;the Natural Science Foundation of Fujian Province,No.2023D009;the Natural Science Foundation of Xiamen City,No.3502Z202373104 and No.3502Z20227162;Scientific Research Foundation for Advanced Talents,Xiang’an Hospital of Xiamen University,No.PM201809170005。

摘　　要：BACKGROUND Type 2 diabetes mellitus is characterized by pancreaticβ-cell dysfunction and insulin resistance.Studies have suggested thatβ-cell dedifferentiation is one of the pathogeneses ofβ-cell dysfunction,but the detailed mechanism is still unclear.Most studies ofβ-cell dedifferentiation rely on rodent models and human pathological specimens.The development of in vitro systems can facilitate the exploration ofβ-cell dedifferentiation.AIM To investigate the molecular mechanism ofβ-cell dedifferentiation.Hence,an in vitro model ofβ-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1832/13 cell line.METHODS The study was further analyzed using RNA-sequencing,transmission electron microscopy,quantitative real-time polymerase chain reaction and Western blot.RESULTS Results showed that the treatment of palmitic acid and high glucose significantly up-regulatedβ-cell forbidden genes and endocrine precursor cell marker genes,and down-regulated the expression ofβ-cell specific markers.Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum(ER)stressrelated genes.Moreover,the results also showed that forkhead box O1(Foxo1)inhibition potentiated genetic changes inβ-cell dedifferentiation induced by palmitic acid and high glucose.CONCLUSION ER stress is sufficient to triggerβ-cell dedifferentiation and is necessary for palmitic acid and high glucose-inducedβ-cell dedifferentiation.Foxo1 inhibition can further enhance these phenomena.

关 键 词：β-cell dedifferentiation High glucose and palmitic acid Forkhead box O1 RNA-sequencing Endoplasmic reticulum stress 

分 类 号：R587.1[医药卫生—内分泌]