Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. May 15, 2025; 16(5): 95431
Published online May 15, 2025. doi: 10.4239/wjd.v16.i5.95431
Endoplasmic reticulum stress and forkhead box protein O1 inhibition mediate palmitic acid and high glucose-induced β-cell dedifferentiation
Li-Kun Wang, Chu-Chu Kong, Ting-Yan Yu, Hui-Song Sun, Lu Yang, Ying Sun, Ming-Yu Li, Wei Wang
Li-Kun Wang, Chu-Chu Kong, Ting-Yan Yu, Lu Yang, Wei Wang, Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
Li-Kun Wang, Chu-Chu Kong, Ting-Yan Yu, Hui-Song Sun, Lu Yang, Ming-Yu Li, Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences, Xiamen University, Xiamen 361102, Fujian Province, China
Ying Sun, Department of Equipment and Materials, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, Fujian Province, China
Co-first authors: Li-Kun Wang and Chu-Chu Kong.
Co-corresponding authors: Ming-Yu Li and Wei Wang.
Author contributions: Li MY and Wang W are the guarantors of this work and, as such, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis; Wang W, Li MY, and Wang LK designed the study; Wang LK performed key experiments and drafted the manuscript; Kong CC, Yu TY, Sun HS, Yang L and Sun Y participated in the planning of the work and the interpretation of the results; Li MY and Wang W revised the paper.
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; and Scientific Research Foundation for Advanced Talents, Xiang’an Hospital of Xiamen University, No. PM201809170005.
Institutional review board statement: The study does not involve any human experiments.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee of Xiamen university.
Conflict-of-interest statement: The authors declare that they have no conflict of interest.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: No additional data are available.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Wei Wang, MD, Chief Physician, Professor, Department of Endocrinology, Xiang’an Hospital of Xiamen University, School of Medicine, Xiamen University, No. 2000 Xiang’an East Road, Xiang’an District, Xiamen 361102, Fujian Province, China. wwei19742007@hotmail.com
Received: April 10, 2024
Revised: January 13, 2025
Accepted: March 24, 2025
Published online: May 15, 2025
Processing time: 379 Days and 23.3 Hours
Abstract
BACKGROUND

Type 2 diabetes mellitus is characterized by pancreatic β-cell dysfunction and insulin resistance. Studies have suggested that β-cell dedifferentiation is one of the pathogeneses of β-cell dysfunction, but the detailed mechanism is still unclear. Most studies of β-cell dedifferentiation rely on rodent models and human pathological specimens. The development of in vitro systems can facilitate the exploration of β-cell dedifferentiation.

AIM

To investigate the molecular mechanism of β-cell dedifferentiation. Hence, an in vitro model of β-cell dedifferentiation induced by palmitic acid and high glucose was established using the INS-1 832/13 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-regulated β-cell forbidden genes and endocrine precursor cell marker genes, and down-regulated the expression of β-cell specific markers. Data showed that dedifferentiated INS-1 cells up-regulated the expression of endoplasmic reticulum (ER) stress-related genes. Moreover, the results also showed that forkhead box O1 (Foxo1) inhibition potentiated genetic changes in β-cell dedifferentiation induced by palmitic acid and high glucose.

CONCLUSION

ER stress is sufficient to trigger β-cell dedifferentiation and is necessary for palmitic acid and high glucose-induced β-cell dedifferentiation. Foxo1 inhibition can further enhance these phenomena.

Keywords: β-cell dedifferentiation; High glucose and palmitic acid; Forkhead box O1; RNA-sequencing; Endoplasmic reticulum stress

Core Tip: β-cell dedifferentiation is one cause of β cell dysfunction, but the underlying mechanisms remain unclear. In this study, we established an in vitro model of β-cell dedifferentiation induced by high-glucose and palmitic acid and showed that the inhibition of forkhead box O1 can further enhance these phenomena. We found that high glucose and palmitic acid treatments significantly downregulated the expression of β-cell-specific markers and upregulated the expression of β-cell-disabling genes and endocrine precursor cell marker genes by RNA-sequencing, and that endoplasmic reticulum stress is the key to β-cell dedifferentiation. This study will be beneficial for investigating the mechanism of β-cell dysfunction caused by dedifferentiation.