Basic Study
Copyright ©The Author(s) 2025. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. May 15, 2025; 16(5): 102994
Published online May 15, 2025. doi: 10.4239/wjd.v16.i5.102994
TERT/FOXO1 signaling promotes islet β-cell dysfunction in type 2 diabetes mellitus by regulating ATG9A-mediated autophagy
Xiao-Tian Lei, Xiang-Fen Chen, Sheng Qiu, Jia-Ying Tang, Shan Geng, Gang-Yi Yang, Qi-Nan Wu
Xiao-Tian Lei, Sheng Qiu, Gang-Yi Yang, Department of Endocrinology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 402360, China
Xiang-Fen Chen, Jia-Ying Tang, Shan Geng, Qi-Nan Wu, Department of Endocrinology, The Affiliated Dazu’s Hospital of Chongqing Medical University, The People's Hospital of Dazu, Chongqing 402360, China
Co-first authors: Xiao-Tian Lei and Xiang-Fen Chen.
Co-corresponding authors: Gang-Yi Yang and Qi-Nan Wu.
Author contributions: Lei XT conducted the animal experiments; Chen XF and Wu QN performed mechanistic studies; Yang GY and Wu QN analyzed data; Tang JY, Qiu S and Geng S contributed to technical assistance and discussion; Geng S provided research material and technical assistance; Lei XT, Chen XF and Qiu S wrote, reviewed, and edited the manuscript; Wu QN, Yang GY, Chen XF designed directed the project, and contributed to the discussion; Yang GY, Wu QN are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Lei XT and Chen XF contributed equally to this work as co-first authors. In our study, the two corresponding authors have made equal contributions at critical stages. Professor Wu played a significant role in the writing and revision of the manuscript, ensuring the clarity of the research findings and the logical rigor, thereby enhancing the overall academic quality of the article. Professor Yang provided crucial guidance in experimental design, data collection, and quality control, ensuring the reliability and scientific validity of the experimental data. The expertise and contributions of the two corresponding authors complemented each other, and their work guaranteed the successful publication of the article. Therefore, it is both reasonable and necessary to list both as corresponding authors, which also serves as an acknowledgment of their respective contributions and aligns with the conventions of academic publishing.
Supported by National Natural Science Foundation of China, No. 82000792; General Project of Chongqing Natural Science Foundation, No. CSTB2023NSCQ-MSX0246 and No. CSTB2022NSCQ-MSX1271; Research Project of the State Administration of Traditional Chinese Medicine on Collaborative Chronic Disease Management of Traditional Chinese Medicine and Western Medicine, No. CXZH2024087; and Science and Health Joint Project of Dazu District Science and Technology Bureau, No. DZKJ2024JSYJ-KWXM1002.
Institutional review board statement: This study and experimental procedures were approved by the Medical Ethics Committee of the Affiliated Dazu’s Hospital of Chongqing Medical University (approval no .2024LLSC126).
Institutional animal care and use committee statement: The research proposal and materials comply with the principles of medical ethics and the requirements of the Helsinki Declaration. The research design has scientific basis, and the selected animal species, grades, quantities, and specifications are appropriate. During the experiment, animals were treated with kindness, anesthesia and analgesia were administered, euthanasia was performed after the experiment, and the animals were treated harmlessly after death without causing any harm to the environment. The experiment complied with ethical standards for animal experimentation.
Conflict-of-interest statement: The authors have no conflicts 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: All the data and materials that are required to reproduce these findings can be shared by contacting the corresponding author, the email: 152299@hospital.cqmu.edu.cn.
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: Qi-Nan Wu, MD, PhD, Professor, Chief Physician, Department of Endocrinology, The Affiliated Dazu’s Hospital of Chongqing Medical University, The People's Hospital of Dazu, No. 1073 Second Ring Road, Dazu District, Chongqing 402360, China. 152299@hospital.cqmu.edu.cn
Received: November 5, 2024
Revised: February 9, 2025
Accepted: March 19, 2025
Published online: May 15, 2025
Processing time: 172 Days and 4.6 Hours
Abstract
BACKGROUND

Type 2 diabetes mellitus (T2DM) is a severe global health problem that causes prolonged disease exposure and an elevated risk for chronic complications, posing a substantial health burden. Although therapies, such as GLP-1 receptor agonists and SGLT2 inhibitors, have been successfully developed, new therapeutic options are still expected to offer better blood glucose control and decrease complications.

AIM

To elucidate the mechanism by which TERT/FOXO1 affects high glucose (HG)-induced dysfunction in islet β-cells via the regulation of ATG9A-mediated autophagy.

METHODS

High-fat diet (HFD)-fed/streptozotocin (STZ)-treated mice or HG-treated MIN6 cells were used to establish T2DM models. Fasting blood glucose (FBG) and insulin levels in mice, as well as morphological changes in islet tissues, were assessed. Cell proliferation and the apoptosis rate were measured via EdU assays and flow cytometry, respectively. The expression levels of TERT, FOXO1, ATG9A and autophagy-related proteins (LC3B, p62) were analyzed via western blotting. The relationship between FOXO1 and ATG9A was assessed using dual-luciferase reporter gene assays and ChIP assays.

RESULTS

T2DM modeling in HFD-fed/STZ-treated mice and HG-treated MIN6 cells led to elevated TERT and FOXO1 expression and reduced ATG9A expression. Mice with T2DM were found to have decreased body weight, worsened morphology, elevated FBG and suppressed insulin levels. HG-treated MIN6 cells presented decreased viability and LC3B expression, in addition to increased p62 expression and apoptosis rates. FOXO1 knockdown both in vitro and in vivo protected mice and cells against islet β-cell dysfunction via the activation of autophagy. The molecular mechanism involved the suppression of ATG9A expression by TERT through FOXO1 transcription activation.

CONCLUSION

Our results suggested that TERT/FOXO1 inhibits ATG9A expression to decrease islet β-cell function in T2DM.

Keywords: TERT; ATG9A; Autophagy; Islet β-cells; Type 2 diabetes mellitus

Core Tip: Our research elucidated the mechanism by which TERT/FOXO1 affects high glucose-induced dysfunction in islet β-cells via the regulation of ATG9A-mediated autophagy. It revealed the mechanism by which TERT/FOXO1 mediates ATG9A to inhibit autophagy in mouse’s β cells. These findings indicated that FOXO1 is a potential target for the treatment of type 2 diabetes mellitus (T2DM) by acting as an autophagy regulator, deepening the understanding of the autophagy mechanisms involved in the regulation of β-cell function in the context of T2DM.