Al Madhoun A, Bahman F, Ahmad R. β-cell dedifferentiation in type 2 diabetes: Interplay of metabolic stress, endoplasmic reticulum dysfunction, and forkhead box protein O1 inhibition. World J Diabetes 2025; 16(9): 109274 [DOI: 10.4239/wjd.v16.i9.109274]
Corresponding Author of This Article
Ashraf Al Madhoun, PhD, Senior Scientist, Department of Translational Medicine, Dasman Diabetes Institute, Jassim AlBahar Street, Dasman 15400, Kuwait. ashraf.madhoun@dasmaninstitute.org
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Editorial
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (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: http://creativecommons.org/licenses/by-nc/4.0/
World J Diabetes. Sep 15, 2025; 16(9): 109274 Published online Sep 15, 2025. doi: 10.4239/wjd.v16.i9.109274
β-cell dedifferentiation in type 2 diabetes: Interplay of metabolic stress, endoplasmic reticulum dysfunction, and forkhead box protein O1 inhibition
Ashraf Al Madhoun, Fatemah Bahman, Rasheed Ahmad
Ashraf Al Madhoun, Department of Translational Medicine, Dasman Diabetes Institute, Dasman 15400, Kuwait
Fatemah Bahman, Rasheed Ahmad, Department of Immunology and Microbiology, Dasman Diabetes Institute, Dasman 15400, Kuwait
Author contributions: Al Madhoun A designed the study, wrote and edited the manuscript; Bahman F and Ahmad R reviewed the literature and revised the manuscript. All authors approved the final version manuscript.
Supported by Kuwait Foundation for the Advancement of Sciences, No. RACB-2021-007.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
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: Ashraf Al Madhoun, PhD, Senior Scientist, Department of Translational Medicine, Dasman Diabetes Institute, Jassim AlBahar Street, Dasman 15400, Kuwait. ashraf.madhoun@dasmaninstitute.org
Received: May 7, 2025 Revised: June 2, 2025 Accepted: July 31, 2025 Published online: September 15, 2025 Processing time: 128 Days and 5.2 Hours
Abstract
In this editorial, we highlight the study by Wang et al published in a recent issue of the World Journal of Diabetes. Type 2 diabetes is increasingly recognized as a β-cell dysfunction disorder, with apoptosis and dedifferentiation being key factors in insulin secretion loss. β-cell dedifferentiation is a regression from a mature insulin-secretory phenotype to a progenitor-like state, characterized by the loss of key transcription factors such as pancreatic and duodenal homeobox 1 and MAF bZIP transcription factor A, and the ectopic expression of developmental markers such as neurogenin 3 and aldehyde dehydrogenase 1 family member A3. This editorial discusses the key role of metabolic stress-saturated fatty acids and high glucose-in triggering dedifferentiation through endoplasmic reticulum (ER) stress and repression of the forkhead box protein O1 (FoxO1) transcription factor. The study by Wang et al demonstrated how ER dysfunction and FoxO1 suppression collaborate to destabilize β-cell identity. Notably, evidence suggests that this process can be reversed under certain circumstances, with potential for therapies aiming to redifferentiate β-cells or prevent identity loss. We also outline the therapeutic potential of modulating ER stress pathways, controlling FoxO1 activity, and developing biomarkers to track β-cell plasticity in patients. Overall, β-cell dedifferentiation knowledge and manipulation offer new avenues for the treatment of diabetes by restoring functional β-cell mass.
Core Tip: This editorial highlights the emerging role of β-cell dedifferentiation as a central mechanism of β-cell failure in type 2 diabetes, alongside apoptosis. We emphasize recent findings that chronic metabolic stressors, namely glucotoxicity and lipotoxicity, initiate ER stress and suppress forkhead box protein O1 activity, leading to the loss of β-cell identity and function. The reversibility of this process introduces new therapeutic possibilities aimed at preserving or restoring endogenous insulin production.
