Li W, Wang YR, Wang SL. Assessment of the role of general control nonderepressible 2 in gestational diabetes mellitus progression and the underlying mechanisms. World J Diabetes 2026; 17(7): 119780 [DOI: 10.4239/wjd.119780]
Corresponding Author of This Article
Shu-Li Wang, MB, Research Fellow, Department of Gynecology and Obstetrics, Shenzhen Nanshan People’s Hospital, No. 89 Taoyuan Road, Nantou Street, Shenzhen 518000, Guangdong Province, China. sznsnancy@163.com
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Endocrinology & Metabolism
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Li W, Wang YR, Wang SL. Assessment of the role of general control nonderepressible 2 in gestational diabetes mellitus progression and the underlying mechanisms. World J Diabetes 2026; 17(7): 119780 [DOI: 10.4239/wjd.119780]
World J Diabetes. Jul 15, 2026; 17(7): 119780 Published online Jul 15, 2026. doi: 10.4239/wjd.119780
Assessment of the role of general control nonderepressible 2 in gestational diabetes mellitus progression and the underlying mechanisms
Wan Li, Ya-Ru Wang, Shu-Li Wang
Wan Li, Ya-Ru Wang, Shu-Li Wang, Department of Gynecology and Obstetrics, Shenzhen Nanshan People’s Hospital, Shenzhen 518000, Guangdong Province, China
Author contributions: Li W, Wang YR and Wang SL designed the research study; Li W and Wang YR performed the research and wrote the manuscript; Wang YR analyzed the data; Li W and Wang SL supervised the study and acquired funding; Wang SL revised the manuscript; and all authors have read and approved the final manuscript.
AI contribution statement: The response to reviewers was not AI-generated. It was developed and reviewed by the authors. We used ChatGPT for language polishing.
Supported by Shenzhen Nanshan District Health Science and Technology Program Project, No. NS2023102; and Municipal Financial Subsidy of Nanshan District Medical Key Discipline Construction.
Institutional animal care and use committee statement: The study was reviewed and approved by the Animal Ethics Committee of the Guangdong Provincial Medical Laboratory Animal Center (Approval No. D202506-14).
Conflict-of-interest statement: The authors declare that they have no competing interests regarding the publication of this paper.
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: The data used to support the findings of this study are available from the corresponding author upon request.
Corresponding author: Shu-Li Wang, MB, Research Fellow, Department of Gynecology and Obstetrics, Shenzhen Nanshan People’s Hospital, No. 89 Taoyuan Road, Nantou Street, Shenzhen 518000, Guangdong Province, China. sznsnancy@163.com
Received: February 6, 2026 Revised: March 31, 2026 Accepted: May 15, 2026 Published online: July 15, 2026 Processing time: 154 Days and 0.4 Hours
Abstract
BACKGROUND
Gestational diabetes mellitus (GDM) is a metabolic disorder occurring during pregnancy that poses substantial risks to both mothers and offspring. General control nonderepressible 2 (GCN2) is a key sensor of cellular stress and a central mediator of the integrated stress response; however, its role in GDM remains unclear.
AIM
To investigate the role of GCN2 in GDM progression and its underlying mechanisms.
METHODS
A GDM mouse model (n = 6/group) was established using a high-fat/high-sugar diet with GCN2 knockdown via shRNA. High glucose (HG)-treated HTR-8/SVneo cells were used as an in vitro model. Gene expression, metabolic parameters, histological changes, oxidative stress, endoplasmic reticulum stress (ERS), and mitochondrial function were assessed using molecular and biochemical methods.
RESULTS
GCN2 expression was increased in placental tissues of GDM mice and in HG-treated trophoblasts. GCN2 silencing significantly improved glucose-lipid metabolic abnormalities, reduced hepatic lipid accumulation, restored hepatic glycogen content, and alleviated placental apoptosis, oxidative stress, ERS activation, and mitochondrial dysfunction (P < 0.05). In HG-exposed trophoblasts, GCN2 knockdown similarly attenuated ERS-mediated mitochondrial impairment, oxidative damage, and apoptosis (P < 0.05), whereas these protective effects were reversed by the ERS activator tunicamycin.
CONCLUSION
GCN2 is involved in GDM progression and may regulate placental injury through ERS-associated mitochondrial dysfunction, suggesting a potential therapeutic target.
Core Tip: General control nonderepressible 2 is an important regulator of cellular stress responses, but its role in gestational diabetes mellitus remains unclear. This study demonstrates that it contributes to metabolic dysfunction and placental injury by modulating endoplasmic reticulum stress-associated mitochondrial dysfunction. Silencing this molecule alleviates oxidative stress and apoptosis while improving glucose and lipid metabolism. These findings suggest a potential mechanistic link between cellular stress and placental dysfunction and highlight a possible therapeutic target.
