Assessment of the role of general control nonderepressible 2 in gestational diabetes mellitus progression and the underlying mechanisms

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.