Enhanced SLC2A4 expression mitigates insulin resistance in gestational diabetes mellitus via the FoxO signaling pathway .

Gestational diabetes mellitus (GDM), a type of diabetes mellitus occurring in pregnant women, increases the risk of birth trauma. Solute carrier family 2 member 4 (SLC2A4) polymorphism is notably associated with GDM susceptibility; however, the mechanism is unknown. In the present study, HTR-8/SVneo cells were treated with high glucose concentrations and transfected with SLC2A4 and Forkhead box O (FoxO)1 to investigate their roles in the insulin (INS) resistance of GDM trophoblast cells. The results showed that the expression levels of SLC2A4, INS receptor (INSR) and INS were significantly decreased in HTR-8/SVneo cells under hyperglycemic conditions. Furthermore, overexpression of SLC2A4 reduced the levels of phosphorylated FoxO (p-FoxO)1, FoxO1, p-FoxO3a and FoxO3a but enhanced the expression levels of INS and INSR, improving glucose uptake within the hyperglycemic environment. Additionally, both the analysis of the signaling pathways related to SLC2A4 and GDM using the Kyoto Encyclopedia of Genes and Genomes pathway analysis and the results of CCK-8 determination of cell vitality both emphasized that the FoxO signaling was a pivotal pathway affected by SLC2A4 in GDM. In conclusion, the present study demonstrated that overexpression of SLC2A4 enhanced the INS signaling pathway, as evidenced by western blotting showing increased levels of INSR and INS, along with elevated glucose uptake. Concurrently, SLC2A4 overexpression inhibited the FoxO signaling pathway, as indicated by reduced protein levels of p-FoxO1, total FoxO1, p-FoxO3a and total FoxO3a. Collectively, these molecular alterations contribute to the alleviation of insulin resistance in patients with GDM.