Gestational Diabetes Mellitus (GDM) affects 1 in 5 women in Australia and causes long-term maternal and fetal risks including cardiovascular, pulmonary and metabolic disorders arising from placental dysfunction. Due to heightened placental insulin resistance, the placenta enters a state of metabolic stress, disrupting cell homeostasis. This cellular stress drives endoplasmic reticulum stress, resulting in NLRP3 inflammasome activation. While the relationship between these pathways has been extensively studied in obesity-related pathologies (T2-D, cardiovascular disease), they have not been studied in the GDM placenta. We aimed to investigate placental gene expression of metabolic, endoplasmic reticulum stress, and NLRP3 inflammasome markers in GDM.
Term placentae were collected from normoglycemic (n=20) and GDM (n=20) pregnancies according to the Australasian Diabetes in Pregnancy Society Guidelines (ADIPS, 2025). Samples were matched by BMI and fetal sex. qPCR was performed on whole tissue to study gene expression of glucose transport (HK2, HIF1A, SLC2A4, SLC2A3, MTOR), endoplasmic reticulum stress (HSPA5, EIF2S1, XBP1S, TXNIP) and NLRP3 inflammasome (CASP1, PYCARD, NLRP3, PPARG, IL6, TNF, IL10, NFKB1) markers.
Overall, there were no changes in gene expression across markers of metabolic, endoplasmic reticulum stress, and NLRP3 inflammasome activation between GDM and healthy pregnancies (p>0.05). Notably, when assessing the impact of fetal sex, normoglycemic male placentae had lower MTOR expression compared to all other groups (p<0.05). HIF1A expression was reduced in GDM female placentae compared to normoglycemic controls (p < 0.05). When examining the effect of GDM management (dietary intervention, insulin administration or insulin + metformin) on gene expression, no significant differences were observed. Further study is required to investigate protein expression across these pathways.
These findings highlight potential sex-specific differences in placentae metabolic gene expression. Though there were no differences observed in endoplasmic reticulum and inflammasome genes, further investigation is required to define changes to protein expression within the GDM placenta