Lipasin Is Associated with Gestational Diabetes Mellitus and Modulates Glucose Handling in Insulin-Resistant HepG2 Cells: Potential Involvement of SREBP1 and AMPK Signaling

Background: The clinical association of Lipasin (ANGPTL8) with gestational diabetes mellitus (GDM) and its cellular correlates remain uncertain. We evaluated Lipasin in clinical specimens and an insulin-resistant HepG2 model. Methods: This retrospective, single-center case–control study included 85 women with GDM and 82 women with normal glucose tolerance (NGT). Serum, cord-blood, and placental Lipasin were assessed. Associations with GDM status were evaluated by multivariable logistic regression. Insulin-resistant HepG2 cells with Lipasin overexpression or knockout were used for functional assessment. Proteomic and metabolomic analyses were interpreted as exploratory and reanalyzed using Benjamini–Hochberg false-discovery-rate (FDR) control. Results: Lipasin expression was higher in the GDM group in the GSE203346 dataset and in maternal serum, cord blood, and placenta. Serum Lipasin was associated with GDM after adjustment for age, pre-pregnancy body mass index, HDL, triglycerides, and total cholesterol (odds ratio, 1.088 per 10 pg/mL; 95% confidence interval, 1.017–1.164; p = 0.0147). In insulin-resistant HepG2 cells, Lipasin overexpression was associated with increased glucose uptake, reduced PCK2 abundance, increased GLUT4 abundance, and changes in SREBP1 abundance and AMPK phosphorylation; Lipasin knockout did not significantly alter the main endpoints. Full-table FDR reanalysis identified 436 FDR-supported proteins and 313 FDR-supported metabolites. Compound C- and metformin-related observations were exploratory. Conclusions: Lipasin is associated with GDM and can modulate glucose handling in the tested HepG2 model. SREBP1- and AMPK-related signals are candidate correlates, not an established causal pathway. The findings do not establish diagnostic performance, therapeutic efficacy, or whole-body relevance.