Circulating RANKL is required for glucose homeostasis during pregnancy

Gestational diabetes mellitus (GDM) poses a significant health burden on women worldwide, necessitating the search for predictive, diagnostic and therapeutic approaches. Increasing evidence suggests that the receptor activator of NF-κB ligand (RANKL) is closely associated with GDM, and this study explored whether RANKL can be used as a biomarker for GDM. A cross-sectional study included 399 women at 24–28 weeks of gestation, including 101 with GDM and 298 without GDM. Multivariable logistic regression, restricted cubic splines and receiver operating characteristic curve were used. An HFD-induced pregnancy-associated glucose-intolerance mouse model and JEG-3/HTR-8 trophoblast cells were used for experimental validation. Higher circulating RANKL was inversely associated with GDM after multivariable adjustment [OR = 0.994 (95% CI, 0.990–0.997)]. Adding RANKL to maternal covariates increased the area under curve from 0.711 to 0.785 ( p < 0.001). RANKL treatment improved glucose and insulin tolerance in HFD-fed pregnant mice. In trophoblast cells, RANKL increased the mRNA expression of several glucose-transporter genes. Circulating RANKL was inversely associated with GDM and provided incremental discriminatory information beyond maternal covariates. Experimental findings further suggest a potential role of RANKL in pregnancy-related glucose homeostasis. Prospective studies are needed to establish temporality and clinical utility.