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BACKGROUND The current study aims to investigate the differences of glycoprotein non-metastatic melanoma protein B (GPNMB) levels between gestational diabetes mellitus (GDM) women and normal blood glucose women during pregnancy to provide the basis for early intervention and treatment of GDM. METHODS The level of GPNMB was detected using an enzyme-linked immunosorbent assay (ELISA). Pearson's correlation assay was performed to analyze the correlation between serum GPNMB and fasting plasma glucose (FPG) or hemoglobin A1c (HbA1c). The receiver operating characteristic (ROC) curve was carried out to analyze the diagnostic value of serum GPNMB. RESULTS Our data showed that the serum GPNMB level in GDM group was higher than that in normal blood glucose group at 5 - 12 weeks, 13 - 23 weeks, and 24 - 28 weeks of gestation, but there was no significant difference at 29 - 37 weeks of gestation. Meanwhile, the total level of serum GPNMB in GDM group was significantly higher than that in normal blood glucose group. Further study indicated that serum GPNMB positively correlated with FPG (r = 0.562, p < 0.0001) or HbA1c (r = 0.652, p < 0.0001). ROC analysis showed that serum GPNMB level at 13 - 23 weeks of gestation had a good predictive effect on predicting GDM at 24 weeks of gestation and beyond. When the cutoff value of serum GPNMB level was 2.46 µg/L, the sensitivity and specificity were 80% and 72%, respectively. CONCLUSIONS The serum GPNMB level at 13 - 23 weeks of gestation is an independent risk factor for GDM in 24 weeks and beyond, and early inhibition with GPNMB may provide a preventive measure in GDM women.