The sex hormone-binding globulin (SHBG) is involved in the onset and progression of insulin resistance and metabolic syndromes, with its expression downregulated in the placental tissues of patients with gestational diabetes mellitus (GDM). However, the underlying mechanisms for these effects remain unclear. In this study, we enrolled an equal number (30) of GDM and non-GDM puerperae who underwent cesarean section at Shengjing Hospital. After due approval by the ethics committee, the expression levels of SHBG and extracellular-signal-regulated kinase (ERK) pathway markers in the placental tissues of these individuals were measured via reverse transcription-polymerase chain reaction (RT-PCR) and Western blot assays. The correlation analysis of these genes revealed that the expression of SHBG in placental tissues was downregulated and negatively correlated with the expression of ERK pathway markers, which were upregulated in placental tissues. Further investigations using the HTR-8/ SVneo trophoblast cell line revealed that the trophoblasts with small interfering RNA (siRNA)-silenced SHBG expression displayed increased mRNA and protein expression levels of ERK pathway markers, as well as reduced apoptosis and enhanced proliferation. In contrast, trophoblasts with high SHBG expression showed a downregulated expression of ERK pathway markers, increased apoptosis, reduced proliferation, and a shorter S phase. Therefore, we believe that SHBG may participate in the onset of insulin resistance and GDM by regulating the activity of the ERK pathway. (C) 2020 Elsevier Inc. All rights reserved.