Vitronectin promotes insulin resistance in trophoblast cells by activating JNK in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is a common disorder in the clinic, which may lead to severe detrimental outcomes both for mothers and infants. However, the underlying mechanisms for GDM are still not clear. In the present study, we performed label-free proteomics using placentas from GDM patients and normal controls. Vitronectin caused our attention among differentially expressed proteins due to its potential role in the pathological progression of GDM. Vitronectin was increased in the placentas of GDM patients, which was confirmed by Western blot analysis. Vitronectin represses insulin signal transduction in trophoblast cells, whereas the knockdown of vitronectin further potentiates insulin-evoked events. Neutralization of CD51/61 abolishes the repressed insulin signal transduction in vitronectin-treated trophoblast cells. Moreover, vitronectin activates JNK in a CD51/61-depedent manner. Inhibition of JNK rescues impaired insulin signal transduction induced by vitronectin. Overall, our data indicate that vitronectin binds CD51/61 in trophoblast cells to activate JNK, and thus induces insulin resistance. In this regard, increased expression of vitronectin is likely a risk factor for the pathological progression of GDM. Moreover, blockade of vitronectin production or its receptors (CD51/61) may have therapeutic potential for dealing with GDM.

Identification of methylation-driven genes, circulating miRNAs and their potential regulatory mechanisms in gestational diabetes mellitus.

OBJECTIVE: Gestational diabetes mellitus (GDM) is a major pregnancy complication. The purpose of this study is to investigate the molecular regulatory mechanisms of GDM. METHODS: RNA-seq and methylation data of GDM were retrieved from the Gene Expression Omnibus database. Following principal component analysis (PCA), differentially expressed mRNAs and microRNAs (miRNAs) in the blood were highlighted between GDM and the control. Then, an abnormally expressed miRNA-mRNA network was constructed, based on which a protein-protein interaction (PPI) network was established to identify hub genes. Differentially expressed and methylated genes were identified for GDM, followed by functional enrichment analysis. RESULTS: According to PCA results, no outlier samples were found. A total of 35 differentially expressed circulating miRNAs were identified for GDM. The miRNA-mRNA regulatory network consisted of 94 miRNA-mRNA pairs. The PPI network contained 10 hub genes, including HIF1A, TLR2, FOS, IL6R, MYLIP, ABCA1, SELL, BCL3, AP1G1 and NECAP1. Furthermore, 22 down-regulated and hypermethylated genes and 8 up-regulated and hypomethylated genes were identified for GDM, which are related to helper T cell (Th) differentiation. CONCLUSION: We identified methylation-driven genes and circulating miRNAs for GDM, which have the potential to serve as novel diagnostic biomarkers.