This study was designed to identify serum and amniotic fluid (AF) metabolic profile changes in response to gestational diabetes mellitus (GDM) and explore the association with maternal–fetal outcomes. We established the GDM rat models by combining a high-fat diet (HFD) with an injection of low-dose streptozotocin (STZ), detected the fasting plasma glucose (FPG) of pregnant rats in the second and third trimester, and collected AF and fetal rats by cesarean section on gestational day 19 (GD19), as well as measuring the weight and crown–rump length (CRL) of fetal rats. We applied liquid chromatography–tandem mass spectrometry (LC-MS/MS) for the untargeted metabolomics analyses of serum and AF samples and then explored their correlation with maternal–fetal outcomes via the co-occurrence network. The results showed that 91 and 68 metabolites were upregulated and 125 and 78 metabolites were downregulated in serum and AF samples exposed to GDM, respectively. In maternal serum, the obvious alterations emerged in lipids and lipid-like molecules, while there were great changes in carbohydrate and carbohydrate conjugates, followed by amino acids, peptides, and analogs in amniotic fluid. The altered pathways both in serum and AF samples were amino acid, lipid, nucleotide, and vitamin metabolism pathways. In response to GDM, changes in the steroid hormone metabolic pathway occurred in serum, and an altered carbohydrate metabolism pathway was found in AF samples. Among differential metabolites in two kinds of samples, there were 34 common biochemicals shared by serum and AF samples, and a mutual significant association existed. These shared differential metabolites were implicated in several metabolism pathways, including choline, tryptophan, histidine, and nicotinate and nicotinamide metabolism, and among them, N1-methyl-4-pyridone-3-carboxamide, 5’-methylthioadenosine, and kynurenic acid were significantly associated with both maternal FPG and fetal growth. In conclusion, serum and AF metabolic profiles were remarkably altered in response to GDM. N1-Methyl-4-pyridone-3-carboxamide, 5’-methylthioadenosine, and kynurenic acid have the potential to be taken as biomarkers for maternal–fetal health status of GDM. The common and inter-related differential metabolites both in the serum and AF implied the feasibility of predicting fetal health outcomes via detecting the metabolites in maternal serum exposed to GDM.
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