Combined Metabolomic Analysis of Plasma and Urine Reveals AHBA, Tryptophan and Serotonin Metabolism as Potential Risk Factors in Gestational Diabetes Mellitus (GDM)

Abstract

Gestational diabetes mellitus during pregnancy has severe implications for the health of the mother and the fetus. Therefore, early prediction and an understanding of the physiology are an important part of prenatal care. Metabolite profiling is a long established method for the analysis and prediction of metabolic diseases. Here, we applied untargeted and targeted metabolomic protocols to analyze plasma and urine samples of pregnant women with and without GDM. Univariate and multivariate statistical analyses of metabolomic profiles revealed markers such as 2-hydroxybutanoic acid (AHBA), 3-hydroxybutanoic acid (BHBA), amino acids valine and alanine, the glucose-alanine-cycle, but also plant-derived compounds like sitosterin as different between control and GDM patients. PLS-DA and VIP analysis revealed tryptophan as a strong variable separating control and GDM. As tryptophan is biotransformed to serotonin we hypothesized whether serotonin metabolism might also be altered in GDM. To test this hypothesis we applied a method for the analysis of serotonin, metabolic intermediates and dopamine in urine by stable isotope dilution direct infusion electrospray ionization mass spectrometry (SID-MS). Indeed, serotonin and related metabolites differ significantly between control and GDM patients confirming the involvement of serotonin metabolism in GDM. Clustered correlation coefficient visualization of metabolite correlation networks revealed the different metabolic signatures between control and GDM patients. Eventually, the combination of selected blood plasma and urine sample metabolites improved the AUC prediction accuracy to 0.99. The detected GDM candidate biomarkers and the related systemic metabolic signatures are discussed in their pathophysiological context. Further studies with larger cohorts are necessary to underpin these observations.

Metabolomic Analysis Reveals Distinct Profiles in the Plasma and Urine Associated with IgE Reactions in Childhood Asthma

“…Furthermore, these urinary hydroxyl acids were strongly correlated with plasma leucine and valine levels. These findings support the statement that the accumulation of the urinary hydroxy acids during ketoacidosis can represent the state of ketosis [19], which may be caused by the derangement of the metabolism of leucine, isoleucine, and valine.…”

The fecal metabolome is associated with gestational diabetes mellitus

“…Metabolomics has been recognized as a powerful approach in the study of gestational diabetes. 18,29 GDM associated metabolic disorders have been reported in maternal blood, 30 maternal urine, 31,32 cord blood 33 and fetal serum. 34 In addition to the previous reports, this study provides evidences to support metabolic disorder in feces of women with GDM.…”

Association of the SLC6A4 gene 5HTTLPR polymorphism and ADHD with epilepsy, gestational diabetes, and parental substance abuse in Mexican mestizo children

“…The occurrence of GDM per se is a risk factor for other conditions, were the onset of this condition occurs within a period of fetal brain development, leading to deficits in fine and gross motor function, lower verbal IQ language impairment, greater inattention and hyperactivity, and poorer general cognitive function (Nomura et al, 2012). Recently, it has been reported that serotonin and related metabolites have notable functions regulating growth and development of the fetus and are involved in a great number of physiological pathways and adaptation processes during pregnancy, where serotonin metabolism is impaired in GDM (Leitner et al, 2017). Even more, a previous epigenetic study showed significant decreased DNA methylation and regulation of SLC6A4 expression in the placenta of pregnant mothers with GDM (Blazevic et al, 2017).…”