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.
Highlights
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or new recognition in pregnancy (Kautzky-Willer et al, 2004, 2016b)
After extraction with methanol/chloroform/water (2.5:1:0.5 (v/v/v)) (MCW) no further phase separation was performed and the complete MCW extract was injected into gas chromatography coupled to mass spectrometry (GC-MS)
Our results could be explained by (1) a different lifestyle of the patients with GDM and those without GDM (2) a higher body mass index (BMI) of women with GDM compared to the control group could be a reason either, or (3) higher serotonin levels in the case of disrupted metabolism, like GDM, could substantiate that serotonin is a factor in maintaining normoglycemia, the increase presenting a possible compensatory mechanism
Summary
Gestational diabetes mellitus (GDM) is defined as glucose intolerance with onset or new recognition in pregnancy (Kautzky-Willer et al, 2004, 2016b). Women who had GDM have an elevated risk to develop Diabetes mellitus Type 2 (T2DM) or cardiovascular disease (Tobias et al, 2011), as well as hyperlipidemia or obesity (Bartha et al, 2008; Clausen et al, 2009; Landon et al, 2009; Gillman et al, 2010; Harreiter et al, 2014) in later life, whereas their children have a higher risk for obesity or impaired fasting glucose (Silverman et al, 1995). Intrauterine exposure to hyperglycemia is linked to an increased risk for neuropsychiatric and neurodevelopmental disorders of the offspring (Xiang et al, 2015; Nahum Sacks et al, 2016)
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