Predictive Metabolomic Markers in Early to Mid-pregnancy for Gestational Diabetes Mellitus: A Prospective Test and Validation Study

Abstract

Gestational diabetes (GDM) predisposes pregnant individuals to perinatal complications and long-term diabetes and cardiovascular diseases. We developed and validated metabolomic markers for GDM in a prospective test-validation study. In a case-control sample within the PETALS cohort (91 GDM, 180 non-GDM; discovery set), a random PETALS subsample (42 GDM, 372 non-GDM; validation set 1), and a case-control sample within the GLOW trial (35 GDM, 70 non-GDM; validation set 2), fasting serum untargeted metabolomics were measured by gas chromatography/time-of-flight mass spectrometry. Multivariate enrichment analysis examined metabolites-GDM associations. Ten-fold cross-validated LASSO regression identified predictive metabolomic markers at gestational weeks (GW) 10-13 and 16-19 for GDM. The purinone metabolites at GW 10-13 and 16-19, and the amino acids, amino alcohols, hexoses, indoles, and pyrimidines metabolites at GW 16-19 were positively associated with GDM risk (FDR <0.05). A 17-metabolite panel at GW 10-13 outperformed the model using conventional risk factors including fasting glycemia (discovery AUC: 0.871 vs. 0.742; validation 1: 0.869 vs. 0.731; validation 2: 0.972 vs. 0.742; P <0.01). Similar results were observed for a 13-metabolite panel at GW 17-19. Dysmetabolism is present early in pregnancy among individuals progressing to GDM. Multi-metabolite panels in early pregnancy can predict GDM risk beyond conventional risk factors.

Urinary Aromatic Amino Acid Metabolites Associated With Postoperative Emergence Agitation in Paediatric Patients After General Anaesthesia: Urine Metabolomics Study

“…The levels of metabolites were log-transformed (base 10) and mean-centred and divided by the standard deviation of each variable. The least absolute shrinkage and selection operator (LASSO) regression using a 10-fold cross-validation was used to select the most predictive metabolites to EA ( Zhu, et al, 2022 ). The selection was judged from the lambda with 1 SE of the minimum partial likelihood of deviance.…”

Interaction and Metabolic Pathways: Elucidating the Role of Gut Microbiota in Gestational Diabetes Mellitus Pathogenesis

“…Amino acid metabolic products, in particular, tyrosine and tryptophan metabolites have been shown to have an impact on GLP-1 synthesis [ 107 ]. The decreased levels of indole compounds, metabolites derived from tryptophan through microbial decarboxylation and dehydrogenation reactions, in maternal serum during early and mid-gestation are associated with an increased risk of GDM [ 108 ], which may be attributed to reduced populations of tryptophan-metabolizing bacteria like Bifidobacterium [ 87 ] and Lactobacillus [ 88 ] in the gut microbiota of GDM patients, consequently leading to impaired synthesis of indole-3-propionic acid and secretion of incretins like GLP-1 and GLP-2, further aggravating insulin resistance in GDM [ 109 ]. Furthermore, γ-aminobutyric acid can affect insulin sensitivity through the GPR41/43 pathway [ 65 ].…”

Perspectives from metabolomics in the early diagnosis and prognosis of gestational diabetes mellitus

“…Zhu et al. ( 58 ) explored metabolomics markers and developed a panel for the early diagnosis of GDM, which paved the way for clinical practice. Time-of-flight GC-MS was performed in cohorts from three population-based studies conducted by different centers, which included 168 patients with GDM and 622 normal controls.…”

“…Finally, Zhu et al. ( 58 ) found that a 17-metabolite panel at 10–13 weeks of gestation and a 13-metabolite panel at 17–19 weeks of gestation outperformed the model using conventional risk factors, including fasting glycemia.…”