Tryptophan and purine metabolites are consistently upregulated in the urinary metabolome of patients diagnosed with gestational diabetes mellitus throughout pregnancy: A longitudinal metabolomics study of Chinese pregnant women part 2

摘要

Abstract Background Gestational diabetes mellitus (GDM) is a pathological state of glucose intolerance associated with adverse pregnancy outcomes and an increased risk of developing maternal type 2 diabetes later in life. The mechanisms underlying GDM development are not fully understood. We examined the pathophysiology of GDM through comprehensive metabolic profiling of maternal urine, using participants from a longitudinal cohort of normal pregnancies and pregnancies complicated by GDM. Methods Based on ultra-performance liquid chromatography/hybrid quadrupole time-of-flight mass spectrometry, an untargeted metabolomics study was performed to explore the differences in the urinary metabolome of GDM cases and healthy controls over the course of pregnancy. Multilevel statistical approaches were employed to address the complex metabolomic data obtained from a longitudinal cohort. Results The results indicated that tryptophan and purine metabolism was associated with GDM. The tryptophan-kynurenine pathway was activated in the GDM subjects before placental hormones or the fetoplacental unit could have produced any physiological effect. Hypoxanthine, xanthine, xanthosine, and 1-methylhypoxanthine were all elevated in the urine metabolome of subjects with GDM. Catabolism of purine nucleosides leads ultimately to the production of uric acid, which discriminated the subjects with GDM from controls. Conclusions The results support the notion that GDM may be a predisposed condition, or prediabetic state, which is manifested during pregnancy. This challenges the conventional view of the pathogenesis of GDM, which assumes placental hormones are the major causes of insulin resistance in GDM. Highlights ? A novel two-step data pre-processing method was developed to combat the dilutional variation of the urine samples. A novel multilevel statistics was used to analyse the time-course data set. ? Altered tryptophan and purine metabolism were observed as early as the first trimester in the subjects diagnosed with GDM. ? The tryptophan-kynurenine pathway was activated in GDM subjects before the placental hormones or fetoplacental unit could have produced a physiological effect. ? Catabolism of purine nucleosides leads ultimately to the production of uric acid, which discriminated the diseased and control subjects. ? This is the first study linking tryptophan and purine metabolism with GDM and supports the notion that GDM may be a predisposed condition that is manifested during pregnancy.