Gestational Diabetes Is Characterized by Decreased Medium-Chain Acylcarnitines and Elevated Purine Degradation Metabolites across Pregnancy: A Case–Control Time-Course Analysis

Abstract

Gestational Diabetes Mellitus (GDM) results in complications affecting both mothers and their offspring. Metabolomic analysis across pregnancy provides an opportunity to better understand GDM pathophysiology. The objective was to conduct a metabolomics analysis of first and third trimester plasma samples to identify metabolic differences associated with GDM development. Forty pregnant women with overweight/obesity from a multisite clinical trial of a lifestyle intervention were included. Participants who developed GDM (n = 20; GDM group) were matched with those who did not develop GDM (n = 20; Non-GDM group). Plasma samples collected at the first (10−16 weeks) and third (28−35 weeks) trimesters were analyzed with ultra-performance liquid chromatography−mass spectrometry (UPLC-MS). Cardiometabolic risk markers, dietary recalls, and physical activity metrics were also assessed. Four medium-chain acylcarnitines, lauroyl-, octanoyl-, decanoyl-, and decenoylcarnitine, significantly differed over the course of pregnancy in the GDM vs Non-GDM group in a group-by-time interaction (p < 0.05). Hypoxanthine and inosine monophosphate were elevated in the GDM group (p < 0.04). In both groups over time, bile acids and sorbitol increased while numerous acylcarnitines and αhydroxybutyrate decreased (p < 0.05). Metabolites involved in fatty acid oxidation and purine degradation were altered across the first and third trimesters of GDM-affected pregnancies, providing insight into metabolites and metabolic pathways altered with GDM development.

Multigenerational diabetes mellitus

“…Excessive fatty acid oxidation, depleted TCA intermediates and insulin resistance may cause overload of maternal mitochondria. This leads to incomplete fatty acid oxidation and an increase in plasma acylcarnitines, though acylcarnitines are noted to decrease as pregnancy progresses, possibly due to dietary changes ( 57 ).…”

“…The kynurenine pathway, which produces nicotinamine adenine dinucleotide (NAD+) from tryptophan, is thought to be activated in GDM before placental hormones can produce a physiological effect ( 56 ). Increased levels of purine degradation metabolites (inosine monophosphate and hypoxanthine) are also seen in GDM, T1D and T2D ( 57 ). Uric acid is a downstream product of hypoxanthine oxidation which is commonly seen in diabetes, attributed to be due to concurrent generation of superoxide anions associated with increased inflammation and impaired insulin secretion ( 57 ).…”

“…Increased levels of purine degradation metabolites (inosine monophosphate and hypoxanthine) are also seen in GDM, T1D and T2D ( 57 ). Uric acid is a downstream product of hypoxanthine oxidation which is commonly seen in diabetes, attributed to be due to concurrent generation of superoxide anions associated with increased inflammation and impaired insulin secretion ( 57 ).…”

Using metabolomics and proteomics to identify the potential urine biomarkers for prediction and diagnosis of gestational diabetes

“… 20 In some studies on plasma purine degradation metabolites, similar results have shown that xanthine, hypoxanthine, and inosine monophosphate (IMP) are elevated in GDM patients. 94 , 95 A meta-analysis including 11 observational studies found that the level of serum uric acid in GDM patients was higher and correlated positively with an increased risk of GDM, especially in the first trimester. 96 Therefore, a model to elucidate the role of tryptophan and purine metabolism in the pathogenesis and pathophysiology of GDM is hypothesized.…”