Gestational Diabetes Alters the Metabolomic Profile in 2nd Trimester Amniotic Fluid in a Sex-Specific Manner.

Kathleen O’Neill,Clementina Mesaros,Ian Blair,Rui Xiao,Sara Pinney,Rikka Azuma,Nathaniel Snyder,Jacqueline Alexander

doi:10.3390/ijms19092696

Abstract

Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring, with specific metabolic characterization based on offspring sex. Gestational diabetes (GDM) has profound effects on the intrauterine milieu, which may reflect and/or modulate the function of the maternal–fetal unit. In order to characterize metabolic factors that affect offspring development, we profiled the metabolome of second trimester amniotic fluid (AF) from women who were subsequently diagnosed with gestational diabetes (GDM) using a targeted metabolomics approach, profiling 459 known biochemicals through gas chromatography/mass spectrometry (GC/MS) and liquid chromatography/mass spectrometry (LC/MS) assays. Using a nested case-control study design, we identified 69 total biochemicals altered by GDM exposure, while sex-specific analysis identified 44 and 58 metabolites in male and female offspring, respectively. The most significant changes were in glucose, amino acid, glutathione, fatty acid, sphingolipid, and bile acid metabolism with specific changes identified based on the offspring sex. Targeted isotope dilution LC/MS confirmatory assays measured significant changes in docosahexaenoic acid and arachidonic acid. We conclude that the sex-specific alterations in GDM maternal–fetal metabolism may begin to explain the sex-specific metabolic outcomes seen in offspring exposed to GDM in utero.

Highlights

Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring [1,2,3,4,5,6,7,8,9,10]
Since secondary bile acids result from interactions between intestinal bacteria and the gut, these results suggest the importance of interactions between the microbiome and the maternal–fetal interface in Gestational diabetes mellitus (GDM)
The characterization of the metabolome of second trimester amniotic fluid (AF) from women subsequently diagnosed with GDM identifies significant changes in metabolic pathways involving glucose, amino acid (AA), glutathione, fatty acid, sphingolipid, and bile acid metabolism, with specific changes identified based on offspring sex

Summary

Introduction

Maternal diabetes and obesity induce marked abnormalities in glucose homeostasis and insulin secretion in the fetus, and are linked to obesity, diabetes, and metabolic disease in the offspring [1,2,3,4,5,6,7,8,9,10]. Individuals whose cord blood or amniotic fluid insulin levels are elevated have a 3–4 fold risk for developing glucose intolerance, obesity, and type 2 diabetes in late childhood and as adults [5,11,12,13]. Identifying women who are at risk for development of GDM early in pregnancy has been stymied by a lack of sensitive and specific diagnostic tools. Profiling the metabolome of second trimester amniotic fluid (AF) exposed to GDM may assist in the identification of biochemicals and pathways that are responsible for the early functional changes in the placenta and fetus exposed to GDM with greater sensitivity than transcriptomics or proteomics

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Results

Discussion

Conclusion