Intergenerational Metabolomic Analysis of Mothers with a History of Gestational Diabetes Mellitus and Their Offspring

Abstract

Shared metabolomic patterns at delivery have been suggested to underlie the mother-to-child transmission of adverse metabolic health. This study aimed to investigate whether mothers with gestational diabetes mellitus (GDM) and their offspring show similar metabolomic patterns several years postpartum. Targeted metabolomics (including 137 metabolites) was performed in plasma samples obtained during an oral glucose tolerance test from 48 mothers with GDM and their offspring at a cross-sectional study visit 8 years after delivery. Partial Pearson’s correlations between the area under the curve (AUC) of maternal and offspring metabolites were calculated, yielding so-called Gaussian graphical models. Spearman’s correlations were applied to investigate correlations of body mass index (BMI), Matsuda insulin sensitivity index (ISI-M), dietary intake, and physical activity between generations, and correlations of metabolite AUCs with lifestyle variables. This study revealed that BMI, ISI-M, and the AUC of six metabolites (carnitine, taurine, proline, SM(-OH) C14:1, creatinine, and PC ae C34:3) were significantly correlated between mothers and offspring several years postpartum. Intergenerational metabolite correlations were independent of shared BMI, ISI-M, age, sex, and all other metabolites. Furthermore, creatinine was correlated with physical activity in mothers. This study suggests that there is long-term metabolic programming in the offspring of mothers with GDM and informs us about targets that could be addressed by future intervention studies.

The Significance of Exposure to Pregestational Type 2 Diabetes in Utero on Fetal Renal Size and Subcutaneous Fat Thickness

“…Research into the developmental origins of health and disease ("DOHaD") that occurs in adulthood is inherently challenging because of the difficulty in determining with certainty whether chronic diseases in adulthood are solely related to the intrauterine environment as opposed to all the other potential environmental, cultural, and familial exposures incurred throughout the life course [44][45][46][47]. Despite these obstacles, the possibility of early identification of offspring at risk of future disease remains important, and there are multiple studies showing a linkage between maternal medical conditions during pregnancy and health outcomes in offspring later in life [9][10][11][12][13][47][48][49]. Fetal ultrasound provides a unique opportunity to study the developmental origins of adult-onset disease given that it is immune to the historic confounders that complicate other DOHaD-related investigations, such as sociodemographic factors or other illnesses and exposures throughout childhood and adulthood.…”

“…For offspring, these risks begin in utero but also confer a heightened lifelong risk of diabetes, obesity, and other medical conditions [ 3 – 9 ]. While family history of T2D is a known risk factor for developing diabetes, there is emerging evidence that suggests a worsening disease severity with each successive generation affected [ 10 – 12 ]. Additionally, T2D is associated long-term with chronic renal disease including the need for dialysis or transplant [ 13 – 15 ].…”

“…For o spring, these risks begin in utero but also confer a heightened lifelong risk of diabetes, obesity, and other medical conditions [3][4][5][6][7][8][9]. While family history of T2D is a known risk factor for developing diabetes, there is emerging evidence that suggests a worsening disease severity with each successive generation a ected [10][11][12].…”

Developmental Effects of (Pre-)Gestational Diabetes on Offspring: Systematic Screening Using Omics Approaches

“…Intergenerationally correlated metabolites included carnitine (C0), glycerophospholipid (PC ae C34:3), two biogenic amines (taurine, creatinine), an amino acid (proline), and sphingolipid (SM-(OH) C14:1). The authors suggested a possible long-term programming effect of maternal GDM on metabolic health in children [ 115 ]. Conversely, even though Shokry et al also found altered metabolites in the cord blood, associated with anthropometric changes in newborn children of mothers with GDM and obesity, these alterations were not detected longitudinally.…”

Sex-Specific Differences in Lysine, 3-Hydroxybutyric Acid and Acetic Acid in Offspring Exposed to Maternal and Postnatal High Linoleic Acid Diet, Independent of Diet

“…[ 16 ]. Plasma metabolomics provides information about individual biological status arising from genetic and environmental interaction [ 17 ]. Previous studies have shown the correlation between various metabolites and incidences of metabolic disorders such as impaired glucose tolerance and insulin resistance [ 18 , 19 ].…”