Sex Dimorphic Associations of Gestational Diabetes Mellitus With Cord Plasma Fatty Acid Binding Protein 4 and Estradiol

Abstract

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

The impact of gestational diabetes on changes in the concentration of selected hormones regulating food intake in umbilical cord blood, and the development of obesity in children in later life

“…Interestingly, the current study did not show statistically significant differences between the concentration of tested hormones in the umbilical cord blood in the group of children from healthy mothers, and from mothers with GDM (data not shown). This is consistent with previous literature data [21], but despite this, interesting interactions were observed that varied depending on the study group. The first interesting observation made during the presented study was the data that did not show greater growth in offspring from women with GDM, which is very often described in the literature.…”

Adipokines in Pregnancy: A Systematic Review of Clinical Data

“…In line with these findings, Ron et al, also reported higher AFABP levels in fetal circulation when compared with AFABP levels in maternal serum and an inverse correlation between cord AFABP and blood glucose of neonates, with a ten-fold increase of umbilical AFABP levels in infants with hypoglycemia [95]. A nested case-control study described a positive correlation between GDM and cord blood AFABP in male offspring, but this correlation was not true for female neonates [96].…”

Estradiol (E2) Improves Glucose-Stimulated Insulin Secretion and Stabilizes GDM Progression in a Prediabetic Mouse Model

“…This could be explained via an overstimulation of ERα by E2, which could provoke IR in the liver and depletion of β-cells, possibly contributing to diabetic phenotypes [ 28 ]. Moreover, GDM was associated with elevated E2 cord plasma concentrations in male newborns [ 29 ].…”