Umbilical cord plasma markers in gestational diabetes: evidence of fetal metaflammation, elevated GGT, and links to neonatal metabolic health

Gestational diabetes mellitus (GDM) is a form of glucose intolerance that develops during pregnancy, affecting approximately 14% of pregnancies worldwide. GDM leads to an excess supply of nutrients to the fetus, influencing fetal metabolism and potentially stimulating metabolic inflammation (metaflammation), which may impact liver function. In fact, increased fetal liver size has been reported in GDM pregnancies. This study investigated the impact of GDM on fetal metaflammation and its potential association with the liver function parameters γ-glutamyl transferase (GGT), alanine transaminase (ALT), and bilirubin, in umbilical cord plasma (UCP). UCP samples were collected following healthy (<i>n</i> = 57) and GDM pregnancies (<i>n</i> = 25). Glucometabolic and lipid profiles, inflammatory markers, and liver function parameters were analyzed and the impact of GDM and the interrelation of liver biomarkers with maternal and neonatal parameters were assessed. UCP from GDM pregnancies exhibited increased levels of metaflammation-associated markers, including triglycerides, interleukin-6 and C-reactive protein (CRP). Among liver parameters, the detoxification and antioxidant defense enzyme GGT was elevated, whereas ALT and bilirubin species remained unchanged. Correlation analysis revealed that although GGT was increased in GDM, it was associated with improved metabolic characteristics, including reduced insulin resistance, insulin, C-peptide, and leptin, and increased high-density lipoprotein. Overall, these findings indicate that the GDM environment shifts fetal metabolism toward metaflammation and elevates GGT, an enzyme involved in detoxification and protection against oxidative stress. The inverse association of GGT with insulin resistance suggests a compensatory role of GGT, potentially mitigating fetal metabolic and inflammatory disturbances in GDM through its antioxidant activity.<b>NEW & NOTEWORTHY</b> Excess fetal nutrient supply in gestational diabetes mellitus (GDM) results in signs of fetal metabolic inflammation (metaflammation) in umbilical cord plasma, and higher levels of γ-glutamyl transferase (GGT), a liver enzyme involved in defense against oxidative stress. The correlations of GGT levels with reduced insulin resistance, C-peptide, and leptin suggest that GGT has a positive effect on fetal metabolic health.