Physiological glucose levels associated with gestational diabetes impact the human placental transcriptome in an ex vivo model

Introduction

Gestational diabetes mellitus (GDM) increases the risk of pathological fetal growth, including rates of large-for-gestational age (LGA) infants, which in turn increases the risk of offspring later developing cardiometabolic complications. Recent continuous glucose monitoring (CGM) studies have revealed that temporal periods of mild hyperglycaemia are linked to LGA, and too tight glycaemic control can increase periods of maternal hypoglycaemia and an increased risk of delivering small-for-gestational age (SGA) infants. The underlying mechanisms are unclear but likely involve the placenta.

Methods

Ex vivo human placental explants from term uncomplicated pregnancies were cultured in varying glucose concentrations for 48 hours to recapitulate in vivo maternal glucose profiles. Glucose, osmolality, human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) were measured in conditioned medium, and RNA sequencing performed, followed by functional enrichment analysis (FEA).

Results

Medium changes every 6-18 hours in variable (5/5.5 mM), or constant 5 mM or 7 mM glucose were appropriate to model maternal normoglycaemia, periods of mild hypoglycaemia and periods of mild hyperglycaemia, respectively. There were 61 differentially expressed genes (DEGs) in explants cultured in mild hyperglycaemic conditions and 54 DEGs in mild hypoglycaemic conditions. FEA revealed that transcripts altered by mild hyperglycaemia were associated with vascular development and lipid metabolism/homeostasis, whilst those altered by mild hypoglycaemia were associated with cell turnover.

Conclusions

Together this data demonstrates that subtle changes in maternal glucose impact the placenta and may contribute to altered fetal growth. This highlights the importance of employing CGM in pregnancies complicated by GDM and utilising physiological glucose levels in ex vivo/in vitro placental studies.