(141) Adrenomedullin Upregulates mRNA Expression of Nutrient Transporters in Human Trophoblast Cell Line: Implications for GDM

Mechanisms underlying the pathophysiology of Gestational Diabetes Mellitus (GDM) and its adverse effects on mother and fetus remain poorly understood. Adrenomedullin (ADM) is elevated in pregnancies complicated by GDM. Studies from our laboratory previously showed elevated ADM levels play a role in maternal dyslipidemia and defective β-cell adaptation associated with GDM. However, the effects of increased circulating ADM levels on placental function and nutrient transport are still unknown. We performed a series of in vitro experiments investigating the effects of increased ADM on the expression of trophoblast cell nutrient transporters.


 

Study Design:

First-trimester human trophoblast cell line HTR8/SVneo was cultured with increasing doses of ADM (0, 0.1, 1.0, or 10 nM) for 24 hours. Cells were then harvested, mRNA extracted, cDNA synthesized, and real-time qPCR performed for genes related to lipid, glucose, and amino acid transport, that have previously been shown to be upregulated in placentas with GDM.


 

Results:

Treatment with ADM increased the expression of several transporter genes: lipid transporters EL (p=0.03), FABP3 (p=0.0002), FABP5 (p=0.006), FABP7 (p=0.02), FATP1 (p=0.01), FATP6 (p=0.01), and CD36 (p=0.0087); glucose transporters GLUT3 (p=0.02) and GLUT4 (p=0.002); amino acid transporters SNAT1 (p=0.04), SNAT2(p=0.03), and LAT2 (p=0.001). LAT1 (p=0.06) was downregulated. These effects in gene expression progressed in a dose-dependent fashion.




 

Conclusion:

These studies demonstrate in vitro treatment with ADM upregulates the expression of trophoblast cell nutrient transporters in a dose-dependent fashion. Data from this study further implicates ADM in the pathogenesis of fetal macrosomia associated with GDM. Future in vivo studies will explore the possibility of using ADM as a biomarker of GDM. By increasing our understanding of molecular pathways involved in placental nutrient transport, we may be able to develop future therapies to reduce the maternal and fetal complications associated with GDM.