Effect of oral hypoglycaemic agents on placental ABC transporter expression and activity

Abstract

Gestational Diabetes Mellitus (GDM) affects between 3-10% of pregnancies with consequences for both the mother and the newborn infant. The target of GDM management is achieving euglycaemia as this has been demonstrated to reduce adverse neonatal events. With the increasing incidence of GDM there is a drive to manage this condition in not only the safest way possible but also in a way which is acceptable to women, with the easiest route of administration of medication and dosing schedule to increase their concordance. Therefore, attention has turned to looking at the use of oral hypoglycaemic agents (OHAs) for the treatment of GDM. There are two classes of OHAs used in pregnancy: biguanides (for example metformin) and sulphonylureas (for example glibenclamide, also known as glyburide). In the placenta a network of apical ATP-binding cassette (ABC) transporters facilitates the efflux of substances away from the fetus, thereby protecting the fetus from exposure to unwanted substances including medications such as metformin and glibenclamide. In this thesis, I have examined the mRNA levels of P-glycoprotein (P-gp), Breast cancer resistance protein (BCRP) and Multidrug resistance-associated protein (MRP) in placentas from women with GDM. I have demonstrated a reduction in P-gp mRNA expression among placentas from those women treated with metformin and insulin compared to placentas from women without GDM and those treated with metformin alone. In vitro treatment of placental explants with metformin and glibenclamide demonstrated no effect upon the mRNA levels of P-gp, BCRP, MRP and Glucose 1 transporter (GLUT 1). While treatment with OHAs is becoming standard care in the management of GDM, little work has been done looking at those mechanisms in place to protect the fetus from such treatments. Future developments in the management of GDM are likely to include combining metformin and glibenclamide; the work in this thesis provides in vitro evidence that this combined treatment does not alter the ABC transporters protecting the fetus and therefore supports future clinical trials for such a treatment.