Effect of oral hypoglycaemic agents on placental ABC transporter expression and activity
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Date
29/11/2016Author
Penneycard, Jessica Marie
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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.