Is adult health trajectory determined by maternal glucose levels during embryo implantation?

Diabetes profoundly affects the outcome of pregnancy, especially when glucose control is poor.

We hypothesise that high glucose levels alter endometrial function, affecting the dialogue with the embryo that occurs at implantation to initiate placental development.

Placentation is a key determinant of pregnancy outcome: elevated nutrient transfer leads to fetal overgrowth, which affects 50% of pregnancies complicated by maternal diabetes, and gives rise to short- and long-term health problems in offspring.

The hexosamine biosynthetic pathway (HBP), is an important glucose-sensing mechanism that regulates cellular function by adding the O-linked sugar b-Nacetylglucosamine to a wide range of proteins.

Having shown that the HBP affects interactions between endometrium and embryo in vitro, we will now determine how altered activity at the time of implantation in vivo affects placentation and pregnancy outcomes.

Using pharmacological strategies to modulate O-GlcNAcylation during early pregnancy in mice, we will: (1) histologically and epigenetically analyse implantation sites; (2) analyse placental and fetal characteristics at term, and; (3) characterise the metabolic and cardiovascular health of the offspring in adulthood.

The incidence of pregnancy complicated by maternal diabetes is increasing; identifying pathways that suggest prevention or treatment strategies will lead to improved pregnancy outcomes and better health in future generations.