Effects of targeted disruption of imprinted fetal growth factor genes on maternal glucose metabolism and blood pressure.

We aim to test the possibility that rises in blood glucose concentrations and blood pressure in pregnancy result from the conflict between the mother’s genes trying to restrict the size of her unborn baby and the baby’s genes trying to boost its growth in an effort to increase its chance of survival. We predict that the baby’s genes do this by causing alterations in how well their mothers respond to insulin and glucose and in her blood pressure. We plan to test this directly in two mouse models (as it is not possible to do this in humans): (1) where pups are born small due to the removal of the placental insulin-like growth factor 2 (IGF2) gene, (2) where pups are born large due to the removal of the H19 gene which usually reduces IGF2’s activity. We plan to accurately measure how well insulin is working in the body, how the body responds to a glucose load and the blood pressure in pregnant mice carrying offspring with these genetic changes and then compare these to measurements from normal controls. These experiments should provide important information about potential causes of gestational diabetes and high blood pressure.

Imprinted genes in a growing fetus are known to contribute to growth in utero: the conflict theory suggests that they will try and increase growth, whereas the maternal genes will try and restrict it. Little is known of how imprinted genes respond to intrauerine growth restriction. We hypothesise that the fetal genome alters maternal metabolism (in particular insulin sensitivity, glucose tolerance and blood pressure). This hypothesis will be tested in two knockout mouse models: one which is null for the paternally expressed placental IGF2 gene (and produces growth restricted pups) and one that is null for the maternally expressed H19 gene (and produces growth enhanced pups). We will carefully document insulin sensitivity (by euglycaemic, hyperinsulinaemic clamps), glucose tolerance and blood pressures (by telemetry) in pregnant mice carrying obligate heterozygote litters, half transgenic litters and wild type litters.