There is substantial evidence that maternal physique and diet have a major influence on the outcome of pregnancy and that growth ~restriction in utero is a predictor of risk of type 2 diabetes, insulin resistance and coronary artery disease in adulthood. The long-term objective of the research proposed is to understand in detail the molecular basis of this chain of events in order to inform the institution of interventions which will prevent or delay these diseases. A combination of small (rat) and large (sheep) animal experiments using dietary restriction before, during and after pregnancy together with studies of human placenta will be used to characterize at the molecular level the events taking place when the fetus is growth restricted by poor nutrition. Rat fetal growth will be restricted in the first or second half of pregnancy by feeding the mothers half the normal amount of protein. This will narrow down the time window of effects of this manoeuvre already demonstrated when applied through the whole of pregnancy. The insulin receptor gene structure and function, shown to be increased by the fetal growth restriction, will be studied at the molecular level to define the mechanism of how this increased expression is instigated. The effect of maternal under and over nutrition on the metabolism of offspring will be studied in the sheep because this large animal allows the direct administration to the fetus of substances such as insulin and insulin-neutralizing antibodies. Experiments will be carried out to determine how early and for how long these substances can be administered to the sheep fetus. Subsequently the effects of over- or under-exposure of the fetus to insulin will be studied in terms of the metabolism of the offspring to test the hypothesis that changes in the availability of insulin to the fetus is a key component of the mechanisms leading to programming of expression of insulin gene and later disease susceptibility. In order to relate these findings directly to changes taking place in humans, specific and general protein expression will be studied in the placentas of pregnancies and infants being studied in great detail in Southampton and Manchester. The objective will be to determine the effect of maternal thinness and nutrition on protein expression in the placenta and to assess the value of defining these changes in placental protein expression for the prediction of the risk of subsequent disease in the offspring.
