Description:

My lab is investigating the molecular causes of birth defects induced by diabetic pregnancy. We have previously shown that birth defects, occuring 3-5 times more frequently in diabetic pregnancies, are caused by increased glucose metabolism by the embryo. This results from increased delivery of glucose from maternal circulation to the embryo. Increased glucose metabolism by the embryo impairs expression of genes which are necessary for structural development. At the stage of development that is susceptible to diabetic pregnancy-induced birth defects, the embryo is not yet vascularized and exists in a hypoxic environment (2-8% O₂, compared to 20% O₂ in post-natal arterial circulation). We hypothesized that increased glucose metabolism by the embryo could consume O₂ faster than it could be replenished.

Progress:

We have found that after 3 hours of maternal hyperglycemia, O₂ flux, an indicator of aerobic metabolism, is significantly suppressed. Since aerobic metabolism depends on O₂ availability, suppression of O₂ flux indicates that, consistent with the hypothesis, excess glucose delivery to the embryo led to O₂ consumption in excess of delivery. We have obtained additional evidence that restricting O₂ delivery to embryos at the same stage of development replicates the adverse effects of maternal diabetes on embryogenesis, supporting the hypothesis that increased glucose metabolism consumes O₂ faster than it is replaced. In future experiments, we propose to assay O₂ and glucose flux at rapid time points after induction of maternal hyperglycemia, to further test the hypothesis that increased oxidative glucose metabolism depletes O₂ utilization.

These studies are highly significant, not only because they provide biochemical insights into the causes of birth defects induced by diabetic pregnancy, but because they implicate metabolic signaling (i.e. O₂ utilization), in activation of developmental control pathways.