EFFECT OF HYPERGLYCEMIA ON NEURALATING MOUSE EMBRYOS

Marine Biological Laboratory, Woods Hole MA

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Abstract

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. We are investigating the molecular causes of birth defects induced by diabetic pregnancy. We have previously shown that birth defects, which occur 3-5 times more frequently in diabetic, than in nondiabetic pregnancies, are caused by increased glucose metabolism by the embryo, resulting 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). Thus, we hypothesized that increased glucose metabolism by the embryo could consume O2 faster than it could be replenished. This research has relevance to disease, because the biochemical and molecular causes of diabetic embryopathy are poorly understood, and understanding whether O2 consumption contributes to the pathogenesis of this diabetic complication may lead to therapies to prevent it. In prior studies at the NCRR BioCurrents Research Center, we found that after 3 hours of maternal hyperglycemia, O2 flux, an indicator of aerobic metabolism, was 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 can be repleted. 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. There is no other resource that I know of which can provide such measurements. Given the proximity of our laboratory in Boston, MA, to the BioCurrents Laboratory in Woods Hole, MA, this is a rare opportunity to characterize maternal hyperglycemia-induced O2 and glucose 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.