Intrauterine growth restriction (IUGR) affects 4-8% of all pregnancies in developed countries;the most common etiology being placental insufficiency and decreased fetal nutrient supply. In order to survive, the fetus adapts in ways which promote the most efficient use of a limited energy supply. Pancreatic (3-cells are key in this adaptation. The p-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. Therefore, the pancreatic (3-cell is one of the most important fetal cell types for matching growth rates to nutrient supply. The best evidence regarding the mechanism of decreased insulin secretion in severe human IUGR is a decrease in the pancreatic p-cell population. Experimental evidence suggests that these adaptations cannot be overcome simply by providing increased nutrients to the growth restricted fetus. Therefore, any hope of treating IUGR to improve fetal growth rates will have to combine strategies to increase fetal nutrient delivery and p-cell insulin secretion. Additionally, if these adaptations which limit the fetal p-cell population and insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. The long-term goal of this project is to determine the responsible mechanisms for limiting the fetal p-cell population and insulin secretion in IUGR with the aim of eventually developing interventions to reverse these adaptations and allow for treatment of IUGR and prevention of type 2 diabetes. New evidence is emerging which shows the importance of p-cell to endothelial cell signaling for maintenance of the normal p-cell population and insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cell signaling as the cause of decreased p-cell mass and insulin secretion in a fetal sheep model of placental insufficiency and IUGR. We will use in vitro assays to measure acute p-cell and insulin stimulated endothelial cell function and show that the response of IUGR pancreatic islet endothelial cells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelial cell function by measuring pancreatic islet vascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronically increasing insulin concentrations in the IUGR fetus can improve pancreatic islet vascularity, angiogenesis, and P-cell mass.
This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal p-cell mass and insulin secretion in intrauterine growth restriction (IUGR). This will allow the development of prenatal therapies designed to improve fetal growth in IUGR and decrease the risk of these individuals developing type 2 diabetes mellitus as adults.
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