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 matchinggrowth 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.Experimentalevidence suggests that these adaptations cannot be overcome simply by providingincreased 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-cellinsulin secretion. Additionally, ifthese adaptations which limitthe fetal p-cell populationand insulin secretion persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously growth restricted adults. The longterm goal of this project is to determine the responsible mechanisms for limitingthe 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-cellto endothelial cell signalingfor maintenance of the normal p-cell populationand insulin secretion. Therefore, this proposal will specifically examine decreased p-cell to endothelial cellsignaling as the cause of decresaed p-cell mass and insulinsecretion in a fetal sheep model of placental insufficincy 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 endothelialcells is decreased. We will then demonstrate the consequences of decreased pancreatic islet endothelialcell function by measuringpancreatic isletvascularity and angiogenesis in IUGR fetuses. Finally, we will determine if chronicallyincreasing 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.
|Rozance, Paul J; Hay Jr, William W (2016) Pancreatic islet hepatocyte growth factor and vascular endothelial growth factor A signaling in growth restricted fetuses. Mol Cell Endocrinol 435:78-84|
|Brown, Laura D; Wesolowski, Stephanie R; Kailey, Jenai et al. (2016) Chronic Hyperinsulinemia Increases Myoblast Proliferation in Fetal Sheep Skeletal Muscle. Endocrinology 157:2447-60|
|Brown, Laura D; Davis, Melissa; Wai, Sandra et al. (2016) Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep. Endocrinology 157:3788-3799|
|Barry, James S; Rozance, Paul J; Brown, Laura D et al. (2016) Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction. Exp Biol Med (Maywood) 241:839-47|
|Houin, Satya S; Rozance, Paul J; Brown, Laura D et al. (2015) Coordinated changes in hepatic amino acid metabolism and endocrine signals support hepatic glucose production during fetal hypoglycemia. Am J Physiol Endocrinol Metab 308:E306-14|
|Brown, Laura D; Rozance, Paul J; Bruce, Jennifer L et al. (2015) Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 309:R920-8|
|Rozance, Paul J; Anderson, Miranda; Martinez, Marina et al. (2015) Placental insufficiency decreases pancreatic vascularity and disrupts hepatocyte growth factor signaling in the pancreatic islet endothelial cell in fetal sheep. Diabetes 64:555-64|
|Andrews, Sasha E; Brown, Laura D; Thorn, Stephanie R et al. (2015) Increased adrenergic signaling is responsible for decreased glucose-stimulated insulin secretion in the chronically hyperinsulinemic ovine fetus. Endocrinology 156:367-76|
|Rozance, Paul J (2014) Update on neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes 21:45-50|
|Houin, Satya; Rozance, Paul Joseph (2014) 50 years ago in the Journal of pediatrics: The incidence of neonatal hypoglycemia in a nursery for premature infants. J Pediatr 164:1485|
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