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 beta-cells are key in this adaptation. The beta-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. Therefore, the pancreatic beta-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 beta-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 beta-cell insulin secretion. Additionally, if these adaptations which limit the fetal beta-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. New evidence is emerging which shows the importance of the pancreatic vasculature and angiogenesis for maintenance of the normal beta-cell population and insulin secretion. Consistent with severe human IUGR, our preliminary data show decreased pancreatic vascularity in a placental insufficiency model of IUGR. Therefore, the long term goal of this proposal is to determie how the fetal nutrient supply reglulates pancreatic vascularity and angiogenesis. The overall hypothesis for this project is that pancreatic vascular endothelial growth factor A (VEGFA) and vascularity are positively regulated by the fetal glucose and amino acid supply and that underdevelopment of the pancreatic beta-cell in IUGR is due to decreased nutrient and insulin stimulated vascularity. We will use a unique combination of in vivo and in vitro studies to achieve these goals. This includes experimental manipulation of fetal nutrient supply in both normally growing and IUGR fetuses combined with analysis of pancreatic and islet vascularity, VEGFA and other angiogeneic growth factors, beta-cell function, mass, and replication, as well as isolation of fetal pancreatic islets and islet derived endothelial cells for functional analysis. In addition to the functional and developmental response of the fetal pancreas and beta-cell to nutrient manipulations, this project will provide important information on the overall response of the IUGR fetus to increased nutrient delivery which will have important implications for the field of fetal medicine and ultimately the development of fetal interventions for IUGR as well as the prevention of adult onset diabetes in previously growth restricted individuals. Finally, these projects will significantly increase our understanding of the regulation of beta-cell replication and mass and the cross-talk between endothelial cells and beta-cells, thereby providing important advances in the field of beta-cell biology.

Public Health Relevance

This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal pancreatic islet vascularity, 2-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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Pregnancy and Neonatology Study Section (PN)
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Silva, Corinne M
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University of Colorado Denver
Schools of Medicine
United States
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Rozance, Paul J; Zastoupil, Laura; Wesolowski, Stephanie R et al. (2018) Skeletal muscle protein accretion rates and hindlimb growth are reduced in late gestation intrauterine growth-restricted fetal sheep. J Physiol 596:67-82
Soto, Susan M; Blake, Amy C; Wesolowski, Stephanie R et al. (2017) Myoblast replication is reduced in the IUGR fetus despite maintained proliferative capacity in vitro. J Endocrinol 232:475-491
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Brown, Laura D; Kohn, Jaden R; Rozance, Paul J et al. (2017) Exogenous amino acids suppress glucose oxidation and potentiate hepatic glucose production in late gestation fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R654-R663
Benjamin, Joshua S; Culpepper, Christine B; Brown, Laura D et al. (2017) Chronic anemic hypoxemia attenuates glucose-stimulated insulin secretion in fetal sheep. Am J Physiol Regul Integr Comp Physiol 312:R492-R500
Limesand, Sean W; Rozance, Paul J (2017) Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency. J Physiol 595:5103-5113
Bourque, Stephanie L; Rozance, Paul J (2017) Does dextrose gel prevent treatment failure in infants with neonatal hypoglycaemia? Acta Paediatr 106:1201
Boehmer, Brit H; Limesand, Sean W; Rozance, Paul J (2017) The impact of IUGR on pancreatic islet development and ?-cell function. J Endocrinol 235:R63-R76
Rozance, Paul J; Hay Jr, William W (2016) Modern Management of Preterm Infants Prevents Adverse Developmental Outcomes From Hypoglycemia. Pediatrics 138:

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