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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK088139-03
Application #
8513983
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2011-09-15
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$475,846
Indirect Cost
$149,596
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
Rozance, Paul J; Hay Jr, William W (2016) New approaches to management of neonatal hypoglycemia. Matern Health Neonatol Perinatol 2:3
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

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