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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08HD060688-03
Application #
8134779
Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Reddy, Uma M
Project Start
2009-09-01
Project End
2014-08-31
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
3
Fiscal Year
2011
Total Cost
$132,300
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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
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
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
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
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
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
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
Dodson, R Blair; Rozance, Paul J; Petrash, Carson C et al. (2014) Thoracic and abdominal aortas stiffen through unique extracellular matrix changes in intrauterine growth restricted fetal sheep. Am J Physiol Heart Circ Physiol 306:H429-37

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