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.

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.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Clinical Investigator Award (CIA) (K08)
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Study Section
Pediatrics Subcommittee (CHHD)
Program Officer
Reddy, Uma M
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University of Colorado Denver
Schools of Medicine
United States
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Rozance, Paul J (2014) Update on neonatal hypoglycemia. Curr Opin Endocrinol Diabetes Obes 21:45-50
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
Limesand, Sean W; Rozance, Paul J; Macko, Antoni R et al. (2013) Reductions in insulin concentrations and ýý-cell mass precede growth restriction in sheep fetuses with placental insufficiency. Am J Physiol Endocrinol Metab 304:E516-23
Gadhia, Monika M; Maliszewski, Anne M; O'Meara, Meghan C et al. (2013) Increased amino acid supply potentiates glucose-stimulated insulin secretion but does not increase *-cell mass in fetal sheep. Am J Physiol Endocrinol Metab 304:E352-62
Thorn, Stephanie R; Brown, Laura D; Rozance, Paul J et al. (2013) Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin. Diabetes 62:65-73
Dodson, R Blair; Rozance, Paul J; Reina-Romo, Esther et al. (2013) Hyperelastic remodeling in the intrauterine growth restricted (IUGR) carotid artery in the near-term fetus. J Biomech 46:956-63
Lavezzi, Jinny R; Thorn, Stephanie R; O'Meara, Meghan C et al. (2013) Increased fetal insulin concentrations for one week fail to improve insulin secretion or *-cell mass in fetal sheep with chronically reduced glucose supply. Am J Physiol Regul Integr Comp Physiol 304:R50-8
Maliszewski, Anne M; Gadhia, Monika M; O'Meara, Meghan C et al. (2012) Prolonged infusion of amino acids increases leucine oxidation in fetal sheep. Am J Physiol Endocrinol Metab 302:E1483-92
Delaney, Cassidy A; Rozance, Paul J; Sandoval, John A et al. (2012) Late onset diaphragmatic hernia complicated by intestinal strangulation. Curr Opin Pediatr 24:274-6
Thorn, Stephanie R; Rozance, Paul J; Brown, Laura D et al. (2011) The intrauterine growth restriction phenotype: fetal adaptations and potential implications for later life insulin resistance and diabetes. Semin Reprod Med 29:225-36

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