The most common etiology of intrauterine growth restriction (IUGR) is 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 ?-cells are key in this adaptation. The ?-cell secretes insulin, which stimulates fetal growth, in a nutrient regulated fashion. In IUGR insulin secretion is impaired. The adaptations resulting in decreased insulin secretion include lower ?-cell mass and impaired pancreatic islet development. If these adaptations persist into adulthood they can contribute to the higher risk of type 2 diabetes mellitus in previously IUGR adults. New evidence is emerging which shows the importance of the islet endothelial cell (EC) for normal adult insulin secretion. Consistent with human IUGR, we show decreased pancreatic vascularity in a sheep placental insufficiency model of IUGR. We also have identified impaired cross talk between the islet EC and ?-cell. Both EC produced hepatocyte growth factor (HGF) and ?-cell produced vascular endothelial growth factor A (VEGFA) are decreased. Importantly, though, our novel preliminary data show that increasing the amino acid supply in IUGR fetal sheep restores fetal insulin secretion and increases ?-cell mass and islet size with a proportional increase in islet vascularity. Therefore, the long term goal of this proposal is to test the hypothesis that reduced fetal amino acid supply is responsible for impaired fetal pancreatic vascularity, ?-cell mass, islet size, and insulin secretion in IUGR and that this is mediated by inhibition of islet HGF and VEGFA production.
In Aim 1 we will use isolated fetal sheep islets and islet ECs to determine the capacity for VEGFA to stimulate islet EC HGF production and for HGF to stimulate ?-cell VEGFA production. This will demonstrate a novel islet feed forward HGF-VEGFA signaling loop which can coordinate islet growth with vascular supply. Furthermore, we will show that this signaling can be increased in IUGR islets when stimulated with the appropriate growth factors.
In Aim 2 we will test the hypothesis that the islet EC is a novel nutrient sensor producing HGF in response to increased amino acids, and that the EC nutrient sensor is responsive to increased amino acids in PI-IUGR.
In aim 3 we will test the hypothesis that chronically decreased amino acid supply to the PI-IUGR fetus is primarily responsible for impaired islet HGF- VEGFA signaling. Following fetal infusions of various amino acid mixtures we will measure in vivo fetal insulin secretion, islet size and vascularity, ?-cell mass, and isolated islet and islet EC signaling and function. This proposal will show that the coordination of fetal islet growth and vascular supply is key in the pathogenesis of impaired islet development and insulin secretion in IUGR. Furthermore, we will show that this process is amenable to manipulation with amino acids in a way that will increase ?-cell mass and insulin secretion. By focusing on EC amino acid sensing and signaling with the ?-cell, our experiments will provide mechanistic insights into islet development and new target pathways for the prevention of diabetes following IUGR.

Public Health Relevance

This research is relevant to public health as it will demonstrate the mechanisms responsible for decreased fetal pancreatic islet vascularity, ?-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
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Boehmer, B H; Brown, L D; Wesolowski, S R et al. (2018) Pulsatile hyperglycemia increases insulin secretion but not pancreatic ?-cell mass in intrauterine growth-restricted fetal sheep. J Dev Orig Health Dis 9:492-499
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
Rozance, Paul J; Wright, Clyde J (2017) Preparing for the first breath: in the developing lung, maternal overnutrition takes centre stage. J Physiol 595:6595-6596
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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