Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses Endocrine factors such as catecholamines promote fetal survival during intrauterine growth restriction (IUGR) by sparing glucose for critical functions. A primary fetal response to IUGR is to suppress 2-cell function and lower the anabolic hormone, insulin. The goal of this research project is to understand the mechanisms by which chronic catecholamine stimulation (coupled with hypoxia and hypoglycemia) modulates insulin secretion in fetal sheep with placental insufficiency, a model system that shares many similarities to human IUGR fetuses with placental insufficiency. Our data indicates that chronic exposure to high catecholamine concentrations leads to 2-cell desensitization by augmenting their insulin secretion responsiveness. In postnatal life, when catecholamine suppression is no long present, a hyper-responsiveness to glucose is apparent, and potentially results from the 2- cells desensitization adaptation to fetal catecholamines. We will test the hypothesis that chronic exposure to elevated catecholamine concentrations lowers insulin secretion in the IUGR fetus, but also leads to adrenergic desensitization in 2-cells that enhances glucose stimulated insulin secretion after suppressive conditions are alleviated in the neonate with the following specific aims. First, we will determine the onset and consequences of chronic catecholamine suppression to glucose stimulated insulin secretion (GSIS) in sheep fetuses with placental insufficiency-induced IUGR. Second, we will determine if chronic catecholamine desensitization for the fetal 2-cells occurs in the proximal adrenergic receptor signaling pathway, insulin stimulus secretion coupling pathway, or both. Finally, in pre-ruminant lambs we will determine whether residual compensatory actions from catecholamine suppression in fetal life leads to the overcorrection in insulin secretion responsiveness as a result of proximal adrenergic signaling or increased insulin stimulus secretion coupling. It is likely that such explanations will increase capacity for promoting 2-cell function in human IUGR infants. These concepts and this type of investigation have not been done in the fetus, but represent reasonable points of regulation that based on the literature and general understanding of catecholamine action should play significant roles. Therefore, these studies will provide new insight into the requirements for clinical intervention to ameliorate pancreatic insufficiency in IUGR fetuses and neonates with the goal of reducing fetal and neonatal morbidity and mortality, and potentially lower the incidence of adult onset diseases that have been correlated with low birth weight.

Public Health Relevance

Fetal growth restriction continues to contribute to major medical problems for the fetus, newborn infant, and even the adult, which is highlighted by recent epidemiological studies in Diabetics. Patients with Type 2 Diabetes are reaching epidemic proportions in the United States and consume one of every eight dollars spent for health care. As much as one fifth of this epidemic arises from a nutritional discordance between prenatal and postnatal life that results in impaired glucose homeostasis. Therefore, we plan to determine how a key stress response alters the developmental program in the fetal 2-cells to impair glucose homeostasis and lead to adulthood pathologies, such as Type 2 Diabetes Mellitus.

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 Arizona
Veterinary Sciences
Schools of Earth Sciences/Natur
United States
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Macko, Antoni R; Yates, Dustin T; Chen, Xiaochuan et al. (2016) Adrenal Demedullation and Oxygen Supplementation Independently Increase Glucose-Stimulated Insulin Concentrations in Fetal Sheep With Intrauterine Growth Restriction. Endocrinology 157:2104-15
Yates, Dustin T; Cadaret, Caitlin N; Beede, Kristin A et al. (2016) Intrauterine growth-restricted sheep fetuses exhibit smaller hindlimb muscle fibers and lower proportions of insulin-sensitive Type I fibers near term. Am J Physiol Regul Integr Comp Physiol 310:R1020-9
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
Limesand, Sean W (2015) Insights Into the Progression of β-Cell Dysfunction Caused by Preterm Birth. Endocrinology 156:3494-5
Steyn, Leah V; Ananthakrishnan, Kameswari; Anderson, Miranda J et al. (2015) A Synthetic Heterobivalent Ligand Composed of Glucagon-Like Peptide 1 and Yohimbine Specifically Targets β Cells Within the Pancreas. Mol Imaging Biol 17:461-70
Davis, Melissa A; Macko, Antoni R; Steyn, Leah V et al. (2015) Fetal adrenal demedullation lowers circulating norepinephrine and attenuates growth restriction but not reduction of endocrine cell mass in an ovine model of intrauterine growth restriction. Nutrients 7:500-16
Chen, Xiaochuan; Green, Alice S; Macko, Antoni R et al. (2014) Enhanced insulin secretion responsiveness and islet adrenergic desensitization after chronic norepinephrine suppression is discontinued in fetal sheep. Am J Physiol Endocrinol Metab 306:E58-64
Yates, Dustin T; Clarke, Derek S; Macko, Antoni R et al. (2014) Myoblasts from intrauterine growth-restricted sheep fetuses exhibit intrinsic deficiencies in proliferation that contribute to smaller semitendinosus myofibres. J Physiol 592:3113-25
Kelly, Amy C; Steyn, Leah V; Kitzmann, Jenna P et al. (2014) Function and expression of sulfonylurea, adrenergic, and glucagon-like peptide 1 receptors in isolated porcine islets. Xenotransplantation 21:385-91
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

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