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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK084842-02
Application #
7802160
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2009-04-15
Project End
2014-03-31
Budget Start
2010-04-01
Budget End
2011-03-31
Support Year
2
Fiscal Year
2010
Total Cost
$371,994
Indirect Cost
Name
University of Arizona
Department
Veterinary Sciences
Type
Schools of Earth Sciences/Natur
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
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Kelly, Amy C; Bidwell, Christopher A; McCarthy, Fiona M et al. (2017) RNA Sequencing Exposes Adaptive and Immune Responses to Intrauterine Growth Restriction in Fetal Sheep Islets. Endocrinology 158:743-755
Limesand, Sean W; Rozance, Paul J (2017) Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency. J Physiol 595:5103-5113
Camacho, Leticia E; Chen, Xiaochuan; Hay Jr, William W et al. (2017) Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction. Am J Physiol Regul Integr Comp Physiol 313:R101-R109
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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
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
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 ? Cells Within the Pancreas. Mol Imaging Biol 17:461-70
Limesand, Sean W (2015) Insights Into the Progression of ?-Cell Dysfunction Caused by Preterm Birth. Endocrinology 156:3494-5

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