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 #
5R01DK084842-05
Application #
8443846
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2009-04-15
Project End
2015-03-31
Budget Start
2013-04-01
Budget End
2015-03-31
Support Year
5
Fiscal Year
2013
Total Cost
$248,826
Indirect Cost
$83,311
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
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
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
Macko, A R; Yates, D T; Chen, X et al. (2013) Elevated plasma norepinephrine inhibits insulin secretion, but adrenergic blockade reveals enhanced *-cell responsiveness in an ovine model of placental insufficiency at 0.7 of gestation. J Dev Orig Health Dis 4:402-10
Green, Alice S; Chen, Xiaochuan; Macko, Antoni R et al. (2012) Chronic pulsatile hyperglycemia reduces insulin secretion and increases accumulation of reactive oxygen species in fetal sheep islets. J Endocrinol 212:327-42
Yates, D T; Loest, C A; Ross, T T et al. (2011) Effects of bacterial lipopolysaccharide injection on white blood cell counts, hematological variables, and serum glucose, insulin, and cortisol concentrations in ewes fed low- or high-protein diets. J Anim Sci 89:4286-93
Green, Alice S; Macko, Antoni R; Rozance, Paul J et al. (2011) Characterization of glucose-insulin responsiveness and impact of fetal number and sex difference on insulin response in the sheep fetus. Am J Physiol Endocrinol Metab 300:E817-23
Brown, Laura D; Green, Alice S; Limesand, Sean W et al. (2011) Maternal amino acid supplementation for intrauterine growth restriction. Front Biosci (Schol Ed) 3:428-44
Chen, Xiaochuan; Fahy, Anna L; Green, Alice S et al. (2010) ýý2-Adrenergic receptor desensitization in perirenal adipose tissue in fetuses and lambs with placental insufficiency-induced intrauterine growth restriction. J Physiol 588:3539-49
Leos, Rafael A; Anderson, Miranda J; Chen, Xiaochuan et al. (2010) Chronic exposure to elevated norepinephrine suppresses insulin secretion in fetal sheep with placental insufficiency and intrauterine growth restriction. Am J Physiol Endocrinol Metab 298:E770-8

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