Intrauterine growth restriction (IUGR) causes perinatal morbidity and mortality. Furthermore, epidemiological evidence shows that surviving IUGR infants are at greater risk of developing glucose intolerance and diabetes during their life span. Nutritional interventions for IUGR have raised concerns for fetal toxicity leaving few therapeutic options available aside from close fetal surveillance to indicate preterm delivery. However, previous strategies to provide exogenous nutrients failed to reduce fetal catecholamine concentrations. In the IUGR fetus, low blood glucose and oxygen concentrations are prevalent and elevate fetal plasma norepinephrine and epinephrine in the final trimester. Administered alone, catecholamines restrict fetal growth in part via action on islets to inhibit insulin secretion. Additionally, our findings also indicate that chronic elevations in catecholamines increase glucose utilization rates yet decrease insulin stimulated glucose oxidation rates in skeletal muscle. Preliminary findings show chronic adrenergic stimulation reduces uncoupling protein 2 (UCP2) in semitendinosus muscle, which makes myofibers dependent on glycolysis. Experiments performed to characterize catecholamine mediated suppression of insulin secretion in IUGR fetuses revealed hyper-insulin secretion after chronic catecholamine exposure. In vitro studies confirmed these findings result from chronic catecholamines, but not from IUGR alone. This adrenergic programming was intrinsic to -cells, in which exome sequencing identified decreased UCP2 expression. Based on these findings, we formulated the hypothesis that chronic adrenergic stimulation promotes glycolysis and inhibits oxidative metabolism in IUGR fetuses through 2-adrenergic desensitization and reductions in UCP2. Furthermore, these effects explain glucose dependence in muscle, enhanced insulin secretion in islets, and ultimately further reductions in fetal growth.
In aim 1 w will measure the effects of chronic adrenergic action in IUGR fetuses by quantifying insulin stimulated glucose metabolism in fetuses with a bilateral adrenal demedullation or sustained norepinephrine infusions.
In aim 2 we will determine the role for UCP2 suppression by catecholamines. Mechanisms will be examined for increased glucose-stimulated insulin secretion in IUGR islets and disrupted metabolic flexibility in IUGR myofibers. Finally, we will assess an intervention strategy of administration of both oxygen and glucose to reduce plasma catecholamines in IUGR fetuses. By alleviating adrenergic signaling and providing glucose, a major nutrient for fetal oxidative metabolism, we expect that insulin mediated glucose disposal will be normalized in IUGR fetuses. Collectively, the proposed work will provide fundamental new knowledge about how chronic adrenergic stimulation reduces fetal growth through persistent metabolic programing adaptations. Furthermore, we will explore a practical method to reverse high fetal catecholamines via maternal intervention, which has potent clinical importance for both short and long term improvements in IUGR outcomes.

Public Health Relevance

Prevention of fetal adrenergic signaling improves metabolic dysfunction in IUGR Project Narrative: Fetal growth restriction continues to contribute to major medical problems for the fetus, newborn, and even the adult, which is highlighted by a greater incidence of diabetes. At present, no effective therapies exist, but fetal stress is believed to ply a critical role in the predisposition for Type 2 Diabetes. We plan to investigate how fetal stress predispose individuals to metabolic diseases and develop novel strategies to reduce stress in the growth restricted fetus to improve both short- and long-term complications.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK084842-06A1
Application #
8886932
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2009-04-15
Project End
2019-01-31
Budget Start
2015-04-01
Budget End
2016-01-31
Support Year
6
Fiscal Year
2015
Total Cost
Indirect Cost
Name
University of Arizona
Department
Veterinary Sciences
Type
Earth Sciences/Resources
DUNS #
806345617
City
Tucson
State
AZ
Country
United States
Zip Code
85721
Kelly, Amy C; Camacho, Leticia E; Pendarvis, Ken et al. (2018) Adrenergic receptor stimulation suppresses oxidative metabolism in isolated rat islets and Min6 cells. Mol Cell Endocrinol 473:136-145
Kelly, Amy C; Bidwell, Christopher A; Chen, Xiaochuan et al. (2018) Chronic Adrenergic Signaling Causes Abnormal RNA Expression of Proliferative Genes in Fetal Sheep Islets. Endocrinology 159:3565-3578
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
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
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
Chen, Xiaochuan; Kelly, Amy C; Yates, Dustin T et al. (2017) Islet adaptations in fetal sheep persist following chronic exposure to high norepinephrine. J Endocrinol 232:285-295
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
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

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