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Prevention of fetal adrenergic signaling improves metabolic dysfunction in IUGR

预防胎儿肾上腺素能信号传导可改善 IUGR 的代谢功能障碍

基本信息

批准号：
8886932
负责人：
SEAN W LIMESAND
金额：
$ 43.57万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-15 至 2019-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8886932
关键词：
Adrenal Glands Adrenergic Agents Adrenergic Receptor Adult Adverse effects Barker Hypothesis Beta Cell Bilateral Blood Glucose Catecholamines Cell Respiration Cells Chronic Clinical Coupling Data Dependence Development Diabetes Mellitus Dietary Intervention Epidemiology Epinephrine Fatty Acids Fetal Growth Fetal Growth Retardation Fetal Tissues Fetus Functional disorder Glucose Glucose Intolerance Glycolysis Growth Hypoglycemia Hypoxemia In Vitro Incidence Individual Infant Infusion procedures Insulin Intervention Islets of Langerhans Knowledge Left Longevity Longitudinal Studies Measures Mediating Medical Metabolic Metabolic Diseases Metabolism Methods Mitochondria Morbidity - disease rate Muscle Muscle Mitochondria Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Nutrient Outcome Oxidative Phosphorylation Oxygen Pattern Perinatal Placental Insufficiency Plasma Predisposition Pregnancy Premature Birth Prevention Production Publishing Reactive Oxygen Species Regulation Reporting Respiration Risk Role Sheep Signal Transduction Site Skeletal Muscle Stress Supplementation Testing Therapeutic Tissues Toxic effect UCP2 protein Work adrenergic adrenergic block aerobic glycolysis base blood glucose regulation desensitization effective therapy exome sequencing fetal flexibility glucose disposal glucose metabolism imprint improved in vivo innovation insulin secretion insulin sensitivity islet mortality muscle metabolism novel novel strategies oxidation prenatal stress programs public health relevance research study response

项目摘要

DESCRIPTION (provided by applicant): 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 ß-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 ß2-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.