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：
9013470
负责人：
SEAN W LIMESAND
金额：
$ 43.69万
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/9013470
关键词：
Adrenal Glands Adrenergic Agents 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 Health 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 Muscle Muscle Mitochondria Newborn Infant Non-Insulin-Dependent Diabetes Mellitus Norepinephrine Nutrient Outcome Oxidative Phosphorylation Oxygen Pattern Perinatal mortality demographics 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 block aerobic glycolysis base beta-2 Adrenergic Receptors beta-adrenergic receptor blood glucose regulation desensitization effective therapy exome sequencing fetal flexibility glucose disposal glucose metabolism imprint improved in vivo innovation insulin secretion insulin sensitivity islet muscle metabolism novel novel strategies oxidation perinatal morbidity prenatal stress programs 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.

描述（由适用提供）：内蛋白内生长限制（IUGR）导致围产期发病率和死亡率。此外，流行病学的证据表明，存活的IUGR婴儿在其寿命中患葡萄糖肠胃和糖尿病的风险更大。 IUGR的营养干预措施提出了人们对胎儿毒性的担忧，几乎没有胎儿监测可用的治疗选择来表明早产。但是，以前提供外源营养素的策略未能降低胎儿儿茶酚胺浓度。在IUGR胎儿中，低血糖和氧气浓度很普遍，升高胎儿血浆去甲肾上腺素和肾上腺素。儿茶酚胺单独使用，部分通过对胰岛抑制胰岛素分泌的作用部分限制了胎儿生长。此外，我们的发现还表明，儿茶酚胺的慢性升高增加了葡萄糖的利用率，但降低了胰岛素刺激骨骼肌中的葡萄糖氧化速率。初步发现表明慢性肾上腺素刺激可减少半牙本质肌肉中的解偶联蛋白2（UCP2），这使肌纤维依赖于糖酵解。进行的实验是为了表征儿茶酚胺介导的IUGR胎儿中胰岛素分泌的抑制，发现慢性儿茶酚胺暴露后的超胰岛素分泌。体外研究证实了这些发现是由慢性儿茶酚胺造成的，但不是仅由IUGR引起的。这种肾上腺素编程是β细胞的固有的，其中表达测序鉴定出UCP2表达降低。基于这些发现，我们提出了以下假设：慢性肾上腺素刺激促进糖酵解并抑制IUGR胎儿中的氧化物代谢，并通过ß2-肾上腺素脱敏和UCP2减少。此外，这些作用解释了肌肉中的葡萄糖依赖性，胰岛中胰岛素的分泌增强，并最终进一步减少胎儿生长。在AIM 1中，通过量化双侧肾上腺脱氧化或持续性去甲肾上腺素输注的胰岛素刺激的葡萄糖代谢，可以通过量化胰岛素刺激的葡萄糖代谢来衡量慢性肾上腺作用在IUGR胎儿中的影响。在AIM 2中，我们将确定儿茶酚胺抑制UCP2的作用。将检查IUGR胰岛中葡萄糖刺激的胰岛素分泌增加的机制，并在IUGR肌纤维中破坏代谢灵活性。最后，我们将评估一种氧和葡萄糖给药的干预策略，以减少IUGR胎儿的血浆儿茶酚胺。通过减轻肾上腺素信号传导并提供葡萄糖，这是胎儿氧化物代谢的主要营养，我们希望胰岛素介导的葡萄糖处置将在IUGR胎儿中标准化。总的来说，拟议的工作将提供有关慢性肾上腺素模拟如何通过持续的代谢编程适应来减少胎儿生长的基本新知识。此外，我们将通过材料干预探索一种实用方法来逆转高胎儿儿茶酚胺，这对于IUGR结果的短期和长期改善具有潜在的临床重要性。