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

• 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
• 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

 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(申请人提供)：宫内生长受限(IUGR)导致围产儿发病率和死亡率。此外，流行病学证据表明，存活的IUGR婴儿在其一生中患糖耐量异常和糖尿病的风险更大。对IUGR的营养干预引起了对胎儿毒性的担忧，除了密切监测胎儿以提示早产外，几乎没有其他治疗选择。然而，以前的提供外源性营养的策略未能降低胎儿的儿茶酚胺浓度。在IUGR胎儿中，低血糖和低氧浓度普遍存在，并在最后三个月升高胎儿血浆去甲肾上腺素和肾上腺素。单独给药，儿茶酚胺在一定程度上通过作用于胰岛抑制胰岛素分泌来限制胎儿生长。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的骨骼肌中的葡萄糖氧化率。初步发现，慢性肾上腺素能刺激减少半腱肌解偶联蛋白2(UCP2)，从而使肌纤维依赖糖酵解。研究儿茶酚胺对IUGR胎儿胰岛素分泌抑制作用的实验结果显示，在长期接触儿茶酚胺后，胎儿体内胰岛素分泌增加。体外研究证实，这些发现是由慢性儿茶酚胺引起的，但不仅仅是IUGR。这种肾上腺素能编程是？细胞所固有的，外显子组测序发现UCP2的表达降低。基于这些发现，我们提出了一个假说，即慢性肾上腺素能刺激通过2-肾上腺素能脱敏和UCP2的减少促进IUGR胎儿的糖酵解和抑制氧化代谢。此外，这些效应解释了肌肉对葡萄糖的依赖，胰岛胰岛素分泌的增加，最终进一步降低了胎儿的生长。在目标1中，我们将通过量化双侧肾上腺剥离或持续注射去甲肾上腺素的胎儿胰岛素刺激的葡萄糖代谢来衡量IUGR胎儿的慢性肾上腺素能作用的影响。在目标2中，我们将确定儿茶酚胺抑制UCP2的作用。将研究IUGR胰岛中葡萄糖刺激的胰岛素分泌增加和IUGR肌纤维代谢灵活性被破坏的机制。最后，我们将评估同时给予氧气和葡萄糖以减少IUGR胎儿血浆儿茶酚胺的干预策略。通过减轻肾上腺素能信号，并提供胎儿氧化代谢的主要营养物质葡萄糖，我们预计胰岛素介导的葡萄糖处置将在IUGR胎儿中正常化。总而言之，这项拟议的工作将提供关于慢性肾上腺素能刺激如何通过持续的代谢程序适应来降低胎儿生长的基本新知识。此外，我们将探索一种实用的方法，通过母体干预逆转胎儿高儿茶酚胺水平，这对改善IUGR结局的短期和长期临床意义重大。