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（由申请人提供）：宫内生长受限（IUGR）会导致围产期发病率和死亡率。此外，流行病学证据表明，幸存的 IUGR 婴儿在其一生中患葡萄糖不耐受和糖尿病的风险更大。 IUGR 的营养干预引起了对胎儿毒性的担忧，除了密切胎儿监测以指示早产之外，几乎没有可用的治疗选择。然而，之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，普遍存在低血糖和低氧浓度，并且在妊娠末期胎儿血浆去甲肾上腺素和肾上腺素升高。单独给药时，儿茶酚胺部分通过作用于胰岛抑制胰岛素分泌来限制胎儿生长。此外，我们的研究结果还表明，儿茶酚胺的慢性升高会增加葡萄糖利用率，但会降低骨骼肌中胰岛素刺激的葡萄糖氧化率。初步研究结果表明，慢性肾上腺素能刺激会减少半腱肌中的解偶联蛋白 2 (UCP2)，从而使肌纤维依赖于糖酵解。为表征儿茶酚胺介导的 IUGR 胎儿胰岛素分泌抑制而进行的实验揭示了慢性儿茶酚胺暴露后胰岛素分泌过多。体外研究证实这些发现是由慢性儿茶酚胺引起的，而不仅仅是 IUGR 引起的。这种肾上腺素能编程是 β 细胞所固有的，其中外显子组测序发现 UCP2 表达降低。基于这些发现，我们提出了这样的假设：慢性肾上腺素刺激通过β2肾上腺素脱敏和UCP2减少促进IUGR胎儿的糖酵解并抑制氧化代谢。此外，这些效应解释了肌肉中的葡萄糖依赖性、胰岛中胰岛素分泌的增强以及最终胎儿生长的进一步减少。目标 1 w 将通过双侧肾上腺脱髓鞘或持续去甲肾上腺素输注量化胎儿中胰岛素刺激的葡萄糖代谢，来测量 IUGR 胎儿的慢性肾上腺素作用的影响。在目标 2 中，我们将确定儿茶酚胺抑制 UCP2 的作用。将检查 IUGR 胰岛中葡萄糖刺激胰岛素分泌增加以及 IUGR 肌纤维代谢灵活性破坏的机制。最后，我们将评估给予氧气和葡萄糖的干预策略，以减少 IUGR 胎儿的血浆儿茶酚胺。通过减轻肾上腺素能信号传导并提供葡萄糖（胎儿氧化代谢的主要营养素），我们预计胰岛素介导的葡萄糖处理将在 IUGR 胎儿中正常化。总的来说，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减少胎儿生长的基本新知识。此外，我们将探索一种通过母亲干预逆转胎儿儿茶酚胺含量高的实用方法，这对于短期和长期改善 IUGR 结局具有重要的临床意义。