Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses

儿茶酚胺对 IUGR 胎儿胰岛素-葡萄糖稳态的影响

• 批准号: 8049119
• 负责人: SEAN W LIMESAND
• 金额: $ 25.8万
• 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 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8049119
• 关键词: Acute; Adrenergic Agents; Adrenergic Receptor; Adult; Affect; Anabolism; Area; Biological Models; Biology; Blood Glucose; Catecholamines; Cell Proliferation; Cell Respiration; Cell physiology; Cells; Chronic; Clinical; Complication; Coupled; Coupling; Data; Defect; Development; Endocrine; Epidemic; Epidemiologic Studies; Epinephrine; Exocrine pancreatic insufficiency; Exposure to; Fetal Growth Retardation; Fetus; Functional disorder; Glucose; Goals; Growth; Health; Healthcare; Hormones; Human; Hypoglycemia; Hypoxia; Incidence; Individual; Infant; Insulin; Intervention; Investigation; Islets of Langerhans; Knowledge; Lead; Life; Literature; Low Birth Weight Infant; Medical; Metabolic; Modeling; Monitor; Neonatal Mortality; Newborn Infant; Non-Insulin-Dependent Diabetes Mellitus; Norepinephrine; Nutrient; Nutritional; Onset of illness; Oxygen; Pancreas; Pathology; Pathway interactions; Patients; Placental Insufficiency; Play; Predisposition; Pregnancy; Receptor Signaling; Regulation; Research Project Grants; Residual state; Role; Ruminants; Sheep; Signal Pathway; Signal Transduction; Small for Gestational Age Infant; Stimulus; Testing; Therapeutic; United States; Work; adrenergic; base; biological adaptation to stress; blood glucose regulation; deprivation; desensitization; design; diabetic; fetal; fetus hypoxia; improved; in utero; insight; insulin secretion; insulin sensitivity; islet; neonatal morbidity; neonate; novel; postnatal; prenatal; programs; research study; response

DESCRIPTION (provided by applicant): Impact of Catecholamines to Insulin-Glucose Homeostasis in IUGR Fetuses Endocrine factors such as catecholamines promote fetal survival during intrauterine growth restriction (IUGR) by sparing glucose for critical functions. A primary fetal response to IUGR is to suppress 2-cell function and lower the anabolic hormone, insulin. The goal of this research project is to understand the mechanisms by which chronic catecholamine stimulation (coupled with hypoxia and hypoglycemia) modulates insulin secretion in fetal sheep with placental insufficiency, a model system that shares many similarities to human IUGR fetuses with placental insufficiency. Our data indicates that chronic exposure to high catecholamine concentrations leads to 2-cell desensitization by augmenting their insulin secretion responsiveness. In postnatal life, when catecholamine suppression is no long present, a hyper-responsiveness to glucose is apparent, and potentially results from the 2- cells desensitization adaptation to fetal catecholamines. We will test the hypothesis that chronic exposure to elevated catecholamine concentrations lowers insulin secretion in the IUGR fetus, but also leads to adrenergic desensitization in 2-cells that enhances glucose stimulated insulin secretion after suppressive conditions are alleviated in the neonate with the following specific aims. First, we will determine the onset and consequences of chronic catecholamine suppression to glucose stimulated insulin secretion (GSIS) in sheep fetuses with placental insufficiency-induced IUGR. Second, we will determine if chronic catecholamine desensitization for the fetal 2-cells occurs in the proximal adrenergic receptor signaling pathway, insulin stimulus secretion coupling pathway, or both. Finally, in pre-ruminant lambs we will determine whether residual compensatory actions from catecholamine suppression in fetal life leads to the overcorrection in insulin secretion responsiveness as a result of proximal adrenergic signaling or increased insulin stimulus secretion coupling. It is likely that such explanations will increase capacity for promoting 2-cell function in human IUGR infants. These concepts and this type of investigation have not been done in the fetus, but represent reasonable points of regulation that based on the literature and general understanding of catecholamine action should play significant roles. Therefore, these studies will provide new insight into the requirements for clinical intervention to ameliorate pancreatic insufficiency in IUGR fetuses and neonates with the goal of reducing fetal and neonatal morbidity and mortality, and potentially lower the incidence of adult onset diseases that have been correlated with low birth weight. PUBLIC HEALTH RELEVANCE: Fetal growth restriction continues to contribute to major medical problems for the fetus, newborn infant, and even the adult, which is highlighted by recent epidemiological studies in Diabetics. Patients with Type 2 Diabetes are reaching epidemic proportions in the United States and consume one of every eight dollars spent for health care. As much as one fifth of this epidemic arises from a nutritional discordance between prenatal and postnatal life that results in impaired glucose homeostasis. Therefore, we plan to determine how a key stress response alters the developmental program in the fetal 2-cells to impair glucose homeostasis and lead to adulthood pathologies, such as Type 2 Diabetes Mellitus.

描述（由申请人提供）：儿茶酚胺对IUGR胎儿内分泌因子（例如儿茶酚胺）在宫内内生长限制（IUGR）期间促进胎儿存活（IUGR）中的胰岛素 - 葡萄糖稳态的影响，从而促进了葡萄糖的关键功能。对IUGR的主要胎儿反应是抑制2细胞功能并降低合成代谢激素，即胰岛素。该研究项目的目的是了解慢性儿茶酚胺刺激（与缺氧和低血糖）调节胎盘绵羊中胰岛素分泌的机制（结合缺氧和低血糖）与胎盘绵羊中的胰岛素分泌，这是一种模型系统，这种模型系统与人类IUGR胎儿具有许多相似之处，与胎盘不足。我们的数据表明，长期暴露于高儿茶酚胺浓度通过增强其胰岛素分泌的反应性而导致2细胞脱敏。在产后寿命中，当没有长时间的儿茶酚胺抑制时，对葡萄糖的过度反应是显而易见的，并且可能是由2-细胞脱敏适应胎儿儿茶酚胺的可能导致的。我们将检验以下假设：长期暴露于儿茶酚胺浓度升高会降低IUGR胎儿中的胰岛素分泌，但也会导致2个细胞的肾上腺素脱敏，从而增强葡萄糖刺激的胰岛素刺激的胰岛素分泌，并在新生酸盐中通过以下特定特定目标减轻了抑制性疾病。首先，我们将确定患有胎盘不足引起的IUGR的绵羊胎儿中慢性儿茶酚胺抑制对葡萄糖刺激的胰岛素分泌（GSI）的发作和后果。其次，我们将确定胎儿2细胞的慢性儿茶酚胺脱敏是否发生在近端肾上腺素能信号传导途径，胰岛素刺激分泌偶联途径或两者中。最后，在前肿瘤前羔羊中，我们将确定胎儿生命中儿茶酚胺抑制中的残留补偿作用是导致胰岛素分泌反应性过度的校正，这是由于近端肾上腺素能信号传导还是增加的胰岛素刺激刺激分泌耦合。这种解释可能会增加促进人IUGR婴儿2细胞功能的能力。这些概念和这种调查尚未在胎儿中进行，但代表了合理的监管点，基于文献和对儿茶酚胺作用的一般理解应起着重要作用。因此，这些研究将为临床干预的需求提供新的见解，以减轻IUGR胎儿和新生儿的胰腺不足，目的是降低胎儿和新生儿的发病率和死亡率，并可能降低与出生体重低相关的成年发病率的发病率。公共卫生相关性：胎儿生长限制继续为胎儿，新生婴儿甚至成年人的重大医学问题做出了贡献，这是最近在糖尿病患者方面的流行病学研究所强调的。 2型糖尿病的患者在美国达到流行比例，每八美元用于医疗保健。多达五分之一的流行病是由于产前和产后生活之间的营养不一致引起的，导致葡萄糖稳态受损。因此，我们计划确定关键应力反应如何改变胎儿2细胞中的发育程序，以损害葡萄糖稳态并导致成年病理，例如2型糖尿病。