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: 7802160
• 负责人: SEAN W LIMESAND
• 金额: $ 37.2万
• 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/7802160
• 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; 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; 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; mortality; neonatal morbidity; neonate; novel; postnatal; prenatal; programs; public health relevance; 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胎儿胰岛素-葡萄糖稳态的影响儿茶酚胺等内分泌因子通过保留关键功能的葡萄糖来促进胎儿在宫内生长限制（IUGR）期间的存活。胎儿对IUGR的主要反应是抑制2细胞功能和降低合成代谢激素胰岛素。本研究项目的目的是了解慢性儿茶酚胺刺激（伴缺氧和低血糖）调节胎盘功能不全胎羊胰岛素分泌的机制，这是一个与人类IUGR胎盘功能不全胎儿有许多相似之处的模型系统。我们的数据表明，长期暴露于高儿茶酚胺浓度会通过增加胰岛素分泌反应性导致2细胞脱敏。在出生后，当儿茶酚胺抑制不再存在时，对葡萄糖的高反应性是明显的，这可能是2细胞对胎儿儿茶酚胺脱敏适应的结果。我们将验证这一假设，即长期暴露于升高的儿茶酚胺浓度会降低IUGR胎儿的胰岛素分泌，但也会导致2细胞的肾上腺素能脱敏，从而在新生儿抑制条件得到缓解后增强葡萄糖刺激的胰岛素分泌。首先，我们将确定慢性儿茶酚胺抑制葡萄糖刺激胰岛素分泌（GSIS）在胎盘功能不全引起的IUGR绵羊胎儿中的发病和后果。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受体信号通路，胰岛素刺激分泌偶联通路，或两者兼有。最后，在前反刍羔羊中，我们将确定胎儿生活中儿茶酚胺抑制的残余代偿行为是否会导致近端肾上腺素能信号或胰岛素刺激分泌偶联增加导致胰岛素分泌反应的过度纠正。这种解释很可能会增加IUGR婴儿促进2细胞功能的能力。这些概念和这种类型的调查尚未在胎儿中进行，但根据文献和对儿茶酚胺作用的一般理解，它们代表了合理的调节点，应该发挥重要作用。因此，这些研究将为改善IUGR胎儿和新生儿胰腺功能不全的临床干预需求提供新的见解，以降低胎儿和新生儿的发病率和死亡率，并有可能降低与低出生体重相关的成人发病疾病的发病率。公共卫生相关性：胎儿生长受限继续对胎儿、新生儿甚至成人造成重大医疗问题，最近的糖尿病流行病学研究强调了这一点。在美国，2型糖尿病患者正达到流行病的程度，每8美元的医疗支出中就有1美元被2型糖尿病患者所消耗。多达五分之一的这种流行病源于产前和产后生活之间的营养失调，导致葡萄糖稳态受损。因此，我们计划确定一个关键的应激反应如何改变胎儿2细胞的发育程序，从而破坏葡萄糖稳态并导致成年期的病理，如2型糖尿病。