Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy

怀孕期间胰岛素抵抗和心血管调节受损

• 批准号: 7373988
• 负责人: VIRGINIA L. BROOKS
• 金额: $ 39.22万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7373988
• 关键词: Affect; Aging; Autonomic nervous system; Baroreflex; Blood; Blood Circulation; Blood Pressure; Blood capillaries; Brain; Brain Stem; Brain region; Cardiovascular system; Cerebrospinal Fluid; Congestive Heart Failure; Conscious; Diabetes Mellitus; Endothelium; Female; Figs - dietary; Functional disorder; Goals; Heart Rate; Hemorrhage; Hypothalamic structure; Impairment; Infusion procedures; Insulin; Insulin Receptor; Insulin Resistance; Kidney; Lateral; Link; Maternal Mortality; Mediating; Metabolic; Metabolic syndrome; Microinjections; Nerve; Neuroendocrinology; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Numbers; Obesity; Pancreatic Hormones; Pathway interactions; Patient currently pregnant; Plasma; Pregnancy; Rattus; Reflex action; Regulation; Resistance; Secondary to; Site; Sympathetic Nervous System; Testing; Ventricular; blood glucose regulation; capillary; energy balance; falls; improved; in vivo; instrument; insulin sensitivity; insulin sensitizing drugs; insulin tolerance; neuroregulation; novel; paraventricular nucleus; research study; rosiglitazone

DESCRIPTION (provided by applicant): Pregnancy decreases baroreflex gain, resulting in reduced tolerance to hemorrhage and increased maternal mortality. However, the mechanism is unknown. Decreased baroreflex gain is produced in several pathophysiological states, including obesity, metabolic syndrome, diabetes mellitus, congestive heart failure, aging, as well as pregnancy, and a hallmark of each of these states is insulin resistance. This association led us to the novel hypothesis that the decreased gain of pregnancy is secondary to reduced insulin sensitivity, and our recent studies are the first to support this hypothesis. However, where and how insulin resistance impairs baroreflex function has not been studied in any state. Intracerebroventricular (icv) insulin infusion increases baroreflex gain in normal rats, and insulin resistance is associated with impaired transport of insulin into the brain. Insulin receptors are expressed in brain regions that participate in regulation of the autonomic nervous system, in particular, a hypothalamic site known to influence baroreflex gain, the paraventricular nucleus (PVN). Therefore, the proposed experiments will test the general hypothesis that, during pregnancy, insulin resistance impairs baroreflex control of heart rate and sympathetic activity by decreasing transport of insulin into the brain, leading to reduced levels and actions of insulin in PVN to increase gain. We will test this hypothesis by determining if pregnancy reduces insulin transport and insulin levels in the cerebrospinal fluid (CSF) and if the insulin sensitizing drug, rosiglitazone, increases insulin sensitivity, insulin transport, CSF levels of insulin, and baroreflex gain in pregnant rats. We will also determine if icv insulin infusion normalizes baroreflex function in late pregnant rats. Finally, complementary neuroanatomical, in vivo electrophysiological and pharmacological studies of PVN neurons will test the hypothesis that the PVN is necessary and sufficient for insulin's action to increase baroreflex gain. Project Narrative: Resistance to the actions of the pancreatic hormone, insulin, develops in several states, including type II diabetes mellitus and pregnancy. One of the consequences of insulin resistance (besides altered regulation of blood glucose levels) appears to be impairment of a critical blood pressure regulating mechanism, the baroreflex; however, the mechanism is unknown. Our studies of pregnancy will mechanistically link insulin resistance and baroreflex function, thereby increasing our understanding of this baroreflex impairment, as well as of the normal changes in energy balance that occur during pregnancy.

描述（由申请人提供）：妊娠减少了压力反射增益，从而降低了出血的耐受性和孕产妇死亡的增加。但是，该机制尚不清楚。在几种病理生理状态下产生的降低压力反射增益，包括肥胖，代谢综合征，糖尿病，糖尿病，充血性心力衰竭，衰老以及妊娠以及这些状态的标志是胰岛素抵抗。这种关联使我们提出了一个新的假设，即怀孕的增加是胰岛素敏感性降低的继发性，而我们最近的研究是第一个支持这一假设的研究。但是，尚未在任何状态下研究胰岛素耐药性损害压力反射功能的何处以及如何损害。脑室内（ICV）胰岛素输注会增加正常大鼠的压力反射增益，胰岛素抵抗与胰岛素输入大脑的运输受损有关。胰岛素受体在参与自主神经系统调节的大脑区域中表达，特别是一个已知会影响脊椎状核（PVN）的下丘脑部位。因此，提出的实验将检验一个总体假设，即在怀孕期间，胰岛素抵抗会通过减少胰岛素进入大脑的运输，从而损害心率和交感活性的压力反射控制，从而导致PVN中胰岛素的水平和作用降低，从而增加增益。我们将通过确定妊娠是否会降低脑脊液（CSF）的胰岛素传输和胰岛素水平来检验这一假设，以及胰岛素敏化药物（Rosiglitazone）是否会提高胰岛素敏感性，胰岛素转运，CSF的胰岛素胰岛素和Baroreflex水平，而怀孕大鼠的Baroreflex升高水平。我们还将确定ICV胰岛素输注是否使晚期孕妇大鼠的压力反射功能归一化。最后，PVN神经元的互补神经解剖学，体内电生理学和药理学研究将检验以下假设：PVN是必要且足够的胰岛素作用，以增加巴洛诺反射增益。项目叙述：胰岛素胰岛素对胰腺激素的作用的抵抗力在几种州发展，包括II型糖尿病和怀孕。胰岛素抵抗的后果之一（除了对血糖水平的调节改变）似乎是调节降压机制的临界血压的损害。但是，该机制尚不清楚。我们对怀孕的研究将从机械上将胰岛素抵抗和压力反射功能联系起来，从而增加我们对这种压力反射障碍的理解，以及怀孕期间能量平衡的正常变化。