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）：怀孕会降低压力反射增益，导致对出血的耐受性降低并增加孕产妇死亡率。然而，其机制尚不清楚。压力反射增益减少是在多种病理生理状态下产生的，包括肥胖、代谢综合征、糖尿病、充血性心力衰竭、衰老以及怀孕，而这些状态的一个标志是胰岛素抵抗。这种关联使我们提出了一个新的假设，即妊娠体重减少是胰岛素敏感性降低的继发因素，而我们最近的研究首次支持了这一假设。然而，胰岛素抵抗在何处以及如何损害压力反射功能尚未在任何州进行研究。脑室内（icv）胰岛素输注会增加正常大鼠的压力感受反射增益，而胰岛素抵抗与胰岛素向大脑的转运受损有关。胰岛素受体在参与自主神经系统调节的大脑区域表达，特别是已知影响压力反射增益的下丘脑部位，即室旁核（PVN）。因此，拟议的实验将检验一般假设，即在怀孕期间，胰岛素抵抗通过减少胰岛素向大脑的转运，损害心率和交感神经活动的压力反射控制，导致PVN中胰岛素的水平和作用降低，以增加增益。我们将通过确定妊娠是否会减少脑脊液 (CSF) 中的胰岛素转运和胰岛素水平以及胰岛素增敏药物罗格列酮是否增加妊娠大鼠的胰岛素敏感性、胰岛素转运、脑脊液胰岛素水平和压力反射增益来检验这一假设。我们还将确定静脉注射胰岛素是否可以使妊娠晚期大鼠的压力反射功能正常化。最后，PVN 神经元的补充神经解剖学、体内电生理学和药理学研究将检验这样的假设：PVN 对于胰岛素增加压力反射增益的作用是必要且充分的。项目叙述：对胰腺激素、胰岛素作用的抵抗力在多种状态下都会出现，包括 II 型糖尿病和妊娠。胰岛素抵抗的后果之一（除了血糖水平调节的改变之外）似乎是关键的血压调节机制——压力反射——受到损害。然而，其机制尚不清楚。我们对怀孕的研究将在机制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损伤以及怀孕期间发生的能量平衡正常变化的理解。