Insulin Resistance and Impaired Cardiovascular Regulation 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，并增加产妇死亡率。然而，其机制尚不清楚。压力感受器反射增益降低是在几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，而这些状态中的每一种都是胰岛素抵抗的标志。这种关联使我们提出了一个新的假设，即怀孕增加的减少是胰岛素敏感性降低的次要因素，我们最近的研究首次支持了这一假设。然而，胰岛素抵抗在哪里以及如何损害压力感受器反射功能在任何状态下都没有被研究过。脑室注射胰岛素可增加正常大鼠的压力感受性反射增益，胰岛素抵抗与胰岛素进入大脑的转运障碍有关。胰岛素受体在参与自主神经系统调节的大脑区域表达，特别是下丘脑中影响压力反射获得的部位，室旁核(PVN)。因此，拟议的实验将检验一个普遍的假设，即在怀孕期间，胰岛素抵抗通过减少胰岛素进入大脑的运输，导致下丘脑室旁核中胰岛素水平的降低和增加增益的作用，损害了压力反射对心率和交感神经活动的控制。我们将通过确定怀孕是否降低胰岛素转运和脑脊液(CSF)中的胰岛素水平，以及胰岛素增敏药物罗格列酮是否增加怀孕大鼠的胰岛素敏感性、胰岛素转运、脑脊液中胰岛素水平和压力反射增加来验证这一假设。我们还将确定脑室注射胰岛素是否能使妊娠晚期大鼠的压力感受器反射功能正常化。最后，对下丘脑室旁核神经元的补充神经解剖学、体内电生理和药理学研究将检验下丘脑室旁核是胰岛素增加压力感受器获得的必要和充分作用的假设。项目简介：对胰腺激素胰岛素作用的抵抗在几种状态下发生，包括II型糖尿病和妊娠。胰岛素抵抗的后果之一(除了血糖水平的调节改变外)似乎是一个关键的血压调节机制--压力感受器反射受损；然而，其机制尚不清楚。我们对怀孕的研究将把胰岛素抵抗和压力感受器反射功能机械地联系起来，从而增加我们对压力感受器反射损伤以及怀孕期间能量平衡正常变化的理解。

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.