Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy

描述（由申请人提供）：怀孕降低了气压反射增益，导致出血耐受性降低，产妇死亡率增加。然而，其机制尚不清楚。在一些病理生理状态下，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，都会产生压力反射增益的降低，而这些状态的一个标志就是胰岛素抵抗。这种联系使我们提出了一种新的假设，即怀孕增加的减少是继发于胰岛素敏感性的降低，我们最近的研究是第一个支持这一假设的研究。然而，在哪里以及如何胰岛素抵抗损害气压反射功能，尚未在任何国家的研究。脑室内胰岛素输注增加正常大鼠的压力反射增益，胰岛素抵抗与胰岛素进入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脑区表达，特别是在已知影响压力反射增益的下丘脑部位室旁核（PVN）。因此，我们提出的实验将验证一个普遍的假设，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，从而损害心率和交感神经活动的压力反射控制，导致PVN中胰岛素水平和作用降低，从而增加体重。我们将通过确定怀孕是否会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会增加怀孕大鼠的胰岛素敏感性、胰岛素转运、脑脊液中的胰岛素水平和压力反射增益来验证这一假设。我们还将确定icv胰岛素输注是否使妊娠后期大鼠的压力反射功能正常化。最后，对PVN神经元的补充神经解剖学、体内电生理和药理学研究将验证PVN对于胰岛素增加压力反射增益的作用是必要和充分的假设。项目描述：对胰腺激素胰岛素作用的抵抗在几种状态下发展，包括II型糖尿病和妊娠。胰岛素抵抗的后果之一（除了改变血糖水平的调节）似乎是一个关键的血压调节机制的损害，压力反射；然而，其机制尚不清楚。我们对妊娠期的研究将把胰岛素抵抗和压力反射功能机械地联系起来，从而增加我们对压力反射损伤的理解，以及怀孕期间能量平衡的正常变化。

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.