Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy

描述（由申请人提供）：妊娠减少压力反射增益，导致对出血的耐受性降低和孕产妇死亡率增加。然而，其机制尚不清楚。压力感受器反射增益降低在几种病理生理状态中产生，包括肥胖、代谢综合征、糖尿病、充血性心力衰竭、衰老以及妊娠，并且这些状态中的每一种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，即妊娠增加的减少是继发于胰岛素敏感性降低，我们最近的研究是第一个支持这一假设的。然而，在任何状态下，胰岛素抵抗在何处以及如何损害压力感受性反射功能尚未研究。脑室内（icv）胰岛素输注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向脑内转运受损有关。胰岛素受体在参与自主神经系统调节的脑区域中表达，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，所提出的实验将测试以下一般假设：在妊娠期间，胰岛素抵抗通过减少胰岛素向大脑的转运而损害心率和交感神经活动的压力感受器反射控制，导致PVN中胰岛素水平和作用降低以增加增益。我们将通过确定妊娠是否减少脑脊髓液（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、CSF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icv胰岛素输注是否能使晚期妊娠大鼠的压力反射功能正常化。最后，补充神经解剖，在体内电生理和药理学研究PVN神经元将测试的假设，即PVN是必要的和足够的胰岛素的行动，以增加压力反射增益。项目叙述：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，压力反射的损害;然而，机制是未知的。我们对妊娠的研究将从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障碍以及妊娠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.