Insulin Resistance and Impaired Cardiovascular Regulation During Pregnancy

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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.