Insulin-sensing capabilities of the carotid chemoreceptors

颈动脉化学感受器的胰岛素感应能力

• 批准号: 8716913
• 负责人: Jacqueline K Limberg
• 金额: $ 5.15万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716913
• 关键词: Acute; Address; Animals; Area; Carotid Body; Chemoreceptors; Chicago; Clinic; Clinical; Data; Diabetes Mellitus; Disease; Dopamine; Dose; Environment; Environmental air flow; Exposure to; Functional disorder; Future; Goals; Health; Human; Hyperinsulinism; Hyperoxia; Hypertension; Hypoxia; Infusion procedures; Insulin; Insulin Resistance; Laboratories; Link; Measures; Mediating; Metabolic Diseases; Metabolic syndrome; Modeling; Muscle; Nerve; Obesity; Oxygen; Physiological; Physiology; Preparation; Prevention; Public Health; Rattus; Reflex action; Research; Research Personnel; Resources; Role; Sensory; Series; Sleep Apnea Syndromes; Training; Universities; afferent nerve; autonomic reflex; carotid sinus; clinically relevant; design; innovation; novel; patient population; public health relevance; response; sensor; translational study

DESCRIPTION (provided by applicant): The goal of this application is to determine if the carotid body chemoreceptors are involved in insulin-mediated sympathoexcitation. This project provides an excellent intellectual and a robust laboratory training opportunity for an F32 application focusing on integrative physiological functions regulated by the carotid bodies. The carotid chemoreceptors are polymodal sensors known for their oxygen-sensing capabilities and recent experimental evidence suggests they may also respond to insulin. [By systematically examining insulin-sensing capabilities of the carotid chemoreceptors using novel, parallel approaches in both animals and humans, the proposed studies will determine the role of the carotid bodies as integrated sensors influencing insulin-mediated sympathoexcitation. Insulin-mediated changes in carotid chemoreceptor activity may provide a potential mechanism for the pathophysiology of a series of metabolic disorders including hypertension, insulin resistance, and sleep apnea. Specific Aim 1 will examine the effect of insulin on carotid chemoreceptor activation ex vivo. Using an isolated rat carotid body preparation, we will directly measure changes in carotid body afferent activity in response to insulin exposure. We hypothesize insulin will result in an increase in carotid sinus nerve activity. We also hypothesize insulin will increae the sensory response to hypoxia, and any insulin-mediated changes in afferent nerve activity will be blunted with hyperoxia. Specific Aim 2 will determine the contribution of the carotid chemoreceptors to insulin-mediated autonomic and cardiorespiratory responses in healthy humans. In Aim 2a, we will compare changes in muscle sympathetic nerve activity (MSNA) with hyperinsulinemia under normoxic and hyperoxic conditions (to inhibit carotid body chemoreceptor- mediated responses). In Aim 2b, we will compare changes in MSNA, ventilation, and carotid body chemosensitivity (hypoxic ventilatory response, HVR) with hyperinsulinemia under control conditions and during a low-dose infusion of dopamine (to inhibit carotid body chemoreceptor-mediated responses). We hypothesize insulin will result in an increase in MSNA, ventilation, and chemoreceptor sensitivity in humans. We also hypothesize the effect of hyperinsuilnemia on MSNA, ventilation, and HVR will be blunted during hyperoxia and/or low-dose dopamine infusion.] We propose novel, high impact, and translational studies investigating the role of the carotid bodies as integrated sensors of circulating insulin that influence sympathetic and cardiorespiratory reflexes. [The research team assembled, combined with the extensive resources at the Mayo Clinic and University of Chicago, provides the optimal training environment to complete studies in this area. Importantly, basic physiological data will be collected under tightly controlled conditions in both ex vivo animal and human studies to systematically examine acute effects of circulating insulin levels that are critical for future targeted studies in patient populations.]

描述（由申请人提供）：本申请的目的是确定颈动脉体化学感受器是否参与胰岛素介导的交感神经兴奋。该项目为 F32 应用提供了良好的智力和强大的实验室培训机会，重点关注颈动脉体调节的综合生理功能。颈动脉化学感受器是多模式传感器，以其氧传感能力而闻名，最近的实验证据表明它们也可能对胰岛素产生反应。 [通过在动物和人类中使用新颖的并行方法系统地检查颈动脉化学感受器的胰岛素感应能力，拟议的研究将确定颈动脉体作为影响胰岛素介导的交感神经兴奋的综合传感器的作用。胰岛素介导的颈动脉化学感受器活性变化可能为包括高血压、胰岛素抵抗和睡眠呼吸暂停在内的一系列代谢性疾病的病理生理学提供潜在机制。具体目标 1 将检查胰岛素对离体颈动脉化学感受器激活的影响。使用离体的大鼠颈动脉体制剂，我们将直接测量颈动脉体传入活动对胰岛素暴​​露的反应的变化。我们假设胰岛素会导致颈动脉窦神经活动增加。我们还假设胰岛素会增加对缺氧的感觉反应，并且任何胰岛素介导的传入神经活动的变化都会因高氧而减弱。具体目标 2 将确定颈动脉化学感受器对健康人胰岛素介导的自主神经和心肺反应的贡献。在目标 2a 中，我们将比较常氧和高氧条件下肌肉交感神经活动 (MSNA) 与高胰岛素血症的变化（以抑制颈动脉体化学感受器介导的反应）。在目标 2b 中，我们将在控制条件下和低剂量输注多巴胺（以抑制颈动脉体化学感受器介导的反应）期间比较 MSNA、通气和颈动脉体化学敏感性（缺氧通气反应，HVR）与高胰岛素血症的变化。我们假设胰岛素会导致人类 MSNA、通气和化学感受器敏感性的增加。我们还假设高胰岛素血症对 MSNA、通气和 HVR 的影响在高氧和/或低剂量多巴胺输注期间会减弱。]我们提出新颖、高影响力和转化性研究，调查颈动脉体作为集成传感器的作用影响交感神经和心肺反射的循环胰岛素。 [组建的研究团队，结合梅奥诊所和芝加哥大学的广泛资源，为完成该领域的研究提供了最佳的培训环境。重要的是，将在严格控制的条件下收集离体动物和人类研究中的基本生理数据，以系统地检查循环胰岛素水平的急性影响，这对于未来针对患者群体的针对性研究至关重要。]