Role of Carotid Bodies in Glucose Regulation and Counter Regulation in Humans

描述（由申请人提供）：本申请探索了颈动脉体在人体全身葡萄糖稳态中的新作用。颈动脉体感知动脉氧分压并调节通气。然而，在分离的颈动脉体细胞和动物模型中的研究表明，这些受体也感知血糖的变化，并且氧分压（pO 2）的变化改变了这种敏感性。在人体中也有证据表明动脉pO 2的变化影响血糖稳态，但颈动脉体在调节血糖中的作用基本上未在人体中探索。为了阐明颈动脉体在人体葡萄糖稳态中的作用，我们将系统地操纵动脉pO 2，并测量三组受试者对低血糖的反调节反应：1）健康人，2）血管球瘤手术后双侧颈动脉去神经支配的人，3）1型糖尿病伴和不伴低血糖无意识的人。在这种情况下，我们将解决以下具体目标：目标1）测试假设动脉pO 2如何影响健康受试者对低血糖的反调节反应。我们将在常氧、高氧和低氧操作期间进行高胰岛素低血糖钳夹，这些操作应抑制（高氧）或增强（低氧）颈动脉体感知低血糖的能力，并改变对低血糖的反调节反应。这些研究将在正常受试者中进行。目的2）检验颈动脉体手术切除如何改变低血糖的反调节反应的相关假设。我们将比较接受双侧颈动脉体去神经治疗血管球瘤的受试者与对照者对高胰岛素低血糖钳夹的生理反应。目的3）验证1型糖尿病患者颈动脉体功能障碍与低血糖无意识相关的假设。我们将在常氧和缺氧条件下测量1型糖尿病患者的低氧反应，并进行低血糖钳夹试验。其观点是，颈动脉体未能感知和启动对低血糖的反应导致了低血糖无意识。摘要：据我们所知，这是第一次尝试系统地测试颈动脉体在人体全身葡萄糖稳态中的作用，这些想法是基于有限数量的分离细胞和动物模型研究的挑衅性数据。在此背景下，我们提出了一套新的目标和假设，并将基本机制的想法与1型糖尿病中具有生物医学意义的病理生理条件（低血糖无意识）联系起来。我们关于颈动脉体作为缺氧和低血糖传感器的想法也对与缺氧相关的疾病（例如也与II型糖尿病相关的睡眠呼吸暂停）产生了影响。最后，我们的总体目标，目的和假设与强调创新，影响和重要性的新NIH审查标准保持一致;我们的团队拥有成功执行我们提出的新实验的专业知识。

DESCRIPTION (provided by applicant): This application explores a novel role for the carotid bodies in whole body glucose homeostasis in humans. The carotid bodies sense arterial oxygen tension and regulate ventilation. However, studies in isolated carotid body cells and animal models indicate these receptors also sense changes in blood glucose and that changes in the partial pressure of oxygen (pO2) alter this sensitivity. There is also evidence in humans suggesting that changes in arterial pO2 influence blood glucose homeostasis, but the role of the carotid bodies in regulating blood glucose is essentially unexplored in humans. To address the role of the carotid bodies in human glucose homeostasis we will systematically manipulate arterial pO2 and measure the counterregulatory responses to hypoglycemia in three groups of subjects: 1) healthy people, 2) people with bilateral carotid denervation after surgery for glomus tumors, and 3) people with type 1 diabetes with and without hypoglycemia unawareness. In this context, we will address the following specific aims: Aim 1) tests hypotheses related to how arterial pO2 influences counterregulatory responses to hypoglycemia in healthy subjects. We will perform hyperinsulinemic hypoglycemic clamps during normoxia, hyperoxia, and hypoxia maneuvers that should suppress (hyperoxia) or enhance (hypoxia) the ability of the carotid bodies to sense hypoglycemia and alter counterregulatory responses to hypoglycemia. These studies will be conducted in normal subjects. Aim 2) tests hypotheses related to how surgical resection of the carotid bodies alters counterregulatory responses to hypoglycemia. We will compare physiological responses to hyperinsulinemic hypoglycemic clamps in subjects who have undergone bilateral carotid body denervation for the treatment of glomus tumors with controls. Aim 3) tests hypotheses related to the idea that carotid body dysfunction in people with Type 1 diabetes is associated with hypoglycemia unawareness. We will measure hypoxic ventilatory responses and perform hypoglycemic clamps during normoxia, and hypoxia in people with type 1 diabetes with and without hypoglycemia unawareness. The idea is that failure of the carotid bodies to sense and initiate responses to hypoglycemia contributes to hypoglycemia unawareness. Summary: To our knowledge this is the first effort to systematically test the role of the carotid bodies in human whole body glucose homeostasis-ideas based on provocative data from a limited number of studies in isolated cells and animal models. In this context, we have proposed a suite of novel aims and hypotheses and linked ideas on basic mechanisms to a biomedically significant pathophysiological condition (hypoglycemia unawareness) in type 1 diabetes. Our ideas about the carotid bodies as sensors of both hypoxia and hypoglycemia also have implications for conditions linked to hypoxia such as sleep apnea which is also associated with type II diabetes. Finally, our overall goal, aims and hypotheses are aligned with the new NIH review criteria that emphasize innovation, impact and significance; and our team has the expertise to successfully execute the novel experiments we are proposing.