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

描述(由申请人提供)：这项申请探索了颈动脉小体在人体全身血糖动态平衡中的新作用。颈动脉小体感知动脉氧分压并调节通气量。然而，在分离的颈动脉体细胞和动物模型中的研究表明，这些受体也能感觉到血糖的变化，氧分压(PO2)的变化会改变这种敏感性。在人类身上也有证据表明，动脉血氧分压的变化会影响血糖的动态平衡，但在人类中，颈动脉小体在调节血糖中的作用基本上是未知的。为了阐明颈动脉小体在人体血糖动态平衡中的作用，我们将系统地操纵动脉血氧分压，并测量三组受试者对低血糖的反向调节反应：1)健康人，2)双侧颈动脉球瘤手术后失神经患者，以及3)1型糖尿病伴或不伴低血糖意识的人。在这种背景下，我们将解决以下具体目标：目的1)测试与动脉血氧分压如何影响健康受试者对低血糖的反调节反应的假说。我们将在常氧、高氧和低氧动作中进行高胰岛素低血糖钳夹，以抑制(高氧)或增强(低氧)颈动脉小体感知低血糖和改变对低血糖的反调节反应的能力。这些研究将在正常受试者中进行。目的2)测试有关手术切除颈动脉小体如何改变对低血糖的反调节反应的假说。我们将比较双侧颈动脉体失神经治疗血管球瘤的受试者和对照组受试者对高胰岛素低血糖钳夹的生理反应。目的测试与1型糖尿病患者颈动脉体部功能障碍与无意识低血糖相关的假说。我们将测量低氧呼吸反应，并在常氧和低氧状态下执行低血糖钳夹，在1型糖尿病患者中有无低血糖意识的人。这种观点认为，颈动脉小体未能感知并启动对低血糖的反应，导致低血糖无意识。摘要：据我们所知，这是第一次系统地测试颈动脉小体在人体整体血糖稳态中的作用--这些想法基于有限数量的分离细胞和动物模型研究中的挑衅性数据。在此背景下，我们提出了一套新的目标和假设，并将基本机制与1型糖尿病具有生物医学意义的病理生理状况(无意识低血糖)联系起来。我们认为颈动脉小体是缺氧和低血糖的感应器，这一观点也适用于与缺氧有关的情况，如睡眠呼吸暂停，这也与II型糖尿病有关。最后，我们的总体目标、目的和假设与新的NIH审查标准保持一致，该标准强调创新、影响和意义；我们的团队拥有成功执行我们提议的新颖实验的专业知识。 与公共健康相关：我们正在测试一种新的想法，即颈部的小器官，即颈动脉小体，作为人类对低血糖反应的葡萄糖传感器和介体。这对糖尿病患者有重大影响。我们将研究1型糖尿病患者的这些器官是否功能失调，这些人在血糖低的时候无法感觉到。由于这个器官也感受氧气，我们关于颈动脉小体是血糖传感器的想法对某些导致低氧水平的情况有一定的影响，例如睡眠呼吸暂停，这也与其他疾病状态有关，如肥胖症和2型糖尿病。

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. PUBLIC HEALTH RELEVANCE: We are testing a novel idea about the role of small organs in the neck, the carotid bodies, as glucose sensors and mediators of the response to low blood sugar in humans. This has major implications for people with diabetes. We will be studying whether these organs are dysfunctional in people with type 1 diabetes who are unable to sense when their blood sugars are low. Since this organ also senses oxygen, our ideas about the carotid bodies as blood sugar sensors have implications for some conditions that result in low oxygen levels such as sleep apnea which is also associated with other disease states such as obesity and type 2 diabetes.