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

描述（由申请人提供）：本申请探讨了颈动脉体在人类全身葡萄糖稳态中的新作用。颈动脉体感知动脉血氧张力并调节通气。然而，在分离的颈动脉体细胞和动物模型中进行的研究表明，这些受体也能感知血糖的变化，而氧分压（pO2）的变化会改变这种敏感性。人类也有证据表明，动脉pO2的变化会影响血糖稳态，但在人类中，颈动脉体在调节血糖中的作用基本上未被探索。为了解决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pO2并测量三组受试者对低血糖的反调节反应：1)健康人群，2)血管球瘤手术后双侧颈动脉失神经患者，3)伴有和不伴有低血糖意识的1型糖尿病患者。在这种情况下，我们将解决以下具体目标：目的1)测试有关动脉pO2如何影响健康受试者对低血糖的反调节反应的假设。我们将在常氧、高氧和低氧运动中实施高胰岛素降糖钳夹，以抑制（高氧）或增强（低氧）颈动脉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)检验与手术切除颈动脉小体如何改变对低血糖的反调节反应有关的假设。我们将比较接受双侧颈动脉体神经支配治疗血管球瘤患者与对照组患者对高胰岛素降糖钳的生理反应。目的3)验证与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。我们将对伴有和不伴有低血糖意识的1型糖尿病患者在常氧和缺氧时测量低氧通气反应并实施低血糖钳夹。这个想法是，颈动脉体未能感知和启动低血糖反应，导致低血糖无意识。总结：据我们所知，这是第一次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令人振奋的数据。在此背景下，我们提出了一套新的目标和假设，并将1型糖尿病的基本机制与生物医学上重要的病理生理状况（低血糖无意识）联系起来。我们关于颈动脉体是缺氧和低血糖的传感器的观点也暗示了与缺氧有关的疾病，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审查标准一致，强调创新、影响和重要性；我们的团队有足够的专业知识来成功执行我们提出的新实验。

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.