Hindbrain mechanisms of hypoglycemia unawarness

低血糖的后脑机制

• 批准号: 6661283
• 负责人: W. Sue Ritter
• 金额: $ 31.6万
• 依托单位: WASHINGTON STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2006-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6661283
• 关键词: autonomic disorder; awareness; behavioral /social science research tag; blood chemistry; brain mapping; brain regulatory center; corticosteroid receptors; corticosterone; diabetes mellitus; eating; epinephrine; hypoglycemia; hypothalamus; immunocytochemistry; injection /infusion; laboratory rat; norepinephrine; pathologic process; receptor expression; rhombencephalon; vasopressins

DESCRIPTION (provided by applicant): The overall aim of this project is to understand the mechanisms underlying Hypoglycemia-Associated Autonomic Failure (HAAF), a life-threatening clinical syndrome of reduced behavioral, autonomic and neuroendocrine responsiveness to hypoglycemia resulting from prior hypoglycemic bouts. Compelling evidence indicates that glucocorticoids are involved in the pathogenesis of HAAF, because they are dramatically elevated by glucoprivation and because administration of exogenous glucocorticoids can reproduce the symptoms of HAAF. This proposal will focus on hindbrain mechanisms involved in HAAF. Hindbrain glucoreceptors control two important glucoregulatory responses, increased food intake and adrenal medullary secretion. The first specific aim is to determine whether hindbrain glucoreceptors also mediate the glucoprivic control of glucocorticoid secretion. The second specific aim focuses on hindbrain NE/E neurons. These neurons are crucial for feeding, adrenal medullary and corticosterone responses to glucoprivation and impairment in their function results in symptoms similar to HAAF. This proposal will investigate the multiple pathways through which their control of corticosterone secretion may be mediated. The third specific aim will investigate the importance of NE/E neurons as a site for corticosterone feedback effects that could result in suppression of their activity during HAAF. Many of these neurons possess glucocorticoid receptors. The proposed work will attempt to relate the presence of glucocorticoid receptors on specific populations of NE/E neurons with their functions and involvement in HAAF. The last specific aim is to identify the parameters of glucocorticoid elevation that result in HAAF with particular focus on the magnitude and duration of the secretory event. Corticosterone infusions and specific stressors with differing effects on corticosterone secretion will be examined for their ability to induce HAAF.

描述（由申请人提供）：该项目的总体目的是了解低血糖相关的自主神经失败（HAAF）的机制，这是一种威胁生命的临床综合征，其行为降低，自主神经和神经内分泌对降低降低性低糖降低的临床综合征。令人信服的证据表明，糖皮质激素参与HAAF的发病机理，因为它们通过葡萄糖量显着升高，并且给予外源性糖皮质激素可以再现HAAF的症状。该提案将重点放在HAAF涉及的后脑机制上。后脑葡萄糖受体控制两个重要的糖调节反应，食物摄入量增加和肾上腺髓分泌。第一个具体目的是确定后脑葡萄糖受体是否还介导了糖皮质激素分泌的糖保护性控制。第二个特定目的侧重于后脑NE/E神经元。这些神经元对于喂养，肾上腺髓质和皮质酮对葡萄糖保护和损害的反应至关重要，导致类似于HAAF的症状。该提案将调查其控制皮质酮分泌的多种途径。第三个具体目的将研究NE/E神经元作为皮质酮反馈作用的部位的重要性，这可能导致其在HAAF期间的活性抑制。这些神经元中的许多具有糖皮质激素受体。提出的工作将尝试将NE/E神经元特定种群的糖皮质激素受体与其功能和参与HAAF联系起来。最后的特定目的是确定糖皮质激素高度的参数，这会导致HAAF特别关注分泌事件的大小和持续时间。皮质酮输注和对皮质酮分泌作用不同的特定压力源，将检查其诱导HAAF的能力。