Hindbrain Mechanisms of Hypoglycemia Unawareness

低血糖无意识的后脑机制

• 批准号: 7496328
• 负责人: W. Sue Ritter
• 金额: $ 36.34万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7496328
• 关键词: Adrenal Glands; Adrenal Medulla; Alpha Cell; Anatomy; Applications Grants; Biological Preservation; Blood; Brain; Brain Injuries; Catecholamines; Cells; Cessation of life; Condition; Data; Development; Epinephrine; Event; Exercise; Failure; Fostering; GABA Receptor; Glucagon; Glucose; Glucose Plasma Concentration; Glycine; Glycogen; Goals; Hormonal; Hormones; Hypoglycemia; Hypothalamic structure; Impairment; Insulin; Lead; Life; Location; Maps; Mediating; Metabolic; Neurons; Pancreas; Pathogenesis; Patients; Phenotype; Plasma; Research; Role; Serotonin; Site; Spinal Cord; Structure of alpha Cell of islet; Subgroup; Symptoms; To specify; Work; blood glucose regulation; diabetic; exhaustion; gamma-Aminobutyric Acid; glucose receptor; hindbrain; hypoglycemia unawareness; inhibitory neuron; nerve supply; neural circuit; neuroregulation; pancreatic juice; prevent; response; restoration

Glucagon and epinephrine are glucoregulatory hormones that mobilize stored glucose during glucose deficit (glucoprivation). When plasma glucose concentration decreases, as it does during insulin-induced hypoglycemia, release of these two hormones fosters restoration of plasma glucose, thereby protecting the brain, which has a continuous and absolute metabolic requirement for glucose. Control of glucagon and epinephrine secretion during glucoprivation is mediated by neural circuits in the brain and spinal cord. In diabetic patients undergoing insulin therapy hypoglycemic episodes can lead to the development of a lifethreatening condition known as hypoglycemia-associated autonomic failure (HAAF). During HAAF, the central neural controls or glucoregulatory responses, including glucagon and adrenal medullary secretion, fail to respond to glucoprivation. This failure of response exacerbates the brain glucose deficit and can lead to permanent brain damage or death. While it is clear that HAAF involves impairment of centrally mediated glucoregulatory responses, specifics of its pathogenesis are few. In fact, our appreciation of the basic central neural circuitry that controls these important glucoregulatory mechanisms is itself very incomplete. Clearly, a complete appreciation of the central glucoregulatory circuits and how they are altered by prior glucoprivic events is important in order to understand and prevent HAAF. The goal of our proposed research plan is to detail the anatomy of the central circuitry that controls two critical glucoregulatory responses, secretion of pancreatic glucagon and adrenal medullary epinephrine. We have already shown that hindbrain, not hypothalamic, glucoreceptors mediate key glucoregulatory responses and have demonstrated that spinally projecting catecholamine neurons are essential for the adrenal medullary response to glucoprivation. In the proposed work, we will identify the specific location and phenotypes of the catecholamine neurons that control adrenal medullary secretion. We also will determine the involvement of both catecholamine and spinally-projecting serotonin neurons in the central glucoprivic control of glucagon secretion. Finally, we will determine that role of hindbrain inhibitory neurons, which innervate hindbrain catecholamine neurons and adrenal medullary and pancreatic autonomic preganglionic neurons, in the control of glucagon and adrenal medullary secretion during glucoprivation and HAAF. We anticipate that our results will provide a detailed map of the circuitry for glucoprivic control of glucagon and adrenal medullary secretion, which ultimately will allow us to specify which circuit components are impaired during HAAF.

胰高血糖素和肾上腺素是葡萄糖调节激素，在葡萄糖缺乏时动员储存的葡萄糖 （葡萄糖纯化）。当血糖浓度降低时，就像胰岛素诱导的 低血糖时，这两种激素的释放促进血糖的恢复，从而保护血糖。 大脑，其对葡萄糖具有持续和绝对的代谢需求。控制胰高血糖素和 葡萄糖缺乏期间的肾上腺素分泌由脑和脊髓中的神经回路介导。在 接受胰岛素治疗的糖尿病患者低血糖发作可导致危及生命的 低血糖相关性自主神经功能衰竭（HAAF）。在HAAF期间， 中枢神经控制或糖调节反应，包括胰高血糖素和肾上腺髓质分泌， 对葡萄糖缺乏反应。这种反应的失败加剧了大脑葡萄糖不足，并可能导致 永久性脑损伤或死亡虽然很明显HAAF涉及中枢介导的 糖调节反应，其发病机制的细节很少。事实上，我们对基本的 控制这些重要的糖调节机制的中枢神经回路本身是非常不完整的。 显然，对中枢葡萄糖调节回路的完整理解以及它们如何被先前的葡萄糖调节回路改变， 葡萄糖减少事件对于理解和预防HAAF是重要的。我们研究的目标是 计划是详细解剖控制两个关键的葡萄糖调节反应的中央回路， 分泌胰高血糖素和肾上腺髓质肾上腺素。我们已经表明， 后脑，而不是下丘脑，葡萄糖受体介导关键的葡萄糖调节反应，并已证明 脊髓投射的儿茶酚胺神经元对于肾上腺髓质对 葡萄糖缺乏在拟议的工作中，我们将确定的具体位置和表型的 控制肾上腺髓质分泌的儿茶酚胺神经元。我们还将确定参与 儿茶酚胺和脊髓投射5-羟色胺神经元在胰高血糖素的中枢胰高血糖素控制中 分泌物。最后，我们将确定支配后脑的抑制性神经元的作用 肾上腺髓质和胰腺自主神经节前神经元， 控制胰高血糖素和肾上腺髓质分泌在葡萄糖缺乏和HAAF。我们预计， 结果将提供胰高血糖素和肾上腺髓质的胰高血糖素控制回路的详细地图。 分泌，这最终将使我们能够指定哪些回路组件在HAAF期间受损。