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，在葡萄糖不足期间动员葡萄糖 （葡萄糖）。当血浆葡萄糖浓度降低时，如胰岛素诱导的 低血糖，这两种激素的释放促进了血浆葡萄糖的恢复，从而保护了 大脑对葡萄糖有连续和绝对的代谢需求。控制胰高血糖素和 葡萄糖过程中肾上腺素的分泌是由大脑和脊髓中的神经回路介导的。在 接受胰岛素治疗的糖尿病患者降血糖发作会导致生命养护的发展 条件称为低血糖相关的自主衰竭（HAAF）。在哈夫期间 中央神经控制或葡萄糖调节反应，包括胰高血糖素和肾上腺髓质分泌， 无法对葡萄糖作出反应。这种反应的失败加剧了大脑葡萄糖不足，可以领导 永久性脑损伤或死亡。虽然很明显，HAAF涉及中央介导的损害 葡萄糖调节反应，其发病机理的细节很少。实际上，我们对基本的赞赏 控制这些重要的葡萄糖调节机制的中央神经回路本身非常不完整。 显然，完全欣赏中央葡萄糖调节电路及其如何改变。 葡萄糖事件对于理解和防止HAAF很重要。我们提议的研究的目标 计划是详细详细介绍中央电路的解剖结构，该解剖控制控制了两个关键的糖调节反应，即 胰腺胰高血糖素和肾上腺髓质肾上腺素的分泌。我们已经表明 后脑脑而不是下丘脑，葡萄糖受体介导关键的葡萄糖调节反应，并证明了 那个旋转的儿茶酚胺神经元对于肾上腺髓质反应至关重要 葡萄糖化。在拟议的工作中，我们将确定特定位置和表型 控制肾上腺髓质分泌的儿茶酚胺神经元。我们还将确定 在胰高血糖素的中央糖保护剂中的儿茶酚胺和旋转的5-羟色胺神经元 分泌。最后，我们将确定后脑抑制性神经元的作用，这使后脑神经化神经元 儿茶酚胺神经元，肾上腺髓质和胰腺自主神经前神经元， 控制葡萄糖和HAAF期间胰高血糖素和肾上腺髓质分泌。我们预计我们的 结果将为胰高血糖素和肾上腺髓质的葡萄糖保护提供详细的电路图 分泌物，最终将使我们能够在HAAF期间指定哪些电路组件受损。