ADRENERGIC MECHANISMS IN METABOLIC PATHOPHYSIOLOGY

代谢病理生理学中的肾上腺素能机制

• 批准号: 3228194
• 负责人: PHILIP E. CRYER
• 金额: $ 20.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-07-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3228194
• 关键词: adenylate cyclase; atropine; autonomic nervous system; blood chemistry; brain circulation; brain metabolism; carbon; chromaffin cells; cognition; cortisol; epinephrine; exercise; glucagon; glucose metabolism; glucose transport; hormone metabolism; hormone receptor; hormone regulation /control mechanism; human subject; hyperglycemia; hypoglycemia; hypopituitarism; insulin; insulin dependent diabetes mellitus; laboratory rat; neuroendocrine system; neurotransmitter metabolism; norepinephrine; pancreatic polypeptide; phentolamine; positron emission tomography; propranolol; radioimmunoassay; radionuclides; somatotropin; spectrometry

To proceed toward our long-term objectives to understand the physiology of glucose counterregulation and its pathophysiology in insulin dependent diabetes mellitus (IDDM) in sufficient detail to permit development of strategies that will effectively eliminate hypoglycemia from their lives, and to expand the knowledge base of human metabolic physiology and pathophysiology, we plan to test a series of hypotheses relevant to five aims: 1. To dissect further the physiological mechanisms of glucose counterregulation. 2. To explore physiological regulation of cerebral blood flow and glucose transport into the brain, and their potential pathophysiological regulation in IDDM. 3. To define the effects of hypoglycemia on cognitive function and determine the mechanisms of awareness of hypoglycemia. 4. To learn to prevent, correct or compensate for defective glucose counterregulation, and thus to reduce the frequency of iatrogenic hypoglycemia in IDDM. 5. To validate further methods for measuring sympathetic neural activity and to study the role of the sympathochromaffin system in the pathophysiology of IDDM. We will study normal persons, patients with panhypopituitarism and patients with IDDM, often with the latter stratified vis-a-vis metabolic control or classic autonomic neuropathy versus defective counterregulation/ hypoglycemia unawareness. We will quantitate plasma levels of metabolic regulatory hormones (insulin, glucagon, epinephrine, growth hormone and cortisol), markers (C-peptide, norepinephrine, pancreatic polypeptide) and substrates/intermediates (glucose, FFA, glycerol, beta-hydroxybutyrate, lactate and alanine), often with kinetic measurements (e.g. glucose, NE); in some studies cellular glucose transporters will be measured. The metabolic environment will be controlled with clamp techniques. Conditions will include the basal state, hypoglycemia, standing, exercise and interventions with counterregulatory hormones, autonomic antagonists and agonists and an amino acid. Endpoints, in addition to glucose concentration and counterregulatory hormone responses, will include positron emission tomography measurements of glucose transport into the brain and cerebral blood flow, quantitation of symptoms, awareness of hypoglycemia and cognitive function; and measurements of norepinephrine kinetics.

朝着我们的长期目标发展生理学 葡萄糖反调节及其胰岛素依赖性的病理生理学 糖尿病（IDDM）足够详细地允许开发 将有效消除低血糖的策略， 并扩大人类代谢生理学的知识基础和 病理生理学，我们计划检验一系列与五个相关的假设 目的：1。剖析葡萄糖的生理机制 反调节。 2。探索脑的生理调节 血流和葡萄糖进入大脑，其潜力 IDDM中的病理生理调节。 3。定义 低血糖对认知功能，并确定 意识到低血糖。 4。学会预防，纠正或补偿 对于有缺陷的葡萄糖反调节，因此降低了频率 IDDM中的医源性低血糖。 5。验证进一步的方法 测量交感神经活动并研究 IDDM的病理生理学中的交感神经菌系统。 我们将学习 普通人，泛拟核患者和IDDM患者， 通常具有后一个分层的Vis-A-Vis代谢控制或经典 自主神经病与缺陷反调节/低血糖 不知情。 我们将定量代谢调节的血浆水平 激素（胰岛素，胰高血糖素，肾上腺素，生长激素和皮质醇）， 标记物（C肽，去甲肾上腺素，胰多肽）和 底物/中间体（葡萄糖，FFA，甘油，β-羟基丁酸， 乳酸和丙氨酸），通常具有动力学测量（例如葡萄糖，NE）； 在一些研究中，将测量细胞葡萄糖转运蛋白。 这 代谢环境将通过夹具技术控制。 条件将包括基础状态，低血糖，站立，运动 和反调节激素，自主拮抗剂的干预措施 和激动剂和氨基酸。 终点，除了葡萄糖 浓度和反调节激素反应将包括 葡萄糖转运到葡萄糖的正电子发射断层扫描测量 大脑和脑血流，症状定量，意识 低血糖和认知功能；和去甲肾上腺素的测量 动力学。