Hypoglycemia-induced NO in glucose sensing neurons and counterregulation

低血糖诱导的葡萄糖传感神经元中的 NO 及其反调节

• 批准号: 8059632
• 负责人: VANESSA H ROUTH
• 金额: $ 33.25万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8059632
• 关键词: 5' -AMP-activated protein kinase; Acetylcysteine; Acute; Address; Adverse effects; Animals; Brain; Complement; Complication; Data; Detection; Development; Diabetes Mellitus; Elements; Enzymes; Euglycemic Clamping; Failure; Feedback; Glucose; Glucose Clamp; Health; Hypoglycemia; Hypothalamic structure; Impairment; In Vitro; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Laboratories; Lead; Life; Neurons; Neurosecretory Systems; Nitric Oxide; Nitric Oxide Signaling Pathway; Pathway interactions; Physiological; Production; Proteins; Recurrence; Refractory; Role; Signal Pathway; Signal Transduction; Soluble Guanylate Cyclase; Syndrome; Techniques; Testing; Translating; blood glucose regulation; counterregulation; desensitization; diabetic; diabetic patient; extracellular; glycemic control; improved; in vivo; patch clamp; prevent; research study; response; therapy development; ventromedial hypothalamic nucleus

DESCRIPTION (provided by applicant): This proposal investigates the effects of recurrent hypoglycemia on glucose sensing neurons (GSNs) in the ventromedial hypothalamic nucleus (VMN). The overall objective is to gain an in depth understanding of the cellular signaling pathways by which hypoglycemia is sensed by the brain and how hypoglycemia induced alterations in these pathways may lead to hypoglycemia- associated autonomic failure (HAAF). The two hypotheses in this proposal directly address these issues. HYPOTHESIS I is that NO is an obligatory step in central glucose sensing and initiation of the counterregulatory response to hypoglycemia. However excess NO production during recurrent insulin-hypoglycemia impairs the counterregulatory response to subsequent hypoglycemia leading to HAAF. A combination of in vitro and in vivo techniques will test this hypothesis at the cellular and whole animal level. These experiments will investigate the role of a positive feedback between NO and AMP activated protein kinase in glucose sensing by VMN GSNs and initiation of the counterregulatory response to hypoglycemia. HYPOTHESIS II is that the supraphysiological NO production in response to insulin-induced hypoglycemia desensitizes the NO signaling pathway, impairing glucose sensing and leading to the developemnt of HAAF. The proposed mechanism for desensitization is that NO causes S-nitrosylation of neuronal soluble guanylyl cyclase (the NO receptor), rendering glucose sensing neurons non-responsive to subsequent NO production. These studies will provide important information regarding the way that recurrent hypoglycemia resets the glucose threshold of the brain, leading to HAAF. This will facilitate the development of new, effective, and safe treatments for Type I diabetes mellitus and its major modern complication, hypoglycemia. PUBLIC HEALTH RELEVANCE: Tight glycemic control with intensive insulin or glucose lowering therapies significantly improves diabetic-related complications. However, recurrent hypoglycemia, a side effect of insulin therapy, impairs the ability of the brain to sense hypoglycemia and initiate corrective responses. This proposal investigates the mechanisms by which the glucose threshold of the brain is reset, and how this may be restored to normal.

描述（由申请方提供）：本提案研究了复发性低血糖对下丘脑腹内侧核（VMN）中葡萄糖敏感神经元（GSN）的影响。总体目标是深入了解大脑感知低血糖的细胞信号传导通路，以及低血糖诱导的这些通路改变如何导致低血糖相关自主神经功能衰竭（HAAF）。本提案中的两个假设直接涉及这些问题。假设I是NO是中枢葡萄糖感知和启动对低血糖的反调节反应的必要步骤。然而，在复发性胰岛素低血糖期间过量的NO产生损害了对随后的低血糖的反调节反应，导致HAAF。体外和体内技术的组合将在细胞和整个动物水平上检验这一假设。这些实验将研究NO和AMP激活的蛋白激酶之间的正反馈在VMN GSNs葡萄糖传感和启动对低血糖的反调节反应中的作用。假说II认为，胰岛素诱导的低血糖引起的超生理NO产生使NO信号通路脱敏，损害葡萄糖敏感性，导致HAAF的发生。所提出的脱敏机制是NO导致神经元可溶性鸟苷酸环化酶（NO受体）的S-亚硝基化，使葡萄糖敏感神经元对随后的NO产生无反应。这些研究将提供关于反复低血糖重置大脑葡萄糖阈值导致HAAF的方式的重要信息。 这将促进I型糖尿病及其主要现代并发症低血糖症的新的、有效的和安全的治疗方法的开发。公共卫生相关性：通过强化胰岛素或降糖治疗严格控制血糖可显著改善糖尿病相关并发症。然而，胰岛素治疗的副作用，即复发性低血糖，会损害大脑感知低血糖和启动纠正反应的能力。该提案研究了大脑葡萄糖阈值重置的机制，以及如何恢复正常。