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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

基本信息

批准号：
8709190
负责人：
VANESSA H ROUTH
金额：
$ 23.21万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-04-20 至 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8709190
关键词：
5&apos -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 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

项目摘要

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.

描述（由申请人提供）：该提案研究了反复低血糖对下丘脑腹内侧核（VMN）中葡萄糖感应神经元（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途径，以及低血糖引起的这些途径的改变如何导致低血糖相关的自主神经衰竭（HAAF）。该提案中的两个假设直接解决了这些问题。假设 I 是 NO 是中枢葡萄糖传感和低血糖反调节反应启动的必要步骤。然而，在反复发生胰岛素低血糖期间，NO 的过量产生会损害对随后导致 HAAF 的低血糖的反调节反应。体外和体内技术的结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 激活蛋白激酶之间的正反馈在 VMN GSN 的葡萄糖感应中的作用以及对低血糖的反调节反应的启动。假设 II 是胰岛素诱导的低血糖导致的超生理性 NO 产生使 NO 信号通路脱敏，损害葡萄糖感应并导致 HAAF 的发生。所提出的脱敏机制是 NO 引起神经元可溶性鸟苷酸环化酶（NO 受体）的 S-亚硝基化，使葡萄糖感应神经元对随后的 NO 产生无反应。这些研究将提供有关反复低血糖如何重置大脑葡萄糖阈值从而导致 HAAF 的重要信息。这将有助于开发针对 I 型糖尿病及其主要现代并发症（低血糖）的新型、有效且安全的治疗方法。