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：
7808053
负责人：
VANESSA H ROUTH
金额：
$ 37.07万
依托单位：
UNIV OF MED/DENT OF NJ-NJ 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 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7808053
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 public health relevance 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. 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（由申请人提供）：该提案研究了腹侧下丘脑核（VMN）中复发性低糖对葡萄糖传感神经元（GSN）的影响。总体目的是深入了解大脑的细胞信号传导途径，以及低血糖诱发这些途径中的变化可能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是中央葡萄糖感应和对低血糖反应的启动的强制性步骤。但是，在复发性胰岛素 - 糖血糖期间，没有过多的产生会损害对随后的低血糖导致HAAF的反应反应。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激活的蛋白激酶之间正面反馈在VMN GSN中的葡萄糖传感中的作用，并启动对低血糖的反应反应。假设II是，超生理学的NO生成响应胰岛素诱导的低血糖使NO信号传导途径脱敏，从而损害了葡萄糖传感并导致HAAF的发展。提出的脱敏的机制是，无引起神经元可溶性鸟叶基环酶（NO受体）的S-亚硝基化，从而使葡萄糖传感神经元无反应使无反应性至随后无产生。这些研究将提供有关复发性低血糖重置大脑葡萄糖阈值的重要信息，从而导致HAAF。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，有效和安全的治疗方法。公共卫生相关性：密集的胰岛素或葡萄糖降低疗法的严格控制可显着改善与糖尿病相关的并发症。但是，胰岛素治疗的副作用复发性低血糖症会损害大脑感知低血糖并启动纠正反应的能力。该提案研究了重置大脑葡萄糖阈值的机制，以及如何将其恢复到正常状态。