AAMP AIM 6: MAPPING THE BRAIN GLUCOSE SENSOR

AAMP 目标 6：绘制大脑葡萄糖传感器图

• 批准号: 7377186
• 负责人: PHILIP E. CRYER
• 金额: $ 1.42万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7377186
• 关键词: AAMP; AIM; MAPPING; BRAIN; GLUCOSE

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Iatrogenic hypoglycemia - the limiting factor in the glycemic management of diabetes - causes recurrent morbidity (and some mortality) in the short-term and precludes full realization of established microvascular and potential macrovascular benefits of glycemic control in the long-term. The concept of hypoglycemia-associated autonomic failure (HAAF) in insulin deficient diabetes posits that recent antecedent iatrogenic hypoglycemia causes both defective glucose counterregulation (by reducing the epinephrine response to a given level of subsequent hypoglycemia in the setting of an absent glucagon response) and hypoglycemia unawareness (by reducing the autonomic and thus the neurogenic symptom response to subsequent hypoglycemia) and thus a vicious cycle of recurrent iatrogenic hypoglycemia. Although there is substantial support for the clinical impact of HAAF, its fundamental mechanisms are unknown. Accordingly, we are testing hypotheses relevant to the mechanism(s) and mediator(s) of HAAF and the mechanisms of two of its fundamental components, loss of the glucagon response to hypoglycemia and glycemic thresholds for autonomic and symptomatic responses that are shifted to lower plasma glucose concentrations. These hyptheses include: 1)Hypoglycemia sufficient to activate glucose counterregulatory systems is a signal to glucose-sensitive brain neurons (identified by increments in regional cerebral blood flow measured with [15O]water and PET) rather than a manifestation of brain metabolic fuel deprivation which occurs only at lower plasma glucose concentrations, and activation of these brain glucose sensors is shifted to lower plasma glucose concentrations following hypoglycemia. 2) To the extent cortisol is the mediator of HAAF,cortisol elevations (during euglycemia)comparable to those that occur during hypoglycemia reduce autonomic neuroendocrine and neurogenic symptom responses(assessed with hyperinsulinemic stepped hypoglycemic clamps)to subsequent hypoglycemia. 3) To the extent the glucagon response to hypoglycemia involves an interaction between a decrement in intraislet insulin and a low a-cell glucose concentration, a rapid decrease in insulin secretion(induced with the KATP channel agonist diazoxide)does not cause increased glucagon secretion during euglycemia but diazoxide-induced suppression of basal insulin secretion prevents the glucagon response to hypoglycemia. 4) While the adrenal medullae(the source of the biologically active epinephrine response)are also a source of the norepinephrine response to hypoglycemia, hypoglycemia per se (insulin constant) stimulates the sympathetic nervous system (quantitated with the forearm norepinephrine spillover technique), as well as the adrenal medullae,and neurogenic(autonomic)symptoms are the result of the perception of physiological changes mediated by sympathetic neural as well as adrenomedullary activation. Insight into these basic physiological issues directly relevant to HAAF can be expected to lead to clinical strategies that will minimize the frequency of iatrogenic hypoglycemia and thus improve the lives of people with diabetes in both the short- and the long-term.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。医源性低血糖-糖尿病血糖管理的限制因素-在短期内导致复发性发病率（和一些死亡率），并妨碍充分实现长期血糖控制的既定微血管和潜在大血管获益。胰岛素缺乏型糖尿病低血糖相关性自主神经功能衰竭（HAAF）的概念认为，近期发生的医源性低血糖导致葡萄糖反调节功能缺陷，（在胰高血糖素反应缺失的情况下，通过将肾上腺素反应降低至随后低血糖的给定水平）和低血糖无意识（通过减少自主神经，从而减少对随后的低血糖的神经源性症状反应），并因此导致复发性医源性低血糖的恶性循环。虽然有大量的支持HAAF的临床影响，其基本机制是未知的。因此，我们正在测试与HAAF的机制和介质及其两个基本成分的机制相关的假设，即胰高血糖素对低血糖的反应丧失以及自主和症状反应的血糖阈值转移到较低的血糖浓度。这些假设包括：1）足以激活葡萄糖反调节系统的低血糖是对葡萄糖敏感的脑神经元的信号（通过用[15 O]水和PET测量的局部脑血流量的增加来识别），而不是仅在较低血糖浓度下发生的脑代谢燃料剥夺的表现，并且这些脑葡萄糖传感器的激活在低血糖后转移到较低的血糖浓度。2)在某种程度上，皮质醇是HAAF的介导剂，皮质醇升高（在正常血糖期间）与低血糖期间发生的皮质醇升高相当，降低了对随后低血糖的自主神经内分泌和神经源性症状反应（用高胰岛素阶梯式低血糖钳夹评估）。3)在胰高血糖素对低血糖的反应涉及胰岛内胰岛素减少和低α-细胞葡萄糖浓度之间的相互作用的程度上，胰岛素分泌的快速减少（用KATP通道激动剂二氮嗪诱导）不会导致正常血糖期间胰高血糖素分泌增加，但二氮嗪诱导的基础胰岛素分泌抑制阻止胰高血糖素对低血糖的反应。4)而肾上腺髓质（生物活性肾上腺素反应的来源）也是去甲肾上腺素对低血糖反应的来源，低血糖本身（胰岛素恒定）刺激交感神经系统（用前臂去甲肾上腺素溢出技术定量），以及肾上腺髓质，神经源性（自主）症状是由交感神经和肾上腺髓质激活介导的生理变化的感知的结果。对这些与HAAF直接相关的基本生理问题的深入了解有望导致临床策略，从而最大限度地减少医源性低血糖的频率，从而改善糖尿病患者的短期和长期生活。