AAMP AIM 6: MAPPING THE BRAIN GLUCOSE SENSOR

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。医源性低血糖--糖尿病血糖控制中的限制因素--在短期内导致复发(和一些死亡)，并妨碍长期充分实现血糖控制的微血管和潜在的大血管益处。胰岛素缺乏性糖尿病的低血糖相关自主神经衰竭(HAF)的概念认为，最近的医源性低血糖既会导致有缺陷的葡萄糖反调节(通过将肾上腺素反应降低到给定水平的后续低血糖，在没有胰高血糖素反应的情况下)，又会导致低血糖无意识(通过降低自主神经，从而导致神经源性症状对后续低血糖的反应)，从而导致反复出现医源性低血糖的恶性循环。尽管HAAF的临床影响得到了实质性的支持，但其基本机制尚不清楚。因此，我们正在测试与HAAF的机制(S)和介体(S)及其两个基本成分的机制相关的假说，这两个基本成分是对低血糖的胰升糖素反应丧失，以及自主神经和症状反应的血糖阈值转移到较低的血糖浓度。这些假说包括：1)足以激活葡萄糖逆向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[150]水和PET测量的局部脑血流量的增加来识别)，而不是仅在较低的血糖浓度下发生的大脑代谢燃料缺乏的表现，并且这些大脑葡萄糖感受器的激活在低血糖后转移到较低的血糖浓度。2)在一定程度上，皮质醇是HAAF的中介，皮质醇升高(在正常血糖期间)与在低血糖期间发生的皮质醇升高相当，会降低自主神经内分泌和神经源性症状对随后低血糖的反应(用高胰岛素阶梯降糖钳评估)。3)在胰岛胰岛素减少和低α细胞葡萄糖浓度之间相互作用的程度上，胰岛素分泌的快速减少(由KATP通道激动剂二氮嗪诱导)不会导致正常血糖时高血糖素分泌的增加，但二氮嗪诱导的基础胰岛素分泌抑制阻止了胰升糖素对低血糖的反应。4)虽然肾上腺髓质(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，但低血糖本身(胰岛素常数)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，神经性(自主)症状是交感神经和肾上腺延髓激活所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了解有望导致临床策略，将医源性低血糖的频率降至最低，从而在短期和长期内改善糖尿病患者的生活。

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.