AAMP AIM 6: MAPPING THE BRAIN GLUCOSE SENSOR

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。医源性低血糖是糖尿病血糖控制的限制因素，它会在短期内引起复发性发病率（和一些死亡率），并妨碍长期控制血糖对微血管和潜在大血管的益处的充分实现。胰岛素缺乏性糖尿病中低血糖相关自主神经衰竭（HAAF）的概念认为，最近的既往医源性低血糖既会导致葡萄糖反调节缺陷（在胰高血糖素反应缺失的情况下，对随后一定水平的低血糖的肾上腺素反应减少），也会导致低血糖不自觉（通过减少对随后低血糖的自主神经症状反应），从而形成反复的医源性恶性循环低血糖症。虽然有大量证据支持HAAF的临床影响，但其基本机制尚不清楚。因此，我们正在测试与HAAF的机制和介质相关的假设，以及它的两个基本组成部分的机制，胰高血糖素对低血糖反应的丧失和自主神经和症状反应的血糖阈值，这些反应转移到较低的血浆葡萄糖浓度。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[15O]水和PET测量的区域脑血流量的增加来识别），而不是仅在较低血浆葡萄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浆葡萄糖浓度。2)在某种程度上，皮质醇是HAAF的中介，皮质醇升高（在血糖正常时）与低血糖时相当，会降低自主神经内分泌和神经源性症状反应（用高胰岛素降糖钳评估），从而导致随后的低血糖。3)在某种程度上，胰高血糖素对低血糖的反应涉及胰岛内胰岛素的减少和低a细胞葡萄糖浓度之间的相互作用，胰岛素分泌的快速减少（由KATP通道激动剂二氮氧化合物诱导）不会导致血糖正常时胰高血糖素分泌增加，但二氮氧化合物诱导的基础胰岛素分泌的抑制阻止了胰高血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）也是低血糖时去甲肾上腺素反应的来源，但低血糖本身（胰岛素常量）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（自主神经）症状是交感神经和肾上腺髓质激活介导的生理变化的感知结果。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，将医源性低血糖的频率降至最低，从而在短期和长期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.