Neural Pathways of Hypoglycemia Unawareness Using fMRI

描述（由申请人提供）：低血糖是限制1型糖尿病（T1DM）患者最佳护理的关键因素。反复低血糖可通过降低葡萄糖感应机制的激活阈值导致低血糖无意识（HU）。HU反过来又增加了进一步低血糖反应的风险。通常推荐的目标是改善血糖控制，尽可能接近非糖尿病范围，这增加了复发性低血糖和HU的可能性。然而，对于与反复低血糖和低血糖无意识相关的葡萄糖感知、皮质活动和认知变化的神经通路知之甚少。拟议的研究将使用功能磁共振成像结合低血糖钳技术来检查三组精心挑选的大脑激活，认知表现和反调节激素分泌：有低血糖意识的T1DM患者（N = 20）；2. 反复低血糖导致意识不清的T1DM患者（N = 20）；和3。非糖尿病志愿者（N = 20）。这项研究的主要目的是建立在我们的试点数据的基础上，仔细描述T1DM患者和非糖尿病患者中参与反调节和激活模式的大脑区域。我们将研究：1)低血糖刺激是否会导致下丘脑神经活动的增加，并且与对照组和T1DM意识患者相比，低血糖无意识的T1DM患者的神经活动会减弱；2)在低血糖刺激的反应中，对照组的下丘脑外区域的激活会比意识或不意识的T1DM患者更大；3)与正常血糖相比，低血糖时认知挑战的区域皮质激活会减少，我们之前研究中T1DM患者大脑中灰质密度相对下降的区域是否在正常血糖和低血糖时都表现出认知挑战的激活减少。这个研究项目将使我们能够识别参与葡萄糖感知的大脑区域，以及处于严重低血糖发作风险的患者群体的大脑活动变化。随着对低血糖反应和调节的这些神经过程的更精确理解，可以更好地设计和开发评估和开发干预措施的方法。

DESCRIPTION (provided by applicant): Hypoglycemia is a critical factor limiting optimal care in type 1 diabetes (T1DM) patients. Recurrent hypoglycemia can lead to hypoglycemia unawareness (HU) by lowering the threshold for activation of glucose sensing mechanisms. HU in turn increases the risk of further hypoglycemic reactions. The commonly recommended goal of improving glycemic control as close to the non-diabetic range as possible increases the likelihood of both recurrent hypoglycemia and HU. However, little is known about the neural pathways underlying the changes in glucose sensing, cortical activity, and cognition associated with recurrent hypoglycemia and hypoglycemia unawareness. The proposed studies will use fMRI in conjunction with the hypoglycemic clamp technique to examine brain activation, cognitive performance, and counterregulatory hormone secretion in three carefully selected groups: 1. T1DM patients with awareness of hypoglycemia (N = 20); 2. T1DM patients with unawareness due to recurrent hypoglycemia (N = 20); and 3. non-diabetic volunteers (N = 20). The primary aim of the proposed research is to build upon our pilot data to carefully delineate both the brain regions involved in counterregulation and the patterns of activation present in T1DM patients and non-diabetic individuals. We will study whether: 1) a hypoglycemic challenge will result in an increase in neural activity in the hypothalamus and will be attenuated in T1DM patients with hypoglycemia unawareness compared to control subjects and T1DM aware patients, 2) activation in regions outside the hypothalamus will be greater in control subjects than in either aware or unaware T1DM patients in response to a hypoglycemic challenge; 3) regional cortical activation in response to cognitive challenge will be reduced during hypoglycemia compared with euglycemia, and whether areas of the brain in T1DM patients that have shown relative gray matter density loss in our previous research will show reduced activation in response to cognitive challenge at both euglycemia and hypoglycemia. This research program will allow us to identify the brain regions involved in glucose sensing as well as the changes in brain activity in patient groups at risk for severe hypoglycemic episodes. With a more precise understanding of these neural processes underlying responses to and regulation of hypoglycemia, approaches to evaluating and developing interventions to address HU can be better designed and developed.