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(T1 DM)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知机制的激活阈值而导致低血糖无意识(HU)。HU反过来增加了进一步低血糖反应的风险。普遍推荐的目标是改善血糖控制，尽可能接近非糖尿病范围，这会增加复发性低血糖和HU的可能性。然而，人们对葡萄糖感觉、皮质活动和认知变化的神经通路知之甚少，这些变化与反复低血糖和低血糖意识不清有关。这项拟议的研究将结合使用功能磁共振成像和降糖钳夹技术，在精心选择的三组人中检查大脑激活、认知表现和反向调节激素分泌：1.意识到低血糖的T1 DM患者(N=20)；2.因反复低血糖而意识不清的T1 DM患者(N=20)；以及3.非糖尿病志愿者(N=20)。这项拟议研究的主要目的是以我们的试点数据为基础，仔细描绘T1糖尿病患者和非糖尿病患者中参与反调节的大脑区域和激活模式。我们将研究：1)低血糖挑战是否会导致下丘脑神经活动增加，并在有低血糖意识的T1 DM患者中是否会减弱；2)与对照组和意识到低血糖的T1 DM患者相比，2)对照组受试者下丘脑以外区域的激活将比有意识或不知道低血糖挑战的患者更大；3)与正常血糖相比，低血糖期间响应认知挑战的区域皮质激活会减少，以及我们之前的研究中已显示相对灰质密度丧失的T1 DM患者大脑区域是否会显示出在正常血糖和低血糖时对认知挑战的反应激活减少。这项研究计划将使我们能够识别参与血糖感应的大脑区域，以及有严重低血糖发作风险的患者组大脑活动的变化。有了对低血糖反应和调节的这些神经过程的更准确的了解，评估和开发干预措施的方法可以更好地设计和开发。

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.