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）患者最佳治疗的关键因素。复发性低血糖可通过降低激活葡萄糖感知机制的阈值而导致低血糖无意识（HU）。HU反过来会增加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，使其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，很少有人知道的神经通路的葡萄糖感知，皮层活动的变化，认知与复发性低血糖和低血糖无意识。拟议的研究将使用功能磁共振成像结合低血糖钳夹技术，以检查大脑激活，认知能力，和反调节激素分泌在三个精心挑选的组：1。2.有低血糖意识的T1 DM患者（N = 20）; T1 DM患者由于复发性低血糖而无意识（N = 20）;和3.非糖尿病志愿者（N = 20）。拟议研究的主要目的是建立在我们的试点数据，仔细描绘参与反调节的大脑区域和T1 DM患者和非糖尿病个体的激活模式。我们会研究：1）低血糖激发将导致下丘脑神经活动增加，并且与对照受试者和T1 DM知晓患者相比，在低血糖无意识的T1 DM患者中将减弱，2）对照受试者中下丘脑外区域的激活将大于对低血糖激发有反应或无反应的T1 DM患者; 3）与正常对照组相比，低血糖时对认知挑战的局部皮层激活会减少，以及在我们之前的研究中显示相对灰质密度损失的T1 DM患者的脑区是否会在正常对照组和低血糖时对认知挑战的激活减少。这项研究计划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以解决HU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.