HIERARCHICAL BRAIN AND PHYSIOLOGICAL RESPONSES TO HYPOGLYCEMIA AND HAAF IN T1DM

 描述（由申请人提供）：低血糖是糖尿病血糖控制的限制因素，导致发病和死亡。反复发生的低血糖导致葡萄糖反调节缺陷和随后低血糖期间低血糖症状的丧失，构成低血糖相关自主神经功能衰竭（HAAF）的临床综合征。低血糖期间这些反应的信号传导和HAAF期间这些反应的丧失的潜在机制被认为涉及大脑。到目前为止，没有有效的临床方法显示可以降低低血糖的发生率而不影响血糖控制。因此，更好地了解低血糖反应丧失的机制可能有助于我们确定新的和创新的治疗靶点。我们假设，有几个低血糖敏感的大脑区域，形成一个功能网络，以应对血糖水平下降的分层激活，在这个网络中的连接的潜在损失导致HAAF的T1 DM个人。通过多学科的方法，我们将测试这一假设，使用综合定量脑成像测量区域血流（ASL-MRI）和功能连接（BOLD rs-fMRI）高胰岛素正常血糖（~ 90 mg/dL）-阶梯式低血糖（~65-55- 45 mg/dL）钳夹在20例1型糖尿病（T1 DM）伴HAAF患者、20例T1 DM不伴HAAF患者和20例健康年轻人HAAF模型中进行。通过确定DM患者HAAF期间BOLD信号的变化，我们将确定一种神经影像学生物标志物，用于表征HAAF在T1 DM患者体内的影响，以预测计划的前瞻性干预研究的结局。

 DESCRIPTION (provided by applicant): Hypoglycemia is the limiting factor in the glycemic control of diabetes, causing morbidity and death. Recurrent hypoglycemia causes both defective glucose counterregulation and loss of hypoglycemic symptoms during subsequent hypoglycemia, constituting the clinical syndrome of hypoglycemia-associated autonomic failure (HAAF). The mechanisms underlying the signaling of these responses during hypoglycemia and the loss of these responses during HAAF are thought to involve the brain. To date no effective clinical method has shown to reduce the incidence of hypoglycemia without the risk of compromising glycemic control. Thus, a better understanding of the mechanisms underlying the loss of the hypoglycemic responses may help us identify new and innovative therapeutic targets. We hypothesize that there is hierarchical activation of several hypoglycemia-sensitive brain regions that form a functional network in response to declining blood glucose levels, and a potential loss of the connectivity in this network leads to HAAF in individuals with T1DM. With a multidisciplinary approach we will test this hypothesis, using integrated quantitative brain imaging measurements of regional blood flow (ASL-MRI) and functional connectivity (BOLD rs-fMRI) during hyperinsulinemic euglycemic (~90mg/dL) - stepped hypoglycemic (~65-55-45mg/dL) clamps in 20 type 1 diabetic (T1DM) patients with HAAF, 20 T1DM without HAAF and in 20 healthy young adults in a model of HAAF. By determining the changes in BOLD signal during HAAF in DM, we will identify a neuroimaging biomarker that characterizes the effects of HAAF in vivo in T1DM patients to predict outcomes in planned prospective interventional studies.