HIERARCHICAL BRAIN AND PHYSIOLOGICAL RESPONSES TO HYPOGLYCEMIA AND HAAF IN T1DM

T1DM 患者对低血糖和 HAAF 的分层大脑和生理反应

• 批准号: 8886223
• 负责人: Ana Maria Arbelaez
• 金额: $ 40.65万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-15 至 2020-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8886223
• 关键词: Acute; Adult; Awareness; Biological Markers; Blood Glucose; Brain; Brain imaging; Brain region; Cause of Death; Cerebrovascular Circulation; Cessation of life; Clinical; Cognition; Complication; Complications of Diabetes Mellitus; Development; Diabetes Mellitus; Epinephrine; Event; Failure; Fire - disasters; Functional Magnetic Resonance Imaging; Glucagon; Glucose; Goals; Hormonal; Hormones; Hypoglycemia; Hypothalamic structure; Impaired cognition; Impairment; Incidence; Individual; Insulin-Dependent Diabetes Mellitus; Intervention; Lead; Life; Magnetic Resonance Imaging; Measurement; Measures; Medial; Mediating; Methods; Modeling; Morbidity - disease rate; Network-based; Neurobehavioral Manifestations; Neurons; Neurotransmitter Receptor; Non-Insulin-Dependent Diabetes Mellitus; Outcome; Patients; Physiological; Play; Prefrontal Cortex; Process; Recruitment Activity; Recurrence; Regional Blood Flow; Rest; Risk; Role; Signal Transduction; Spin Labels; Symptoms; Syndrome; System; Testing; Thalamic structure; Therapeutic; blood glucose regulation; counterregulation; experience; falls; glycemic control; imaging modality; improved; in vivo; innovation; insulin secretion; interdisciplinary approach; neural circuit; neuroimaging; non-diabetic; prevent; prospective; public health relevance; response; therapeutic target; type I diabetic; young adult

 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.

 描述（由适用提供）：低血糖是糖尿病血糖控制的限制因素，导致发病率和死亡。复发性低血糖会导致糖糖反调节缺陷和随后低血糖期间低血糖的丧失，构成低血糖相关自主神经衰竭（HAAF）的临床综合征。据认为，在低血糖期间这些反应信号传导的基础机制以及HAAF期间这些反应的丧失涉及大脑。迄今为止，尚未显示出有效的临床方法可以降低低血糖的发生率，而没有受到血糖控制的风险。这是对低血糖反应丧失的机制的更好理解，可能有助于我们确定新的和创新的治疗靶标。我们假设几种低血糖敏感的大脑区域存在层次激活，它们响应血糖水平下降而形成功能网络，并且该网络中连通性的潜在丧失导致T1DM患者的HAAF。使用多学科的方法，我们将使用在高胰岛素葡萄糖（〜90mg/dl）期间对区域血流（ASL-MRI）和功能连接性（BOLD RS-FMRI）进行整合的定量大脑成像测量（BOLD RS-FMRI）进行检验。 Haaf，20 T1DM没有HAAF，在HAAF模型中，有20名健康的年轻人。通过确定DM中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，该神经影像标志物表征了HAAF在T1DM患者中的影响，以预测计划的前瞻性介入研究中的结果。