Identifying the Brain Substrates of Hypoglycemia Unawareness in Type 1 Diabetes

识别 1 型糖尿病低血糖无意识的脑基质

• 批准号: 9269187
• 负责人: Silvia Mangia
• 金额: $ 54.38万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-07 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9269187
• 关键词: Area; Awareness; Blood Glucose; Brain; Brain region; Cerebrovascular Circulation; Cessation of life; Clinical; Complications of Diabetes Mellitus; Data; Development; Diabetes Mellitus; Disease; Drops; Drug Design; Failure; Feasibility Studies; Fright; Functional Magnetic Resonance Imaging; Future; Glucose; Goals; Hormones; Human; Hypoglycemia; Image; Impaired cognition; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Knowledge; Lead; Life; Literature; Location; Magnetic Resonance Imaging; Measures; Methods; Microvascular Dysfunction; Monitor; Multicenter Studies; Outcome; Pathologic; Patient Care; Patients; Pattern; Pharmacotherapy; Phase; Physiological; Population; Positioning Attribute; Protocols documentation; Recruitment Activity; Recurrence; Regimen; Research; Research Design; Research Project Grants; Rest; Risk; Role; Signal Transduction; Symptoms; Syndrome; Techniques; Testing; Thalamic structure; Time; base; blood glucose regulation; brain abnormalities; connectome; design; diabetes control; diabetes management; effective intervention; effective therapy; experience; frontal lobe; hypoglycemia unawareness; improved; insulin secretagogues; magnetic field; non-invasive monitor; prevent; public health relevance; relating to nervous system; response; targeted treatment

DESCRIPTION (provided by applicant): Patients with type 1 diabetes (T1DM) are exposed to the risk of experiencing severe episodes of hypoglycemia (HG) as they undergo insulin treatment to maintain the glucose control that is necessary to prevent diabetes complications. Recurrent HG can lead to development of the hypoglycemia-associated autonomic failure (HAAF) and to the syndrome of HG unawareness, where patients lose the ability to recognize symptoms of HG until they become unable to treat themselves. Strict avoidance of HG partially restores awareness of HG, however it is very difficult to achieve. Drugs and therapies that directly target the brain mechanisms responsible for HG unawareness have promise as better ways to prevent and/or reverse HAAF, thus crucially advancing care for patients with diabetes. In order to effectively design and monitor such treatments, it is necessary however to first characterize the physiological and pathological brain responses to HG, a research topic that has been only partly covered by current literature and that is at the center of the current proposal. I this project we will utilize state-of-the-art MRI methods to monitor non-invasively the brain responses during controlled experimental HG in a subject population which includes HG-unaware and HG-aware T1DM subjects, and healthy controls with and without a treatment that induces HAAF. Hypoglycemia-induced brain activations will be identified during different phases of HG by changes in cerebral blood flow. Multiple brain functionally- connected networks will also be monitored by using resting-state functional MRI, with an imaging protocol recently developed within the Human Connectome Project. Our central hypothesis is that altered brain responses to HG in HG-unaware T1DM subjects, as indentified by measures of brain activation patterns and functionally-connected brain networks, are a result of antecedent HG episodes, not diabetes. Therefore we expect that the activation patterns and the brain networks of HG-unaware T1DM subjects will be different from healthy and HG-aware T1DM subjects, but will resemble those of healthy controls who undergo HAAF induction. Our research team is uniquely positioned to conduct this research, as it has gained extensive expertise in mastering high magnetic field MR applications, and holds a long track record of MR research in diabetes. Ultimately, the study design of this proposal will allow identifying with unprecedented sensitivity the altered brain responses to HG in those T1DM patients who are unable to recognize the symptoms of HG, thus filling a critical gap of knowledge which will have significant impact in defining strategies that will reduce the complications of management of diabetes. Our study has been designed to be conducted on a clinical 3 Tesla scanner, thus making a transition to future multi-center studies feasible and seamless.

描述（由申请人提供）：1型糖尿病（T1DM）患者在接受胰岛素治疗以维持血糖控制以预防糖尿病并发症时，面临严重低血糖发作（HG）的风险。反复发作的HG可导致低血糖相关性自主神经衰竭（HAAF）和HG无意识综合征，患者失去识别HG症状的能力，直到无法自我治疗。对汞的严格避免在一定程度上恢复了人们对汞的认识，但这很难实现。直接针对导致HG无意识的大脑机制的药物和疗法有望成为预防和/或逆转HAAF的更好方法，从而至关重要地推进糖尿病患者的护理。然而，为了有效地设计和监测这种治疗方法，有必要首先描述大脑对HG的生理和病理反应，这是目前文献中仅部分涉及的研究主题，也是当前建议的中心。在这个项目中，我们将利用最先进的MRI方法来监测受控实验HG期间受试者群体的非侵入性大脑反应，其中包括未意识到HG和意识到HG的T1DM受试者，以及接受和未接受诱导HAAF治疗的健康对照组。低血糖诱导的脑激活将在HG的不同阶段通过脑血流的变化来识别。多个大脑功能连接的网络也将通过静息状态功能MRI进行监测，该成像协议是最近在人类连接组项目中开发的。我们的中心假设是，通过对脑激活模式和脑功能连接网络的测量，在不了解HG的T1DM受试者中，大脑对HG的反应发生了改变，这是先前HG发作的结果，而不是糖尿病的结果。因此，我们预计未察觉到hg的T1DM受试者的激活模式和大脑网络将不同于健康和意识到hg的T1DM受试者，但与接受HAAF诱导的健康对照相似。我们的研究团队在进行这项研究方面具有独特的优势，因为他们在掌握高磁场磁共振应用方面获得了广泛的专业知识，并在糖尿病磁共振研究方面拥有长期的记录。最终，该提案的研究设计将以前所未有的灵敏度进行识别