Glucoregulatory Hormone Interactions in Diabetes

糖尿病中的葡萄糖调节激素相互作用

• 批准号: 10220945
• 负责人: Janice Jin Hwang
• 金额: $ 84.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1977
• 资助国家: 美国
• 起止时间: 1977-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10220945
• 关键词: Acids; Acute; Address; Adverse effects; Age; Applications Grants; Artificial Pancreas; Automobile Driving; Award; Awareness; Blinded; Blood - brain barrier anatomy; Body mass index; Brain; Brain Injuries; Brain imaging; Brain region; Cerebrum; Clinical; Closure by clamp; Complex; Corpus striatum structure; Cues; Data; Defense Mechanisms; Diabetes Mellitus; Exposure to; Food; Foundations; Frequencies; Fright; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Glucose; Glucose Clamp Technique; Glycosylated hemoglobin A; Goals; Grant; Health Benefit; Hormonal; Hormones; Human; Hyperglycemia; Hypoglycemia; Impairment; Individual; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention; Investigation; Knowledge; Magnetic Resonance Spectroscopy; Metabolic; Metabolism; Modeling; Molecular; Motivation; National Institute of Diabetes and Digestive and Kidney Diseases; Neurocognitive; Outcome; Oxidative Stress; Parietal; Participant; Pathway interactions; Patients; Pattern; Prefrontal Cortex; Protocols documentation; Randomized; Rattus; Recurrence; Rest; Rewards; Risk; Rodent; SLC2A1 gene; Short-Term Memory; Stress; Symptoms; System; Techniques; Testing; Visual; base; brain dysfunction; cognitive function; design; diabetic; diabetic rat; euglycemia; falls; functional MRI scan; glucose metabolism; glucose monitor; glucose transport; glucose uptake; hypoglycemia unawareness; improved; non-diabetic; polyol; preservation; prevent; response; risk minimization; spectroscopic imaging

Project Summary/Abstract Hypoglycemia and its adverse effects on brain function remain the major factor limiting the use of intensified insulin therapy that has been shown to prevent or delay the long-term complications in type 1 diabetes (T1DM). Higher cognitive functions (e.g. working memory) that involve the prefrontal cortex are particularly sensitive to neuroglycopenia. This proposal seeks continued support of a long-term RO-1 grant with the long-term goal of documenting the health benefits of insulin delivery strategies that minimize the risk of frequent bouts of hypoglycemia in T1DM patients. The specific aims of the current project outlined below use functional magnetic resonance imaging (fMRI) and magnetic resonance spectroscopy (MRS) techniques to assess the changes in brain function and fuel metabolism caused by acute hypoglycemia and acute hyperglycemia in T1DM patients with hypoglycemia unawareness (versus hypoglycemia-aware T1DM patients and healthy controls) as well as the potential beneficial impact of employing closed-loop insulin delivery systems to improve brain function in hypoglycemia unaware T1DM individuals. The protocols rely heavily on human investigation involving non-diabetic as well as hypoglycemia aware and unaware T1DM subjects exposed to experimental mild and moderate hypoglycemia and acute hyperglycemia using the glucose clamp technique while undergoing brain imaging. However, we also take advantage of the power of rodent diabetic models to test specific mechanistic hypotheses. The primary hypothesis of this proposal is that hypoglycemia unaware T1DM patients not only have impaired hormonal and symptomatic responses, but also lack another key hypoglycemia defense mechanism, namely the capacity of the brain to activate motivation/reward circuits due to adaptive increases in brain glucose transport and metabolism as well as stimulation of the polyol pathway. The specific aims are to determine: 1) If T1DM patients with hypoglycemia unawareness (vs. T1DM and non-diabetic controls) lose the capacity to elicit brain responses to visual food cues as well as functional connectivity in striatal and a variety of other brain regions in response to food cues during mild and moderate hypoglycemia using the glucose clamp technique; 2) If patients with T1DM and hypoglycemia unawareness display adaptive changes causing excessive increases in brain glucose transport and metabolism in response to acute hyperglycemia that induce adverse neurocognitive effects within the pre-frontal cortex, a key brain region for cognitive function not previously examined in humans using magnetic resonance spectroscopy (MRS). In addition, mechanistic studies will be conducted in diabetic rats exposed to recurrent hypoglycemia to define the molecular mechanisms driving the changes in brain fuel metabolism induced by intensive insulin treatment; and 3) if reducing glycemic variability with a closed loop insulin delivery system in patients with hypoglycemia unawareness can reverse alterations in brain glucose transport/metabolism as well as functional connectivity, thereby reverse brain dysfunction induced by current intensive T1DM insulin treatment.

项目摘要/摘要 低血糖及其对脑功能的不良影响仍然是限制使用加剧的主要因素 胰岛素疗法已证明可以预防或延迟1型糖尿病（T1DM）的长期并发症。 涉及前额叶皮层的较​​高认知功能（例如工作记忆）对 神经胶质细胞减少症。该建议寻求持续支持长期RO-1赠款，其长期目标 记录胰岛素输送策略的健康益处，以最大程度地减少经常出现的风险 T1DM患者低血糖。以下概述的当前项目的具体目的使用功能 磁共振成像（fMRI）和磁共振光谱（MRS）技术评估 急性低血糖和急性高血糖引起的大脑功能和燃料代谢的变化 T1DM低血糖的患者不认识（与低血糖感知T1DM患者和健康 控制）以及采用闭环胰岛素输送系统的潜在有益影响 低血糖中的大脑功能不知道T1DM个体。协议严重依赖人类调查 涉及非糖尿病和低血糖意识和不知道暴露于实验的T1DM受试者 使用葡萄糖夹技术轻度和中度低血糖和急性高血糖，而 进行大脑成像。但是，我们还利用了啮齿动物糖尿病模型测试的力量 特定的机械假设。该提议的主要假设是低血糖不知道T1DM 患者不仅患有荷尔蒙和症状反应受损，而且缺乏另一种关键低血糖症 防御机制，即大脑因适应性而激活动机/奖励电路的能力 脑葡萄糖转运和代谢以及多元型途径的刺激增加。具体 目的是确定：1​​）如果低血糖患者不了解T1DM患者（与T1DM和非糖尿病患者 控件）失去引起大脑对视觉食品提示的反应以及功能连接的能力 在轻度和中度低血糖期间，纹状体和各种大脑区域响应食物线索 使用葡萄糖夹技术； 2）如果患有T1DM和低血糖的患者不认识表现出适应性 变化导致大脑葡萄糖转运和代谢响应急性的过度增加 高血糖诱导额外皮层内不良神经认知作用的高血糖，这是一个关键的大脑区域 以前使用磁共振光谱（MRS）在人类中未检查的认知功能。在 此外，将在暴露于复发性低血糖症的糖尿病大鼠中进行机械研究，以定义 分子机制推动了密集胰岛素治疗引起的脑燃料代谢的变化； 3）如果低血糖患者的闭环胰岛素输送系统可降低血糖变异性 不认识可以逆转大脑葡萄糖传输/代谢以及功能连接性的改变， 因此，当前密集型T1DM胰岛素治疗引起的脑功能障碍会逆转大脑功能障碍。