Glucoregulatory Hormone Interactions in Diabetes

糖尿病中的葡萄糖调节激素相互作用

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要低血糖及其对脑功能的不利影响仍然是限制强化治疗使用的主要因素胰岛素治疗已被证明可以预防或延缓 1 型糖尿病 (T1DM) 的长期并发症。涉及前额皮质的高级认知功能（例如工作记忆）对神经性低血糖症。该提案寻求长期 RO-1 赠款的持续支持，其长期目标是记录胰岛素输送策略对健康的益处，最大限度地降低频繁发作的风险 T1DM 患者的低血糖。下面概述的当前项目的具体目标使用功能磁共振成像（fMRI）和磁共振波谱（MRS）技术来评估急性低血糖和急性高血糖引起的脑功能和燃料代谢的变化不知晓低血糖的 T1DM 患者（与知晓低血糖的 T1DM 患者和健康人相比）控制）以及采用闭环胰岛素输送系统来改善的潜在有益影响未意识到低血糖的 T1DM 个体的脑功能。该协议严重依赖人类调查涉及非糖尿病以及有低血糖意识和不意识的 T1DM 受试者暴露于实验使用葡萄糖钳技术治疗轻度和中度低血糖和急性高血糖，同时正在进行脑部成像。然而，我们还利用啮齿动物糖尿病模型的力量来测试具体的机制假设。该提案的主要假设是 T1DM 患者未意识到低血糖患者不仅荷尔蒙和症状反应受损，而且缺乏另一个关键的低血糖症防御机制，即大脑由于适应性而激活动机/奖励回路的能力增加大脑葡萄糖转运和代谢以及刺激多元醇途径。具体的目的是确定：1) T1DM 患者是否对低血糖不知情（与 T1DM 和非糖尿病患者相比）控制）失去了引发大脑对视觉食物线索反应的能力以及功能连接轻度和中度低血糖期间纹状体和各种其他大脑区域对食物线索的反应使用葡萄糖钳夹技术； 2）如果患有T1DM且低血糖无意识的患者表现出适应性导致大脑葡萄糖转运和代谢过度增加的变化，以应对急性高血糖会在前额皮质（大脑的关键区域）内引起不良的神经认知影响以前未使用磁共振波谱（MRS）对人类的认知功能进行过检查。在此外，还将在暴露于反复低血糖的糖尿病大鼠中进行机制研究，以确定驱动强化胰岛素治疗引起的脑燃料代谢变化的分子机制； 3) 如果使用闭环胰岛素输送系统降低低血糖患者的血糖变异性无意识可以逆转大脑葡萄糖转运/代谢以及功能连接的改变，从而逆转当前 T1DM 胰岛素强化治疗引起的脑功能障碍。