Glucoregulatory Hormone Interactions in Diabetes

项目总结/摘要 脑功能减退及其对脑功能的不良影响仍然是限制使用强化 胰岛素治疗已被证明可以预防或延迟1型糖尿病（T1 DM）的长期并发症。 涉及前额叶皮层的高级认知功能（例如工作记忆）对 神经性低血糖症该提案寻求继续支持长期RO-1赠款，其长期目标是 记录胰岛素给药策略的健康益处，最大限度地减少频繁发作的风险， T1 DM患者的低血糖。下面概述的当前项目的具体目标使用函数 磁共振成像（fMRI）和磁共振波谱（MRS）技术，以评估 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， 低血糖无意识的T1 DM患者（与低血糖意识的T1 DM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，以改善 无低血糖意识的T1 DM个体的脑功能。协议严重依赖于人类调查 涉及非糖尿病以及低血糖知晓和不知情的T1 DM受试者，暴露于实验性 轻度和中度低血糖和急性高血糖，使用葡萄糖钳夹技术， 进行脑部成像然而，我们也利用啮齿动物糖尿病模型的力量来测试 具体的机械假说。该建议的主要假设是，无意识低血糖的T1 DM 患者不仅激素和症状反应受损，而且缺乏另一个关键的低血糖症， 防御机制，即大脑激活动机/奖励电路的能力，由于适应性 增加脑葡萄糖转运和代谢以及刺激多元醇途径。具体 目的是确定：1）T1 DM患者是否存在低血糖无意识（与T1 DM和非糖尿病患者相比 控制）失去了引起大脑对视觉食物线索的反应的能力， 轻度和中度低血糖期间纹状体和各种其他脑区对食物提示的反应 使用葡萄糖钳夹技术; 2）如果患有T1 DM和低血糖无意识的患者显示适应性 引起脑葡萄糖转运和代谢过度增加的变化， 高血糖症在前额叶皮层内诱导不良神经认知效应，前额叶皮层是 认知功能以前没有在人类中使用磁共振波谱（MRS）检查。在 此外，将在暴露于复发性低血糖的糖尿病大鼠中进行机制研究，以确定 胰岛素强化治疗引起脑燃料代谢变化的分子机制; 以及3）如果在低血糖患者中用闭环胰岛素输送系统降低血糖变异性 无意识可以逆转脑葡萄糖转运/代谢以及功能连接的改变， 从而逆转当前强化T1 DM胰岛素治疗引起的脑功能障碍。

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.