Glucoregulatory Hormone Interactions in Diabetes

项目摘要/摘要 低血糖及其对大脑功能的不良影响仍然是限制使用强化治疗的主要因素 胰岛素治疗已被证明可以预防或延缓1型糖尿病(T1 DM)的长期并发症。 涉及前额叶皮质的高级认知功能(如工作记忆)对 神经性低血糖。这项建议寻求继续支持长期RO-1赠款，其长期目标是 记录胰岛素给药策略的健康益处，将频繁发作的风险降至最低 1型糖尿病患者的低血糖。以下概述的当前项目的具体目标使用Functional. 磁共振成像(FMRI)和磁共振波谱(MRS)技术评估 急性低血糖和急性高血糖对脑功能和能量代谢的影响 有低血糖意识的T1 DM患者(与有低血糖意识的T1 DM患者和健康人相比 控制)以及采用闭环式胰岛素递送系统来改善 不知道低血糖的T1 DM患者的脑功能。协议在很大程度上依赖人工调查 涉及非糖尿病以及低血糖意识和不知道T1 DM受试者暴露于实验性 应用葡萄糖钳夹技术治疗轻、中度低血糖和急性高血糖 正在接受脑部成像。然而，我们也利用啮齿动物糖尿病模型的力量来测试 具体的机械论假说。这一建议的主要假设是低血糖不知道T1 DM 患者不仅荷尔蒙和症状反应受损，而且还缺乏另一个关键的低血糖。 防御机制，即大脑由于自适应而激活动机/奖励回路的能力 增加大脑葡萄糖的运输和新陈代谢，以及刺激多元醇途径。具体的 目的是确定：1)T1 DM患者是否有低血糖意识(与T1 DM和非糖尿病患者相比 控制)丧失对视觉食物提示的大脑反应能力以及在 轻度和中度低血糖时纹状体和其他多种脑区对食物提示的反应 使用葡萄糖钳夹技术；2)如果T1 DM和低血糖患者无意识地表现出适应性 引起脑葡萄糖转运和代谢过度增加的变化 高血糖会在前额叶皮质引起不良的神经认知影响，这是大脑中 以前没有使用磁共振波谱(MRS)检查过人类的认知功能。在……里面 此外，将对暴露于反复低血糖的糖尿病大鼠进行机制研究，以确定 胰岛素强化治疗引起脑内燃料代谢改变的分子机制； 3)如果在低血糖患者中使用封闭的胰岛素递送系统来降低血糖变异性 意识不清可以逆转大脑葡萄糖运输/新陈代谢以及功能连接的变化， 从而逆转目前强化T1 DM胰岛素治疗所致的脑功能障碍。

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.