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A glucose-responsive network

葡萄糖反应网络

基本信息

批准号：
MR/R002991/1
负责人：
Simon Luckman
金额：
$ 59.51万
依托单位：
University of Manchester
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2017
资助国家：
英国
起止时间：
2017 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FR002991%2F1
关键词：
glucose responsive network

项目摘要

It is estimated that 4.5 million people in the UK suffer with diabetes and many of these patients regulate their blood-sugar levels by taking insulin. A major problem with this treatment is that is can lead to repeated bouts of low glucose or "hypos." This is when there is too little glucose in the bloodstream (hypoglycaemia), which can cause serious problems. For example, a patient might start feeling agitated or dizzy, and may even collapse unconscious. These feelings stimulate the body to release natural, protective hormones and alert the patient to eat something sugary. Unfortunately, diabetic patients taking insulin may suffer from bouts of hypoglycaemia so regularly that they start to become unaware of the warning signs, increasing the probability that they may collapse and even fall into a coma. If we are to help these patients in the future, it is critical that we understand how the brain normally detects and responds to hypoglycaemia. We have made the important discovery of a specific type of brain cell, which contains a chemical signal called PACAP. These cells can sense low sugar levels and initiate a series of physiological responses. We have mapped the other parts of the brain with which PACAP cells connect and, importantly, each of these areas has previously been implicated in the brain's response to hypoglycaemia. Thus, together they initiate the release of the protective hormones or produce a change in behaviour (e.g. cause hunger and sugar seeking). Critically, our discovery has provided us with a key to "open up" the brain and understand the complex electrical circuits which sense and respond to hypoglycaemia. Our experiments allow us to make PACAP cells shine under fluorescent light. This means we can cut slices of mouse brain from dead animals and record specifically the electrical activity of PACAP cells. This shows us exactly how PACAP cells respond to low sugar levels and how they then send this information to the other brain areas. Similar techniques also allow us to activate PACAP neurones in living mice, either by shining a light into their brains through an optic fibre or by giving the mice a special "designer" drug by an injection under their skin. The mice do not feel anything unusual, but by activating PACAP cells or other specific cell types in the brain (as happens naturally with hypoglycaemia), we will map the circuits which control the release of protective hormones and cause awareness of hypoglycaemia. By carefully profiling PACAP and other brain cells, we should be able to identify additional key cell types and fit them into our glucose-sensing network. Thus, we will be able to build up a picture of exactly how the brain senses and responds to hypoglycaemia. By understanding the complex circuits in this network, we should begin to understand why patients lose their awareness of hypoglycaemia after long-term insulin treatment. We hope to be able to suggest new ways of detecting and preventing impaired awareness of hypoglycaemia and, thus, improve the safety of diabetic patients.

据估计，英国有450万人患有糖尿病，其中许多患者通过服用胰岛素来调节血糖水平。这种治疗的一个主要问题是它会导致反复发作的低血糖或“hypos”。“这是当血液中的葡萄糖太少（低血糖），这可能会导致严重的问题。例如，患者可能会开始感到焦躁或头晕，甚至可能昏迷不醒。这些感觉刺激身体释放自然的保护性激素，并提醒患者吃一些含糖的东西。不幸的是，服用胰岛素的糖尿病患者可能会经常发生低血糖，以至于他们开始意识不到警告信号，增加了他们可能崩溃甚至陷入昏迷的可能性。如果我们将来要帮助这些患者，了解大脑通常如何检测和响应低血糖至关重要。我们发现了一种特殊类型的脑细胞，它含有一种叫做PACAP的化学信号。这些细胞可以感知低糖水平并启动一系列生理反应。我们已经绘制了PACAP细胞连接的大脑其他部分，重要的是，这些区域中的每一个都与大脑对低血糖的反应有关。因此，它们一起启动保护性激素的释放或产生行为变化（例如引起饥饿和寻求糖分）。重要的是，我们的发现为我们提供了一把钥匙，可以“打开”大脑，了解感知和响应低血糖的复杂电路。我们的实验使我们能够使PACAP细胞在荧光灯下发光。这意味着我们可以从死亡的动物身上切下老鼠的大脑切片，专门记录PACAP细胞的电活动。这向我们展示了PACAP细胞如何对低糖水平做出反应，以及它们如何将这些信息发送到其他大脑区域。类似的技术也使我们能够激活活老鼠的PACAP神经元，通过光纤将光线照射到它们的大脑中，或者通过皮下注射给老鼠一种特殊的“设计师”药物。小鼠没有感觉到任何异常，但通过激活大脑中的PACAP细胞或其他特定细胞类型（如低血糖自然发生），我们将绘制控制保护性激素释放并引起低血糖意识的回路。通过仔细分析PACAP和其他脑细胞，我们应该能够识别其他关键细胞类型，并将它们融入我们的葡萄糖传感网络。因此，我们将能够准确地了解大脑如何感知和响应低血糖。通过了解这个网络中的复杂回路，我们应该开始理解为什么患者在长期胰岛素治疗后会失去对低血糖的意识。我们希望能够提出检测和预防低血糖意识受损的新方法，从而提高糖尿病患者的安全性。