A glucose-responsive network

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，它可能会导致反复发作的低血糖或“低血糖”。这是当血液中的葡萄糖太少(低血糖)时，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。这些感觉刺激身体释放天然的保护性荷尔蒙，并提醒患者吃含糖的东西。不幸的是，服用胰岛素的糖尿病患者可能会经常出现一阵阵低血糖，以至于他们开始意识不到警告信号，从而增加了他们崩溃甚至昏迷的可能性。如果我们要在未来帮助这些患者，了解大脑正常情况下如何检测低血糖并对其做出反应是至关重要的。我们发现了一种特殊类型的脑细胞，它含有一种名为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。我们已经绘制了连接PACAP细胞的大脑其他部分的图谱，重要的是，这些区域中的每一个之前都与大脑对低血糖的反应有关。因此，它们共同启动了保护性荷尔蒙的释放，或导致行为的改变(例如，导致饥饿和寻求糖分)。重要的是，我们的发现为我们提供了一把钥匙，让我们能够“打开”大脑，了解感知低血糖并对其做出反应的复杂电路。我们的实验使我们能够让PACAP细胞在荧光灯下发光。这意味着我们可以从死去的动物身上切下小鼠大脑的切片，并专门记录PACAP细胞的电活动。这向我们确切地展示了PACAP细胞如何对低糖水平做出反应，以及它们如何将信息发送到其他大脑区域。类似的技术也允许我们激活活着的小鼠的PACAP神经元，要么通过光纤照射它们的大脑，要么通过皮下注射给小鼠一种特殊的“特制”药物。小鼠没有感觉到任何异常，但通过激活大脑中的PACAP细胞或其他特定类型的细胞(就像低血糖时自然发生的那样)，我们将绘制控制保护性激素释放的电路，并引起对低血糖的意识。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，并将它们纳入我们的血糖感应网络。因此，我们将能够建立一幅关于大脑对低血糖的确切感觉和反应的图景。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的胰岛素治疗后失去了低血糖的意识。我们希望能够提出新的方法来检测和预防低血糖意识受损，从而提高糖尿病患者的安全性。

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.