Determining how glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) synergistically regulate beta cell function

2型糖尿病（T2 DM）是社会面临的一个巨大的医疗挑战。在英国，有470万人患有糖尿病。目前，NHS每小时花费100万英镑治疗这种疾病;大部分用于其并发症（例如失明，截肢，心脏病，肾衰竭）。尽管有这样的预算，但英格兰40%的T2 DM患者没有达到降低这些并发症风险所需的血糖控制目标。在过去的十年中，新的药物已被证明在改善血糖控制和减轻体重方面取得了成功。这些药物的目标是被称为“肠促胰岛素”的天然身体激素，它有助于胰岛素从胰腺器官释放。胰岛素是一种降低血糖的激素。肠促胰岛素包括胰高血糖素样肽1（GLP 1）和葡萄糖依赖性促胰岛素肽（GIP）。肠促胰岛素类药物的优点是，它们只在血糖水平高时释放胰岛素，因此降低了血糖水平过低的风险，这可能导致危险的影响，例如昏倒。基于肠促胰岛素的糖尿病治疗的主要类型之一激活在许多体细胞中发现的GLP 1受体（GLP 1 R）。这与糖尿病和肥胖症有关，因为GLP 1 R的激活通过减缓胃排空和使大脑的饥饿信息失活而导致胰岛素释放和食欲降低。相比之下，作用于GIP受体（GIPR）的药物在治疗糖尿病或肥胖症方面无效，这可能是因为GIPR存在于较少的细胞中，或者是因为这些细胞内的沟通或信号传递不良。GIPR在细胞中的循环方式也可能存在差异。然而，在过去的几年里，研究人员发现，同时作用于GIPR和GLP 1 R的单一药物“twincretin”，在血糖控制和体重减轻方面的反应甚至比单独使用任何一种药物都要好，即“整体大于部分之和”。由于这些发现，“twincretin”药物目前正在临床试验中。然而，基于GIP的治疗与基于GLP 1的治疗如此有效的原因仍然不清楚，理解这一点是我项目的目标。通过揭示这背后的原因，我们可以改进这些新药的输送方式（例如，有些人会从中受益更多还是更少？）本研究的目的是通过研究GIP和GLP 1对人类胰腺β细胞功能和活性的影响来揭示这些机制。β细胞释放胰岛素，并与α细胞和δ细胞聚集在一起形成胰腺中的“胰岛”。在T2 DM中，这些胰岛功能失调，无法产生足够的胰岛素来控制血糖水平。与国际研究合作者合作，我将从患有和没有T2 DM的人中获得供体人类胰岛，并将它们与葡萄糖，一种肠促胰岛素，一种双肠促胰岛素或两种肠促胰岛素作为单独的激素进行治疗（看看将两种激素结合到一种双肠促胰岛素药物中是否会产生差异）。实验将确定以下方面的差异：a）胰岛随后释放的胰岛素量，B）胰岛细胞上表达的GIPR和GLP 1 R的数量，以及c）GIPR和GLP 1 R在受到刺激后如何再循环。这3组实验将使我能够确定GIP和GLP 1协调工作的关键机制。如上所述，这些实验的结果将与目前临床试验中的twincretin药物的递送相关。然而，这些实验的结果也将与其他研究T2 DM治疗的研究人员以及那些研究肠促胰岛素如何在身体其他部位（例如大脑，肝脏）工作的研究人员相关。

Type 2 diabetes (T2DM) is a big healthcare challenge facing society. In the UK, 4.7 million people have diabetes. Currently, the NHS spends £1 million per hour treating this disease; the majority spent on its complications (e.g. blindness, amputations, heart disease, kidney failure). Despite this budget, 40% of people with T2DM in England do not meet the target for blood sugar control needed to reduce the risk of these complications. In the past decade, new drugs have proven successful at improving blood sugar control and reducing weight. These drugs target natural body hormones called "incretins" which help insulin to be released from the pancreas organ. Insulin is a hormone that lowers blood sugar. Incretins include glucagon-like peptide 1 (GLP1) and glucose-dependent insulinotropic peptide (GIP). The advantage of incretin-based drugs is that they only release insulin when blood sugar levels are high, therefore reducing the risk of blood sugar levels dipping too low which can cause dangerous effects e.g. passing out. One of the main types of incretin-based diabetes treatment activates the GLP1 receptor (GLP1R) found in many body cells. This is relevant to diabetes and obesity as activation of the GLP1R leads to insulin release and reduced appetite by slowing stomach emptying and deactivating hunger messages from the brain. In contrast, drugs that work on the GIP receptor (GIPR) are ineffective in treating diabetes or obesity, perhaps because GIPR are found in fewer cells or because of poor communication, or signalling, within these cells. There may also be differences in how the GIPR are recycled in the cell.In the last few years, however, researchers have found that a single drug acting on both the GIPR and GLP1R, "twincretin", lead to an even better response upon blood sugar control and weight loss that either drug alone i.e. "the whole is greater than the sum of the parts". Due to these findings, "twincretin" drugs are currently in clinical trials.However, the reason behind GIP-based therapy working so well with GLP1-based therapy remains unclear and understanding this is the goal of my project. By uncovering the reasons behind this, we can improve how these new drugs are delivered (e.g. will some people benefit more or less from them?) and also open the door to developing other methods of manipulating the incretins to improve outcomes for people with diabetes.The aim of this study is to unveil these mechanisms by investigating the effect of GIP given with GLP1 upon the function and activity of beta cells in the human pancreas. Beta cells release insulin and are found grouped together with alpha and delta cells to form "islets" in the pancreas. In T2DM, these islets become dysfunctional and fail to produce enough insulin to control blood glucose levels. Working with international research collaborators, I will obtain donor human islets from people with and without T2DM and treat them with either glucose, one incretin, a twincretin or both incretins as separate hormones (to see if combining the two hormones into a single twincretin drug is what makes a difference). Experiments will determine differences in a) the amount of insulin subsequently released by the islets, b) the number of GIPR and GLP1R expressed on islet cells and c) how the GIPR and GLP1R are recycled after they are stimulated. These 3 sets of experiments will allow me to identify the key mechanisms by which GIP and GLP1 work harmoniously.As described above, results from these experiments will be relevant to the delivery of the twincretin medications currently in clinical trials. However, the findings from these experiments will also be relevant to other researchers investigating treatments for T2DM and those looking at how the incretins work in other parts of the body (e.g. the brain, liver).