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

确定葡萄糖依赖性促胰岛素多肽 (GIP) 和胰高血糖素样肽 1 (GLP1) 如何协同调节 β 细胞功能

• 批准号: MR/W000881/2
• 负责人: Anne Yingchol De Bray
• 金额: $ 29.57万
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Fellowship
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FW000881%2F2
• 关键词: Determining; how; glucose; dependent; insulinotropic

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).

2型糖尿病（T2DM）是社会面临的一大医疗保健挑战。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；大部分用于治疗其并发症（如失明、截肢、心脏病、肾衰竭）。尽管有这样的预算，英国仍有40%的2型糖尿病患者没有达到降低这些并发症风险所需的血糖控制目标。在过去的十年里，新药已经被证明在改善血糖控制和减肥方面取得了成功。这些药物针对的是一种叫做“肠促胰岛素”的天然体内激素，这种激素可以帮助胰岛素从胰腺器官中释放出来。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 （GLP1）和葡萄糖依赖性胰岛素促胰岛素肽（GIP）。以肠促胰岛素为基础的药物的优点是，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，因为血糖水平过低会导致昏倒等危险后果。以肠促胰岛素为基础的糖尿病治疗的主要类型之一是激活许多身体细胞中的GLP1受体（GLP1R）。这与糖尿病和肥胖有关，因为GLP1R的激活会导致胰岛素释放，并通过减缓胃排空和抑制大脑发出的饥饿信息来降低食欲。相比之下，作用于GIP受体（GIPR）的药物对治疗糖尿病或肥胖无效，可能是因为GIPR存在于更少的细胞中，或者是因为这些细胞内的通信或信号传导不良。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，一种同时作用于GIPR和GLP1R的药物，“twincretin”，在控制血糖和减肥方面比单独使用任何一种药物都有更好的效果。“整体大于部分之和”。由于这些发现，“twincretin”药物目前正处于临床试验阶段。然而，基于gip的治疗与基于glp1的治疗如此有效的原因尚不清楚，了解这是我项目的目标。通过揭示其背后的原因，我们可以改善这些新药的交付方式（例如，一些人会从中受益或多或少？），并为开发其他操纵肠促胰岛素的方法打开大门，以改善糖尿病患者的预后。本研究的目的是通过研究GIP与GLP1对人胰腺β细胞功能和活性的影响来揭示这些机制。细胞释放胰岛素，与细胞和细胞一起在胰腺中形成“胰岛”。在2型糖尿病患者中，这些胰岛功能失调，不能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，我将从患有和不患有2型糖尿病的人身上获得供体胰岛，并用葡萄糖、一种肠促胰岛素、一种肠促胰岛素或两种肠促胰岛素作为单独的激素来治疗他们（看看是否将两种激素结合成一种肠促胰岛素药物会产生差异）。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GLP1R的数量，以及c) GIPR和GLP1R在受到刺激后如何循环。这3组实验将使我能够确定GIP和GLP1和谐工作的关键机制。如上所述，这些实验的结果将与目前处于临床试验中的双肠促肽药物的递送有关。然而，这些实验的发现也将与其他研究2型糖尿病治疗方法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（如大脑、肝脏）起作用的研究人员有关。

项目成果

Hypothalamic and brainstem glucose-dependent insulinotropic polypeptide receptor neurons employ distinct mechanisms to affect feeding.

• DOI: 10.1172/jci.insight.164921
• 发表时间: 2023-05-22
• 期刊: JCI INSIGHT
• 影响因子: 8
• 作者: Adriaenssens, Alice;Broichhagen, Johannes;de Bray, Anne;Ast, Julia;Hasib, Annie;Jones, Ben;Tomas, Alejandra;Burgos, Natalie Figueredo;Woodward, Orla;Lewis, Jo;O'Flaherty, Elisabeth;El, Kimberley;Cui, Canqi;Harada, Norio;Inagaki, Nobuya;Campbell, Jonathan;Brierley, Daniel;Hodson, David J.;Samms, Ricardo;Gribble, Fiona;Reimann, Frank
• 通讯作者: Reimann, Frank

Acid-Resistant BODIPY Amino Acids for Peptide-Based Fluorescence Imaging of GPR54 Receptors in Pancreatic Islets

用于胰岛 GPR54 受体肽基荧光成像的耐酸 BODIPY 氨基酸

• DOI: 10.1002/ange.202302688
• 发表时间: 2023
• 期刊: Angewandte Chemie
• 作者: Mendive-Tapia L

Acid-Resistant BODIPY Amino Acids for Peptide-Based Fluorescence Imaging of GPR54 Receptors in Pancreatic Islets.

用于胰岛 GPR54 受体肽基荧光成像的耐酸 BODIPY 氨基酸。

• DOI: 10.1002/anie.202302688
• 发表时间: 2023
• 期刊: Angewandte Chemie (International ed. in English)
• 作者: Mendive-Tapia L