Molecular mechanisms underlying divergent incretin receptor responses in alpha versus beta cells

α细胞与β细胞中肠促胰岛素受体反应不同的分子机制

• 批准号: MR/X021467/1
• 负责人: Alejandra Tomas
• 金额: $ 75.13万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX021467%2F1
• 关键词: Molecular; mechanisms; underlying; divergent; incretin

Diabetes is a disease that has reached epidemic proportions, with millions of people dying or suffering from a myriad of associated complications. Amongst the current treatments for the disease are incretin therapies, which are based on mimicking the function of incretin hormones, secreted from the gut in response to food intake and able to stimulate the release of insulin from the pancreas by binding specifically to proteins at the surface of cells in the pancreas called receptors. The incretins can also activate their target receptors in the brain to promote fullness and hunger reduction which is an added benefit for diabetic patients who require weight loss. There are two incretins, GLP-1 and GIP, and each one binds to its own receptor. Most incretin therapies to date have been directed at the GLP-1 receptor because the GIP receptor does not work at all in diabetic patients. However, we now know that if blood sugar levels are brought under control by other means, the GIP receptor will start working again, and as this is a very strong receptor that can work even better than the GLP-1 receptor in normal conditions, there is a good case for developing therapies that target both receptors at the same time. This has recently been achieved with a new medicine called tirzepatide, giving superior effects in controlling blood sugar levels as well as promoting weight loss. However, the way that these two receptors work in the pancreas is not completely clear. While they both promote insulin release from pancreatic beta cells, the GLP-1 receptor inhibits the release of another hormone, glucagon, from another cell type in the pancreas called alpha, which balances the effect of insulin, while the GIP receptor promotes glucagon release from these alpha cells. It is also not clear if glucagon is good or bad for diabetes, as on the one hand it promotes blood sugar levels to rise because of its effects in the liver, while on the other hand it makes beta cells in the pancreas release more insulin, so latest investigations suggest that it is actually an overall beneficial hormone for diabetic patients. In addition, the two receptors are not equally distributed amongst alpha and beta cells. In fact, there is considerably more GLP-1 receptor than GIP receptor in beta cells and much less GLP-1 receptor than GIP receptor in alpha cells. Despite this, the GIP receptor appears to function better than the GLP-1 receptor in healthy beta cells, while the GLP-1 receptor works almost as well as the GIP receptor in alpha cells in spite of its very low expression level. It is therefore likely that these receptors will work in different ways in these two cell types, as the amount of signal they send does not directly correlate with the amount of receptor there is in each one, and in alpha cells they are actually acting in opposite ways. In this project, we plan to clarify how exactly each receptor works in alpha versus beta cells by investigating how they move across the cell, the signals they send in each cell type, the partners they interact with and how much they depend on the action of an important known regulator of their function called beta-arrestin 2. Finally, we will also analyse how natural genetic variants of each receptor that exist in the general population can change the way these receptors function in the alpha versus beta cells of the pancreas. Overall, this project will help us understand why these receptors work differently to each other, why they have different strengths making them work better in some cases despite being present at much lower levels, and how genetic variation across individuals can modify the way they work in the two pancreatic cell types studied. This study will help us predict how well incretin therapies targeting each receptor will work for specific individuals, and give us new ideas about how best to target each receptor in alpha and beta cells to design newly improved therapies in the fight against type 2 diabetes.

糖尿病是一种已经达到流行病的疾病，数以百万计的人死亡或遭受无数相关并发症的困扰。目前对该疾病的治疗方法是泌乳素疗法，这些疗法基于模仿肠血凝素激素的功能，该疗法从肠道中分泌出来，以响应食物摄入，并能够通过特异性地结合了胰腺所谓受体的细胞表面，从而刺激胰岛从胰腺中释放。肠降量还可以激活其大脑中的靶心受体，以促进饱满度和减少饥饿，这对于需要减肥的糖尿病患者是一个额外的好处。有两个肠静脉素，GLP-1和GIP，每个肠to与其自身的受体结合。迄今为止，大多数肠降血糖素疗法都是针对GLP-1受体的，因为GIP受体在糖尿病患者中根本不起作用。但是，我们现在知道，如果通过其他方式控制血糖水平，则GIP受体将重新开始工作，并且由于这是一个非常强大的受体，在正常情况下可以比GLP-1受体更好地工作，因此有一个很好的案例可以同时开发靶向两种受体的疗法。最近，通过一种称为tirzepatide的新药物来实现这一目标，在控制血糖水平以及促进体重减轻方面产生了优势。但是，这两个受体在胰腺中起作用的方式并不完全清楚。尽管它们都促进了从胰腺β细胞中释放胰岛素，但GLP-1受体抑制了一种称为Alpha的胰腺中另一种细胞类型的另一种激素胰高血糖素的释放，该细胞抑制了胰岛素的效果，而GIP受体则促进胰高血糖素从这些Alpha细胞中释放出来。尚不清楚胰高血糖素对糖尿病是好还是坏，因为一方面它会促进血糖水平升高，因为它在肝脏中的作用，而另一方面，它使胰腺中的β细胞释放出更多的胰岛素，因此最新的研究表明，它实际上是对糖尿病患者的总体有益激素。另外，这两个受体在α和β细胞之间并未平均分布。实际上，在β细胞中，GLP-1受体比GIP受体要多得多，而GLP-1受体的受体比α细胞中的GIP受体要少得多。尽管如此，在健康β细胞中，GIP受体似乎比GLP-1受体的功能更好，而GLP-1受体尽管其表达水平非常低，但GLP-1受体的起作用几乎和Alpha细胞中的GIP受体一样。因此，这些受体可能在这两种细胞类型中以不同的方式工作，因为它们发送的信号量与每个受体的量与每个受体的量无直接相关，而在α细胞中，它们实际上以相反的方式起作用。在这个项目中，我们计划通过调查它们如何在细胞中移动，它们在每种细胞类型中发送的信号，与他们互动的伴侣，与他们的功能重要调节剂相互作用的程度来阐明每个受体在Alpha与Beta细胞中的工作原理，并依赖于其功能的重要调节剂的作用，称为Beta-arrestin 2。胰腺细胞。总体而言，该项目将有助于我们了解为什么这些受体彼此之间的工作不同，为什么它们具有不同的优势在某些情况下使它们在较低水平的情况下可以更好地工作，以及各个个体之间的遗传变异如何改变他们研究的两种胰腺细胞类型的工作方式。这项研究将有助于我们预测靶向每个受体对特定个体的靶向肠静脉疗法的状况，并为我们提供有关如何最好地靶向α和β细胞中每个受体的新想法，以设计与2型糖尿病斗争的新疗法。