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

糖尿病是一种已经达到流行程度的疾病，数百万人死亡或患有无数相关的并发症。目前治疗这种疾病的方法包括胰岛素疗法，这种疗法基于模仿胰岛素激素的功能，这种激素在食物摄入后从肠道分泌，能够通过与胰腺细胞表面称为受体的蛋白质特异性结合来刺激胰腺释放胰岛素。胰岛素还可以激活大脑中的目标受体，促进饱腹感和减少饥饿感，这对需要减肥的糖尿病患者来说是一个额外的好处。有两种生长素，GLP-1和GIP，每一种都与自己的受体结合。到目前为止，大多数胰岛素治疗都是针对GLP-1受体，因为GIP受体在糖尿病患者中根本不起作用。然而，我们现在知道，如果通过其他方式控制血糖水平，GIP受体将重新开始工作，由于这是一种非常强大的受体，在正常情况下甚至可以比GLP-1受体工作得更好，因此有很好的理由开发同时针对这两种受体的治疗方法。最近，一种名为tirzepatide的新药实现了这一点，该药在控制血糖水平和促进减肥方面具有优越的效果。然而，这两种受体在胰腺中的作用方式还不完全清楚。虽然两者都促进胰岛β细胞释放胰岛素，但GLP-1受体抑制胰腺中另一种细胞类型α释放的另一种激素--胰高血糖素，后者平衡胰岛素的作用，而GIP受体促进这些α细胞释放胰高血糖素。目前也不清楚高血糖素对糖尿病是好是坏，因为一方面它会促进血糖水平上升，因为它对肝脏有影响，另一方面它会让胰腺中的β细胞释放更多的胰岛素，所以最新的研究表明，它实际上是一种对糖尿病患者整体有益的激素。此外，这两种受体在α细胞和β细胞中的分布并不均匀。事实上，在β细胞中，GLP-1受体比GIP受体多得多，而在α细胞中，GLP-1受体比GIP受体少得多。尽管如此，GIP受体在健康的β细胞中的功能似乎好于GLP-1受体，而GLP-1受体在阿尔法细胞中的功能几乎与GIP受体一样好，尽管其表达水平非常低。因此，这些受体很可能在这两种细胞类型中以不同的方式发挥作用，因为它们发出的信号量与每种细胞中的受体数量并不直接相关，而在阿尔法细胞中，它们实际上以相反的方式发挥作用。在这个项目中，我们计划通过研究每个受体如何在细胞内移动，它们在每种细胞类型中发出的信号，它们与之相互作用的伙伴，以及它们在多大程度上依赖于其功能的重要已知调节因子--β-arrestin 2的作用，来阐明每个受体在阿尔法和贝塔细胞中的确切作用。最后，我们还将分析存在于普通人群中的每个受体的自然遗传变异如何改变这些受体在胰腺的阿尔法和贝塔细胞中的功能。总体而言，这个项目将帮助我们了解为什么这些受体的工作方式不同，为什么它们具有不同的强度，使它们在某些情况下工作得更好，尽管它们的水平要低得多，以及个体之间的遗传差异如何改变它们在两种所研究的胰腺细胞类型中的工作方式。这项研究将帮助我们预测针对每个受体的胰岛素疗法对特定个体的效果如何，并为我们提供新的想法，即如何最好地针对阿尔法和贝塔细胞中的每个受体来设计新改进的治疗方法，以对抗2型糖尿病。

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.