Regulation of insulin biosynthesis

胰岛素生物合成的调节

• 批准号: 2107399
• 金额: --
• 依托单位: University of Oxford
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2107399
• 关键词: Regulation; insulin; biosynthesis

Insulin, secreted from pancreatic beta-cells, plays an essential role in the regulation of blood glucose homeostasis, and diabetes results when circulating insulin levels fall below that required to sustain normoglycaemia. Too much insulin, by contrast, leads to life-threatening hypoglycaemia. As a consequence, insulin production is tightly regulated. Recent studies have revealed the existence of pacemaker beta-cells (hub cells), that respond more rapidly to glucose and drive oscillations in insulin secretion [1]. Surprisingly, these cells produce less insulin than the follower cells they entrain. Why hub cells produce less insulin and whether this is a cause or a consequence of their enhanced ability to respond to glucose (or their increased sensitivity to apoptosis), is unknown. It is speculated that reducing insulin production may increase ATP levels and thereby enhance insulin secretion, but this yet to be established. How beta-cell stress, such as oxidative stress or exposure to chronically elevated lipids or glucose, impairs insulin biosynthesis is also unresolved. Glucolipotoxicity also induces a state of dedifferentiation [2,3], but whether dedifferentiation reduces insulin production (or vice versa), or if these events are simply correlated, is unclear. Thus, this project has three aims. First, to determine why hub cells produce less insulin, and whether less insulin production leads to a reduction in beta-cell ATP levels (or vice versa). Second, to determine the molecular mechanisms underlying reduced insulin biosynthesis caused by glucolipotoxicity, and its relationship to beta-cell dedifferentiation, and to proliferation. Third, to determine the extent to which impaired insulin production can be corrected by peptide hormones such as GLP-1. This will include systematically screening a library of all endogenous protein ligands and a library of previously unstudied peptides provided by Novo Nordisk, using high-throughput screening infrastructure at Novo Nordisk. The results will provide insight into a key biological question - how is insulin production regulated, and will have important implications for studies aimed at generating insulin-secreting cells from stem cells, and for preserving donor beta-cells for transplant. Long-term benefits will include improvements in the design and development of peptides/drugs targeted at enhancing insulin secretion in diabetes.

胰岛素由胰腺β细胞分泌，在调节血糖稳态中起着重要作用，当循环胰岛素水平低于维持正常血糖所需的水平时，糖尿病就会发生。相比之下，过多的胰岛素会导致危及生命的低血糖。因此，胰岛素的产生受到严格的调控。最近的研究揭示了起搏器β细胞（中枢细胞）的存在，它对葡萄糖的反应更快，并驱动胰岛素分泌的振荡。令人惊讶的是，这些细胞产生的胰岛素比它们所携带的跟随细胞要少。为什么中枢细胞产生较少的胰岛素，以及这是它们对葡萄糖反应能力增强（或它们对细胞凋亡的敏感性增加）的原因还是结果，目前尚不清楚。据推测，减少胰岛素产生可能会增加ATP水平，从而增加胰岛素分泌，但这尚未得到证实。β细胞应激，如氧化应激或暴露于长期升高的脂质或葡萄糖，如何损害胰岛素的生物合成也尚未解决。糖脂毒性也会诱导去分化状态[2,3]，但去分化是否会减少胰岛素生成（反之亦然），或者这些事件是否只是相关，目前尚不清楚。因此，这个项目有三个目的。首先，确定中枢细胞产生较少胰岛素的原因，以及胰岛素产生较少是否导致β细胞ATP水平降低（反之亦然）。其次，确定糖脂毒性引起的胰岛素生物合成减少的分子机制，及其与β细胞去分化和增殖的关系。第三，确定受损胰岛素产生可以通过肽激素如GLP-1纠正的程度。这将包括使用诺和诺德的高通量筛选基础设施，系统筛选所有内源性蛋白质配体文库和诺和诺德提供的先前未研究的肽文库。这一结果将为一个关键的生物学问题提供见解——胰岛素的产生是如何被调节的，并将对旨在从干细胞中产生胰岛素分泌细胞的研究以及保存供体β细胞用于移植的研究具有重要意义。长期的好处将包括改进设计和开发针对糖尿病胰岛素分泌的肽/药物。