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Chronic hyperglycaemia and impaired pancreatic beta-cell function.

慢性高血糖和胰腺β细胞功能受损。

基本信息

批准号：
MR/T002107/1
负责人：
Frances Ashcroft
金额：
$ 98.34万
依托单位：
University of Oxford
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2019
资助国家：
英国
起止时间：
2019 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT002107%2F1
关键词：
Chronic hyperglycaemia impaired pancreatic beta

项目摘要

Diabetes affects >425 million people worldwide and accounts for one death every 6 seconds. In the UK, ~3.7 million people currently have the disease (90% have type 2 diabetes) and a further 1 million are undiagnosed. Diabetes increases the risk of heart disease, stroke, kidney disease and blindness, and reduces life expectancy by up to 10 years. It also consumes about 10% of the UK's direct healthcare costs. If we are to ameliorate the severe socio-economic impact of diabetes, and to develop new and better therapies, it is essential to have a clearer understanding of the underlying molecular mechanisms involved. The overall aim of this proposal is to generate this knowledge and to identify new pathways and targets for therapeutic drug development.Type 2 diabetes is characterised by a chronically elevated level of blood sugar (chronic hyperglycaemia), which results from insufficient secretion of the hormone insulin from the beta-cells of the pancreas. The hyperglycaemia fuels diabetes progression by further reducing beta-cell function and mass. We aim to understand how chronic hyperglycaemia impairs beta-cell function and mass, so speeding beta-cell decline. Such fundamental knowledge is currently lacking but has the potential to transform therapy, facilitating the development of novel drugs targeted at improving insulin secretion and preserving beta-cell function. It is well established that glucose (sugar) must be metabolised in order to stimulate insulin secretion. Work from several laboratories, including our own, has previously shown that this is because a glucose metabolite known as ATP, regulates the activity of a tiny pore in the beta-cell membrane known as the KATP channel. When this pore is open, insulin is not released. An acute rise in blood glucose leads to ATP generation, KATP channel closure and insulin release. However, studies suggest that chronic elevation of blood glucose adversely affects beta-cell metabolism, leading to a failure of ATP generation and KATP channel closure. Consequently, insulin secretion is prevented. Our recent studies indicate this is because hyperglycaemia causes marked changes in the expression of metabolic genes. Why this happens is unknown. We now aim to understand precisely how chronic hyperglycaemia, like that which occurs in diabetes, leads to changes in beta-cell metabolism, gene and protein expression, and ATP production. Understanding how hyperglycaemia impairs beta-cell function and mass in diabetes will provide novel insights into how its deleterious effects can be prevented and/or reversed, and identification of the pathways involved should help pinpoint specific targets for therapeutic drug development.

糖尿病影响全球超过 4.25 亿人，每 6 秒就有 1 人死亡。在英国，目前约有 370 万人患有这种疾病（90% 患有 2 型糖尿病），另有 100 万人尚未确诊。糖尿病会增加患心脏病、中风、肾病和失明的风险，并导致预期寿命缩短长达 10 年。它还消耗了英国约10%的直接医疗费用。如果我们要减轻糖尿病造成的严重社会经济影响，并开发新的更好的治疗方法，就必须更清楚地了解所涉及的潜在分子机制。该提案的总体目标是产生这些知识并确定治疗药物开发的新途径和靶点。2 型糖尿病的特点是血糖水平长期升高（慢性高血糖），这是由于胰腺 β 细胞分泌胰岛素激素不足所致。高血糖通过进一步降低β细胞功能和质量来促进糖尿病进展。我们的目标是了解慢性高血糖如何损害 β 细胞功能和质量，从而加速 β 细胞衰退。目前缺乏此类基础知识，但有潜力改变治疗方法，促进开发旨在改善胰岛素分泌和保护 β 细胞功能的新药物。众所周知，葡萄糖（糖）必须被代谢才能刺激胰岛素分泌。包括我们自己的实验室在内的多个实验室之前的工作表明，这是因为一种称为 ATP 的葡萄糖代谢物调节 β 细胞膜上称为 KATP 通道的小孔的活动。当这个毛孔打开时，胰岛素不会被释放。血糖急剧升高导致 ATP 生成、KATP 通道关闭和胰岛素释放。然而，研究表明，血糖长期升高会对 β 细胞代谢产生不利影响，导致 ATP 生成失败和 KATP 通道关闭。因此，胰岛素分泌被阻止。我们最近的研究表明这是因为高血糖导致代谢基因表达的显着变化。为什么会发生这种情况尚不清楚。我们现在的目标是准确了解慢性高血糖（如糖尿病中发生的情况）如何导致 β 细胞代谢、基因和蛋白质表达以及 ATP 产生的变化。了解高血糖如何损害糖尿病中的β细胞功能和质量将为如何预防和/或逆转其有害影响提供新的见解，并且识别所涉及的途径应有助于确定治疗药物开发的具体目标。