Chronic hyperglycaemia and impaired pancreatic beta-cell function.

糖尿病影响着全球4.25亿人，每6秒就有一人死亡。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100万人未确诊。糖尿病会增加心脏病、中风、肾病和失明的风险，并使预期寿命减少长达10年。它还消耗了英国约10%的直接医疗成本。如果我们要改善糖尿病严重的社会经济影响，并开发新的更好的治疗方法，那么更清楚地了解相关的潜在分子机制是至关重要的。这项建议的总体目标是产生这种知识，并为治疗药物开发确定新的途径和靶点。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细胞分泌的胰岛素激素不足造成的。高血糖会进一步降低β细胞的功能和质量，从而加剧糖尿病的进展。我们的目标是了解慢性高血糖如何损害胰岛细胞的功能和质量，从而加速胰岛细胞的衰退。这些基础知识目前尚缺乏，但有可能改变治疗方法，促进以改善胰岛素分泌和保护β细胞功能为目标的新药的开发。众所周知，葡萄糖(糖)必须经过代谢才能刺激胰岛素的分泌。包括我们自己在内的几个实验室此前的研究表明，这是因为一种名为ATP的葡萄糖代谢物调节着β细胞膜上名为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。血糖的急剧升高导致ATP生成、KATP通道关闭和胰岛素释放。然而，研究表明，慢性血糖升高会对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，胰岛素的分泌被阻止了。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还不得而知。我们现在的目标是准确地了解慢性高血糖是如何导致β细胞代谢、基因和蛋白质表达以及ATP产生的变化的，就像糖尿病一样。了解高血糖如何损害糖尿病患者的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，而相关途径的识别将有助于准确定位治疗药物开发的特定靶点。

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.