Chronic hyperglycaemia and impaired pancreatic beta-cell function.

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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.