An estimated 415 million people globally are living with diabetes. With nearly 5 million people diagnosed with the condition in the UK, it costs the NHS some £10 billion each year. Around 90% of cases are type 2 diabetes (T2D), which is characterised by the failure of pancreatic beta-cells to produce insulin, resulting in chronically elevated blood glucose. T2D normally presents in later adult life, and by the time of diagnosis, as much as 50% of beta cell function has been lost. While researchers have known for some time that chronically elevated blood sugar (hyperglycaemia) leads to a progressive decline in beta-cell function, what exactly causes beta-cell failure in T2D has remained unclear.
Now a new study led by Dr Elizabeth Haythorne and Professor Frances Ashcroft of the Department of Physiology, Anatomy and Genetics at the University of Oxford has revealed how chronic hyperglycaemia causes beta-cell failure. Using both an animal model of diabetes and beta-cells cultured at high glucose, they showed, for the first time, that glucose metabolism, rather than glucose itself, is what drives the failure of beta-cells to release insulin in T2D. Importantly, they also demonstrated that beta-cell failure caused by chronic hyperglycaemia can be prevented by slowing the rate of glucose metabolism.
Professor Ashcroft said: ‘This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.’
The blood glucose concentration is controlled within narrow limits. When blood glucose is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. Chronic elevation of the blood glucose concentration is also dangerous, as it gives rise to the serious complications found in poorly controlled diabetes such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. Insulin, released from pancreatic beta-cells when blood glucose levels rise, is the only hormone that can lower the blood glucose concentration and diabetes (high blood glucose) results if insulin secretion is insufficient. In T2D, the beta-cells are still present (unlike T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Previous work from the Oxford team has shown that chronic hyperglycaemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that prolonged hyperglycaemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage and less insulin secretion - which causes an even greater increase in blood glucose and a further decline in beta-cell function.
Dr Haythorne said: ‘We realised that we next needed to understand how glucose damages beta-cell function, so we can think about how we might stop it and so slow the seemingly inexorable decline in beta-cell function in T2D.’
The team’s new study is important because it shows that a breakdown product of glucose metabolism, rather than glucose itself, is what causes the failure of beta-cells to release insulin in diabetes. High blood glucose levels cause an increased rate of glucose metabolism in the beta-cell which leads to a metabolic bottleneck and the pooling of upstream metabolites. These metabolites switch off the insulin gene, so less insulin is made, as well as switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no longer respond to changes in blood glucose with insulin secretion.
Crucially, the team found that blocking an enzyme called glucokinase, which regulates the first step in glucose metabolism, could prevent the gene changes taking place and maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycaemia.
Professor Ashcroft said: ‘This is potentially a useful way to try to prevent beta-cell decline in diabetes. Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesised that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results.
‘Our data suggests that glucokinase activators could have an adverse effect and, somewhat counter-intuitively, that a glucokinase inhibitor might be a better strategy to treat T2D. Of course, it would be important to reduce glucose flux in T2D to that found in people without diabetes - and no further. But there is a very long way to go before we can tell if this approach would be useful for treating beta-cell decline in T2D. In the meantime, the key message from our study if you have type 2 diabetes is that it is important to keep your blood glucose well controlled.’
