Researchers from the University of Oxford have, for the first time, uncovered the chemicals that reprogramme the metabolism of the pancreatic cells and cause the progression of type 2 diabetes.
Glucose metabolites, produced when glucose is broken down, rather than the glucose itself, have been shown to drive the failure of pancreatic beta-cells. Once damaged, these cells cannot produce insulin, resulting in the onset of type 2 diabetes.
The findings, which are the first to show the cause of beta-cell failure, are published in Nature Communications.
Nearly five million people in the UK have been diagnosed with diabetes, costing the NHS £10bn annually, and 90% of these cases are type 2 diabetes, where the pancreatic beta-cells no longer produce enough insulin to maintain safe blood sugar levels, the University of Oxford said.
Insulin is the only hormone that can lower blood glucose concentration. When levels become chronically high, it can lead to severe complications such as retinopathy, nephropathy, peripheral neuropathy, and cardiac disease. By the time a patient receives a diagnosis of type 2 diabetes, as much as 50% of beta cell function can be lost.
The scientists examined diabetes progression in mice and beta-cells cultured at high glucose. Researchers knew that hyperglycaemia, or chronically elevated blood sugar levels, damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise, but it was unclear what exactly causes the failure of beta-cells in type 2 diabetes.
Dr Paula Haythorne, from the University of Oxford 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 type 2 diabetes.’
High blood glucose levels caused an increased rate of glucose metabolism in beta-cells, leading to a pooling of metabolites. The bottleneck of metabolites switches off the insulin gene, meaning less insulin is produced, and the beta-cells no longer respond to changes in blood glucose levels.
By blocking an enzyme called glucokinase, which is involved in the first step of glucose metabolism, the researchers could prevent the gene from being damaged and maintain insulin production even in chronic high blood sugar levels.
Professor Frances Ashcroft from the University of Oxford said: ‘This suggests a potential way in which the decline in beta-cell function in type 2 diabetes might be slowed or prevented.’
She added: ‘Because glucose metabolism normally stimulates insulin secretion, it was previously hypothesised that increasing glucose metabolism would enhance insulin secretion in type 2 diabetes. Our data suggests that a glucokinase inhibitor might be a better strategy to treat type 2 diabetes.’
This comes after a study this month found that previously undetectable proteins in the blood can be used for early detection of prediabetes, which puts patients at increased risk of developing type 2 diabetes.