New research has illuminated the key cause of type 2 diabetes, finding that high blood glucose reprograms the metabolism of pancreatic cells.
Around 415 million people globally are living with diabetes. Within this figure, nearly five million people are diagnosed every year in the UK, costing the NHS £10 billion each year. Around 90% of cases are type 2 diabetes, which is characterised by the failure of pancreatic beta-cells to produce insulin, resulting in chronically elevated blood glucose. The cause of type 2 diabetes remained unclear until researchers from the University of Oxford made a striking discovery.
The 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 triggers beta-cell failure, which evidently can be a cause of type 2 diabetes.
The full paper is published in Nature Communications.
Discovering the cause of type 2 diabetes
Glucose metabolites (chemicals produced when glucose is broken down by cells), rather than glucose itself, are a key cause of type 2 diabetes. In this condition, the pancreatic beta-cells do not release enough insulin, which naturally lowers blood glucose levels. This is because glucose metabolite damages pancreatic beta-cell function.
The researchers used both an animal model of diabetes and beta-cells cultured at high glucose, and for the first time, they found that glucose metabolism is what drives the failure of beta-cells to release insulin in type 2 diabetes. Furthermore, the research highlighted 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 damaging effects of chronic hyperglycaemia
Previous work from Oxford researchers has shown that chronic hyperglycaemia damages the ability of the beta-cell to produce insulin and release it when blood glucose levels rise. This suggested that prolonged hyperglycaemia can be a key cause of type 2 diabetes, by initiating beta-cell damage and less insulin secretion.
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.”
However, the new study is critical because it shows that a breakdown product of glucose metabolism, rather than glucose itself, is a cause of type 2 diabetes as a result of beta-cells failure. 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, and 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.
Importantly, the researchers found that blocking an enzyme called glucokinase, which regulates the first step in glucose metabolism, could prevent gene changes from 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 a 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 suggest 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.”