Team identifies key cause of type 2 diabetes
Tuesday November 15th 2022
Glucose metabolites have been identified as a key cause of type 2 diabetes, a new University of Oxford study has found.
While it is already known that hyperglycaemia leads to a progressive decline in beta-cell function, the cause of beta-cell failure in type 2 diabetes (T2D) was unclear, researchers say.
Research led by Dr Elizabeth Haythorne and Professor Frances Ashcroft of the Department of Physiology, Anatomy and Genetics at the University of Oxford has shown for the first time that glucose metabolism, rather than glucose itself, is what drives the failure of beta-cells to release insulin in T2D.
Writing in the latest Nature Communications, they also demonstrate that beta-cell failure caused by chronic hyperglycaemia can be prevented by slowing the rate of glucose metabolism.
This new study complements previous work by the Oxford team, which showed that chronic hyperglycaemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise.
This, said the researchers, suggested 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 found that high blood glucose levels cause an increased rate of glucose metabolism in the beta-cell. This leads to a metabolic bottleneck and the pooling of upstream metabolites, which switch off the insulin gene, which results in less insulin being made and the switching off of several genes involved in metabolism and stimulus-secretion coupling.
This results in the beta-cells becoming glucose blind, which means they can no longer respond to changes in blood glucose with insulin secretion.
When they blocked glucokinase, an enzyme that regulates the first step in glucose metabolism, it prevented the gene changes taking place and maintained 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."
Haythorne E, Lloyd M, Walsby-Tiuckle J et al. Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic ?-cells. Nature Communications 14 November 2022; doi: 10.1038/s41467-022-34095-x
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