Oxford Research has reveals how high blood glucose reprograms the metabolism of pancreatic beta-cells in diabetes, acting as a major causal factor of Type 2 diabetes. This is significant because glucose metabolites (chemicals produced when glucose is broken down by cells), rather than glucose itself, have been discovered to be key to the progression of Type 2 diabetes.
With diabetes, the pancreatic beta-cells do not release enough of the hormone insulin, which lowers blood glucose levels. This is because a glucose metabolite damages pancreatic beta-cell function. 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.
Around 90 percent of global cases of diabetes are Type 2 diabetes (T2D). T2D normally presents in later adult life, and by the time of diagnosis, as much as 50 percent of beta cell function has been lost. In T2D, the beta-cells have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Scientists have previously established that chronically elevated blood sugar (hyperglycaemia) leads to a progressive decline in beta-cell function. 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. However, as to what exactly causes beta-cell failure in T2D has remained unclear.
The new study reveals how chronic hyperglycaemia causes beta-cell failure. This was demonstrated using both an animal model of diabetes and beta-cells cultured at high glucose. Both experiments showed that glucose metabolism, rather than glucose itself, is the factor that drives the failure of beta-cells to release insulin in T2D.
The significance of the research in terms of medical understanding is that by reducing the rate at which glucose is metabolised, and the rate at which these glucose metabolites build up, can prevent the effects of hyperglycaemia. This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.
The researchers found that blocking an enzyme called glucokinase, which regulates the first step in glucose metabolism, holds the potential to prevent the gene changes taking place and maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycaemia. This is potentially a useful way to try to prevent beta-cell decline in diabetes.
The research appears in the journal Nature Communications, titled “Altered glycolysis triggers impaired mitochondrial metabolism and mTORC1 activation in diabetic β-cells”.