Understanding of the key mechanisms underlying the progression of type 2 diabetes has been advanced by new research from Oxford (England) University suggesting potential ways to “slow the seemingly inexorable decline in beta-cell function in T2D”.
The study in mice elucidated a “key cause” of T2D by showing that
Scientists already knew that chronic hyperglycemia leads to a progressive decline in beta-cell function and, conversely, that the failure of pancreatic beta-cells to produce insulin results in chronically elevated blood glucose. However, the exact cause of beta-cell failure in T2D has remained unclear. T2D typically presents in later adult life, and by the time of diagnosis as much as 50% of beta-cell function has been lost.
In the United Kingdom there are nearly 5 million people diagnosed with T2D, which costs the National Health Service some £10 billion annually.
Glucose metabolites, rather than glucose itself, drives failure of cells to release insulin
The new study, published in, used both an animal model of diabetes and in vitro culture of beta-cells in a high glucose medium. In both cases the researchers showed, for the first time, that it is glucose metabolites, rather than glucose itself, that drives the failure of beta-cells to release insulin and is key to the progression of type 2 diabetes.
Senior researcher Frances Ashcroft, PhD, of the department of physiology, anatomy and genetics at the University of Oxford said: “This suggests a potential way in which the decline in beta-cell function in T2D might be slowed or prevented.”
Blood glucose concentration is controlled within narrow limits, the team explained. When it is too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. However chronic elevation of blood glucose leads 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 insufficient secretion results in diabetes. In T2D, the beta-cells are still present (unlike in T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.
Vicious spiral of hyperglycemia and beta-cell damage
Previous work by the same team had shown that chronic hyperglycemia damages the ability of the beta-cell to produce insulin and to release it when blood glucose levels rise. This suggested that “prolonged hyperglycemia 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,” the team explained.
Lead researcher Elizabeth Haythorne, PhD, said: “We realized 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.”
In the new study, they showed that altered glycolysis in T2D occurs, in part, through marked up-regulation of mammalian target of rapamycin complex 1 (mTORC1), a protein complex involved in control of cell growth, dysregulation of which underlies a variety of human diseases, including diabetes. Up-regulation of mTORC1 led to changes in metabolic gene expression, oxidative phosphorylation and insulin secretion. Furthermore, they demonstrated that reducing the rate at which glucose is metabolized and at which its metabolites build up could prevent the effects of chronic hyperglycemia and the ensuing beta-cell 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,” the team said. “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.”