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A team of researchers from the University of Oxford revealed that glucose metabolites, rather than glucose itself, play a key role in type 2 diabetes. According to the study, high blood glucose reprograms and damages the function of pancreatic beta-cells. As a result, these cells cannot release enough Insulin hormone, leading to the progression of type 2 diabetes. Reducing the rate at which glucose is metabolized could offer a new way to treat the disease.
According to WHO, about 422 million people worldwide have diabetes. A vast majority of them suffer from type 2 diabetes, characterized by hyperglycemia, where high glucose levels circulate in the bloodstream.
Blood glucose is the main source of energy and comes mainly from food intake. Insulin, a hormone made by pancreatic beta cells, helps glucose get into cells to be used for energy. In type 2 diabetes, the body doesn't make enough insulin or doesn't use insulin well. Too much glucose then stays in the blood, and not enough reaches the cells.
While researchers have known that chronically elevated blood sugar leads to a progressive decline in beta-cell function. What they haven't clearly understood was exactly how it damages our insulin-producing beta cells.
A 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 hyperglycemia causes beta-cell failure.
Through a series of cell and animal studies, the researchers discovered it isn't glucose itself that is impairing the function of insulin-producing beta cells but products generated through metabolizing glucose. 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, as well as switch 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.
The team also 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 hyperglycemia.
'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 hypothesized that increasing glucose metabolism would enhance insulin secretion in T2D and glucokinase activators were trialled, with varying results," said Professor Ashcroft
'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.'
The study is published in Nature Communications.
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