December 5, 2022

Research uncovers key cause of kind 2 diabetes

In diabetes, the pancreatic beta-cells usually do not release enough of the body hormone insulin, which lowers blood sugar levels

Blood sugar metabolites (chemicals produced whenever glucose is broken down by cells), rather than glucose alone, have been discovered to be essential to the progression of type 2 diabetes.

In diabetes, the pancreatic beta-cells usually do not release enough of the body hormone insulin, which lowers blood sugar levels. This is because a blood sugar metabolite damages pancreatic beta-cell function.

An estimated 415 million people globally are living with diabetes. Along with nearly 5 million individuals diagnosed with the condition in the UK, this costs the NHS some £ 10 billion every year. Around 90% of cases are type 2 diabetes (T2D), which is characterized by the particular failure of pancreatic beta- cells   to produce insulin, resulting in chronically elevated blood  glucose .

T2D normally presents in later on adult life, and by time of diagnosis, as much as 50 percent of beta cell perform has been lost. While researchers have known for some time that will chronically elevated  blood sugar   (hyperglycemia) results in a progressive decline in beta-cell function, what exactly causes beta-cell failure in T2D has remained unclear.

Now a new study led by Dr . At the Haythorne and Professor Frances Ashcroft of the Department of Physiology, Anatomy and Genetics at the University of Oxford has revealed how persistent hyperglycemia causes beta-cell failing.

Using both an animal model of diabetes plus beta-cells cultured at high glucose, they showed, for the first time, that glucose metabolism, instead of glucose itself, is what drives the failure of beta-cells to release insulin in T2D. Importantly, they also demonstrated that will beta-cell failure caused by chronic hyperglycemia can be prevented simply by slowing the rate of glucose metabolism.

Teacher Ashcroft said, “ This suggests a potential way in which the particular decline in beta-cell perform in T2D might be slowed or prevented. ”

The blood glucose focus is controlled within slim limits. When blood glucose is simply too low for more than few minutes, consciousness is rapidly lost because the brain is starved of fuel. Chronic elevation of the blood glucose concentration is also harmful, as it gives rise to the serious complications found in poorly controlled diabetes such as retinopathy, nephropathy, peripheral neuropathy, and heart disease.

Insulin, released from pancreatic beta-cells when  blood glucose ranges   rise, will be the only hormone that can decrease the blood glucose concentration and diabetes (high blood glucose) results if  insulin secretion   is insufficient. In T2D, the beta-cells are still present (unlike T1D), but they have a reduced insulin content and the coupling between glucose and insulin release is impaired.

Previous work in the Oxford team has shown that will chronic hyperglycemia damages the capability of the beta-cell to produce insulin and to release it whenever blood glucose levels rise. This particular suggested that prolonged hyperglycemia sets off a vicious spiral in which an increase in blood glucose leads to beta-cell damage plus less insulin secretion— which causes an even greater increase in blood glucose as well as a further decline in beta-cell function.

Doctor Haythorne 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. ”

The team’s new study is important because it shows that a breakdown product associated with glucose metabolism, rather than glucose itself, is what causes the failure of beta-cells to release insulin in diabetes. 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 turn off the insulin gene, so less insulin is made, along with switching off numerous genes involved in metabolism and stimulus-secretion coupling. Consequently, the beta-cells become glucose blind and no lengthier respond to changes in  blood   glucose with insulin secretion.

Crucially, the group found that blocking a good enzyme called glucokinase, which usually regulates the first step in glucose metabolism, could prevent the gene changes taking place and maintain glucose-stimulated insulin secretion even in the presence of chronic hyperglycemia.

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 hypothesized that increasing  blood sugar metabolism   would enhance  insulin   secretion in T2D and glucokinase activators had been trialed, with varying results. ”

“ Our data suggests that glucokinase activators could have an adverse impact and, somewhat counter-intuitively, that the glucokinase inhibitor might be a much better strategy to treat T2D. Naturally , it would be important to reduce blood sugar flux in T2D to that found in people without diabetes— and no further. ”

“ But there is a very long way to go before we are able to tell if this approach will be useful for treating beta-cell decline in T2D. In the meantime, the main element message from our study in case you have type 2  diabetes   is that it is essential to keep your  blood sugar   well managed. ”

The research was published in  Nature Communications .

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