Science

Type 2 Diabetes: Researchers Finally Find the Real Cause

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Although it has been known for decades that type 2 diabetes is caused by chronic hyperglycemia, the exact mechanisms that cause damage to insulin-producing cells are still unclear. This misunderstanding has led to the development of treatments that are mostly palliative in nature and that patients are forced to follow for life. A new preliminary study, contrary to common sense, suggests that type 2 diabetes is caused by glucose metabolites, not glucose itself. Ultimately, this discovery may lead to the development of more effective treatment strategies for this disease.

Worldwide, about 415 million people live with diabetes, the causes of which may be genetic or dietary related. The vast majority of cases are type 2 diabetes, which is characterized, in particular, by insufficient production of insulin in the cells of the pancreas. Remember that the difference with type 1 is that the insulin-producing cells function more or less normally, but are ineffective in controlling blood sugar levels. In type 1 diabetes, the production of the regulatory hormone is simply absent.

Type 2 diabetes symptoms usually come and go with age, and by the time patients are diagnosed, they have usually already lost up to 50% of the function of the pancreatic beta cells thought to produce insulin. Insulin naturally controls blood sugar so it doesn’t get too high or too low. Chronic hyperglycemia caused by a defect in insulin production can lead to serious complications such as retinopathy, nephropathy, peripheral neuropathy, and heart disease, and hypoglycemia can cause varying degrees of discomfort (with or without loss of consciousness).

Thus, it is known that chronic hyperglycemia is closely associated with a decrease in the number of pancreatic beta cells, interfering with their production of insulin and increasing downstream glycemia and, more importantly, glycemia, which in turn leads to further damage to more cells. pancreas. However, the exact mechanisms causing this damage cascade are still not understood.

“We realized that we then needed to understand how glucose damages beta cell function so that we can think about how we can stop this and thereby slow the seemingly inexorable decline in beta cell function in T2DM,” explains Elizabeth Haythorne in a press release. , professor in the Department of Physiology, Anatomy and Genetics at the University of Oxford and lead author of a new study published in Nature Communications.

The researchers found that the destruction of pancreatic cells was caused by glucose metabolites (rather than glucose itself), even when blood levels were high. Intervention in this metabolic process can lead to a better strategy for treating the disease.

Glucokinase inhibition may be key

In their experiments, the scientists used animal models and isolated pancreatic beta cells in high-glucose cultures. Once produced by cellular metabolism, glucose metabolites have been shown to trigger a process that damages these cells. Therefore, this damage could be prevented by slowing down the rate of glucose metabolism.

Although hyperglycemia leads to increased metabolic activity, researchers have found that blocking glucokinase prevents the synthesis of metabolites. These metabolites deactivate the gene responsible for activating insulin production, in addition to deactivating many other genes that stimulate hormone secretion (so beta cells become glucose insensitive).

On the other hand, glucokinase is an enzyme that regulates the first step in glucose metabolism and thereby lowers blood sugar levels. However, surprisingly, enzyme inhibition increased insulin production in animal models. Thus, this inhibition can prevent the genetic process of glucose metabolism while maintaining normal insulin levels even in the case of chronic hyperglycemia.

“Our data suggest that glucokinase activators may have adverse effects and, somewhat paradoxically, glucokinase inhibitors may be the best strategy for treating type 2 diabetes,” says Francis Ashcroft, professor in the same department as Haythorne and co-author of the study. new research.

However, researchers have yet to determine the exact metabolites responsible for this genetic process that damages beta cells. Pending further results and then clinical consequences, the best option remains strict control of blood sugar through a healthy diet or insulin injections in more severe cases. “Of course, it would be important to reduce the flow of glucose to match that seen in people without diabetes,” notes Ashcroft.

Nature Communications.

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