a new target to treat it by stimulating insulin production

THE ESSENTIAL

  • Hitherto unknown, the enzyme pyruvate kinase is thought to help the pancreas to detect the level of glucose in the blood and to secrete the right dose of insulin in patients with type 2 diabetes.
  • This discovery could lead to a drug dedicated to patients affected by diabetes who do not produce enough insulin.

Will diabetic patients soon be able to control their insulin production? While type 2 diabetes affects nearly 3.3 million people in France, or 5% of the population, new work by researchers at the University of Wisconsin-Madison (United States) gives hope for the upcoming exploration of a new therapeutic avenue. In the review Cell Metabolism, they publish two studies in which they explain having identified a hitherto unknown enzyme, pyruvate kinase, capable of helping the beta cells of the pancreas detect sugar levels and thereby release the correct amount of insulin.

A key new enzyme

Type 2 diabetes is a chronic disease caused by a deficit of insulin, a hormone produced by the pancreas that naturally regulates the level of glucose in the blood. Characterized by an abnormally high level of sugar in the blood, type 2 diabetes is regulated by changes in lifestyle, daily blood sugar checks and, where appropriate, by insulin therapy.

The discovery made by researchers at the University of Wisconsin-Madison could help in the development of a new treatment, however. which would stimulate insulin production.

This is said to be made by the enzyme pyruvate kinase which not only increases insulin secretion but has other metabolic protective effects in the liver, muscles and red blood cells. “Too much insulin can drop blood sugar to dangerous levels, and too little insulin can lead to diabetes,” summarizes Matthew Merrins, professor of medicine in the school of medicine and public health, who led the work. The question we’re asking here is: How do nutrients like glucose and amino acids activate pancreatic beta cells to release the amount of insulin they need? “

A release of the right dose of insulin

For decades, scientists believed it was the mitochondria, the energy generators in cells, that initiate insulin secretion. They then discovered that the enzyme pyruvate kinase – which converts sugar into energy, independent of the mitochondria – also played a role in the production of insulin by the pancreas.

In the first experiments, the researchers delivered sugar and ADP – the low-energy molecule produced by mitochondria – to sections of pancreatic cells containing pyruvate kinase. The enzyme then engulfed both components, which depleted ADP. Since the pyruvate kinase was located near the ADP sensing protein which triggers insulin secretion, it had a strong effect. “This is one of the important concepts of our article: the location of the metabolism is essential for its function”, underlines Professor Merrins.

The researchers then conducted new experiments that used pancreatic islets from mice and humans, the groups of cells that release insulin. By trying to stimulate pyruvate kinase activity, they were able to quadruple the production of insulin by pancreatic cells. But only when one condition was present: when there was no more sugar. For researchers, this is a sign that the pyruvate kinase enzyme cannot be forced to release too much insulin.

“Pyruvate kinase doesn’t change the amount of fuel that goes into the cell, it just changes the way that fuel is used, explains Prof. Merrins. Drugs that activate pyruvate kinase strongly stimulate insulin secretion without causing too much insulin release which can lead to hypoglycemia. “

A new therapeutic avenue

In the follow-up study, the researchers examined how pyruvate kinase activators affected metabolism in healthy and obese rats. In a series of experiments, they found that activating pyruvate kinase increased both insulin secretion and insulin sensitivity while improving sugar metabolism in the liver and red blood cells.

According to the authors, these treatments could be Cettet therefore have a dysfunctional sugar metabolism. “The therapeutic idea is to rewire the metabolism to trigger insulin secretion more effectively while improving the functioning of other organs”, concludes Professor Merrins.


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