For the first time, researchers have discovered an enzyme capable of telling pancreatic cells how much insulin to detect. A valuable advance that could benefit patients with type 2 diabetes by developing drugs that would stimulate their insulin production.
- Until now unknown, the enzyme pyruvate kinase would 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 and 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 carried out by researchers from the University of Wisconsin-Madison (United States) gives hope for the forthcoming exploration of a new therapeutic avenue. In the review Cell Metabolismthey publish two studies in which they explain that they have identified a hitherto unknown enzyme, pyruvate kinase, capable of helping pancreatic beta cells to detect sugar levels and thus release the appropriate amount of insulin.
A new key enzyme
Type 2 diabetes is a chronic disease caused by a lack of insulin, a hormone produced by the pancreas that naturally regulates blood glucose levels. Characterized by an abnormally high level of sugar in the blood, type 2 diabetes is regulated by a change in lifestyle, daily glycemic controls and, if necessary, by insulin therapy.
The discovery made by researchers at the University of Wisconsin-Madison could, however, help in the development of a new treatment that would stimulate the production of insulin.
This is believed to be done by the enzyme pyruvate kinase which not only increases insulin secretion but has other metabolic protective effects in liver, muscle 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 at 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 initiated insulin secretion. They then discovered that the enzyme pyruvate kinase – which converts sugar into energy, independently of the mitochondria – also plays a role in the production of insulin by the pancreas.
In early 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 the two components, which depleted the ADP. Since pyruvate kinase was located near the ADP-sensing protein that triggers insulin secretion, it had a strong effect. “This is one of the important concepts of our article: the localization of metabolism is essential to its function”underlines Professor Merrins.
The researchers then conducted new experiments that used mouse and human pancreatic islets, the groups of cells that release insulin. By trying to stimulate the activity of pyruvate kinase, they succeeded in quadrupling the production of insulin by the pancreatic cells. But only when one condition was present: when there was no more sugar. For the researchers, this is a sign that the enzyme pyruvate kinase cannot be forced to release too much insulin.
“Pyuvate kinase doesn’t change the amount of fuel that goes into the cell, it just changes how that fuel is used, explains Professor Merrins. Drugs that activate pyruvate kinase strongly stimulate insulin secretion without causing too much insulin release that can lead to hypoglycemia.”
A new therapeutic avenue
In the companion study, the researchers looked at 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 Thisand therefore have a dysfunctional sugar metabolism. “The therapeutic idea is to rewire the metabolism to trigger insulin secretion more efficiently while improving the functioning of other organs”concludes Professor Merrins.
.