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“Reconnecting” metabolism in insulin-producing cells may help the treatment of type 2 diabetes-health | Instant News


Researchers have discovered a previously unknown method by which pancreatic cells determine how much insulin they secrete.It could provide a promising new target to develop drugs to increase insulin production in diabetic patients Type 2 diabetes.

In two recently published papers Cell metabolismScientists at the University of Wisconsin-Madison and their colleagues pointed out that an overlooked enzyme called pyruvate kinase is the main way for pancreatic beta cells to sense sugar levels and release the right amount of insulin.

Through several proof-of-concept experiments conducted on rodent and human pancreatic cells, the research team found that drugs that stimulate pyruvate kinase not only increase insulin secretion, but also have other metabolic protective effects on the liver, muscles, and red blood cells. Research results indicate that activation of pyruvate kinase may be a new way to increase insulin secretion to fight type 2 diabetes, but more research is needed before any new treatments are available.

Matthew Merrins, professor of medicine at the University of Western Australia School of Medicine and School of Public Health, who is in charge of this work, said: “Too much insulin will lower blood sugar to dangerous levels, and too much insulin can lead to diabetes.” The question to ask is: How do nutrients such as glucose and amino acids open up the beta cells in the pancreas to release the right amount of insulin?”

This work is based on a careful analysis of the contradictory timing of key biochemical events, when it was generally understood how pancreatic beta cells respond to nutrients in the blood. The researchers pointed out a new and richer model to understand how to control this important process to resolve these contradictions.

For decades, scientists have believed that mitochondria, the energy generators in cells, trigger insulin secretion. This is a natural explanation, because mitochondria produce the high-energy molecule ATP, and in the process deplete the low-energy form of ATP, ADP. The decline in ADP stimulates calcium, the ultimate trigger for the release of stored insulin.

But time makes no sense. Mitochondria are most active when insulin secretion has already begun, not before. In addition, the mitochondria will stall before they exhaust enough ADP to trigger insulin secretion.

The clues to resolve these obvious paradoxes came from the study of cardiomyocytes in the 1980s. At the time, scientists discovered that pyruvate kinase (which converts sugar into energy and does not rely on mitochondria) may also severely deplete ADP. This process occurs near the ADP sensor protein involved in insulin release in the pancreas. Mellins’ team believes that perhaps the pancreas uses this proximity to fine-tune insulin release.

In the initial experiment, the researchers provided sugar and ADP to pancreatic cell slices containing pyruvate kinase. Enzymes engulf these two components and deplete ADP. Since pyruvate kinase is located near the ADP sensor protein that triggers insulin secretion, it has a great effect.

“This is one of the important concepts in our paper: The location of the metabolism is critical to its function,” Merrins said.

The researchers used mouse and human islets, clusters of cells that release insulin, to try to stimulate the activity of pyruvate kinase. The drug that activates this enzyme increases the release of insulin four-fold, but only if there is enough sugar around-pyruvate kinase cannot be forced to release too much insulin.

Merrins said: “Pyruvate kinase does not change the amount of fuel that enters the cell, but only changes the way the fuel is used.” “Drugs with active pyruvate kinase can strongly promote insulin secretion without causing excessive insulin release. Hypoglycemia.”

Overall, they found a more complicated way, which is evidence of how pancreatic beta cells decide when and how much insulin they release, similar to a two-stroke engine. In the first cycle, pyruvate kinase processes blood sugar and consumes ADP. Mitochondria maintain this process by supplying more material to pyruvate kinase, which can cause ADP levels to collapse and ultimately stimulate enough calcium to enter the cell to release insulin.

In the second cycle, mitochondria transition from adding material to pyruvate kinase to producing the high-energy molecule ATP, which is necessary for the complete release of insulin. Then, the process will reset.

In an accompanying study by colleagues at Yale University Mellins, researchers studied how pyruvate kinase activator affects the metabolism of healthy and obese rats. In a series of experiments, they found that activating pyruvate kinase can increase insulin secretion and insulin sensitivity, while improving glucose metabolism in the liver and red blood cells. This type of treatment may be useful for patients with type 2 diabetes, who cannot produce enough insulin and therefore have abnormal glucose metabolism.

Mellins said: “The therapeutic idea here is that we can rearrange our metabolism to trigger insulin secretion more effectively while improving the function of other organs.

(This story was posted from a telecommunications company feed and has not been modified.)

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