Medical

Rewiring the metabolism of pancreatic cells may keep diabetes in check

Rewiring the metabolism of pan...
Scientists have discovered a new way insulin secretion is controlled via pancreatic cells, opening new avenues for the development of treatments for diabetes
Scientists have discovered a new way insulin secretion is controlled via pancreatic cells, opening new avenues for the development of treatments for diabetes
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Scientists have discovered a new way insulin secretion is controlled via pancreatic cells, opening new avenues for the development of treatments for diabetes
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Scientists have discovered a new way insulin secretion is controlled via pancreatic cells, opening new avenues for the development of treatments for diabetes

Through a newfound understanding of the way insulin secretion is triggered in pancreatic cells, scientists at the University of Wisconsin-Madison have uncovered an exciting new pathway for the development of treatments for type 2 diabetes. Not only does the discovery shine a light on how the cells work to keep blood sugar in check, the team was able to demonstrate how the mechanism could be targeted with a certain enzyme to hold it at healthy levels.

For sufferers of type 2 diabetes, insulin deficiency is brought on by the gradual deterioration of pancreatic beta cells, which would normally secrete the hormone to regulate levels of glucose in the blood. The research carried out by the UW-Madison team sought to better understand how these beta cells are able to sense blood glucose levels and respond by producing insulin in just the right quantities.

“Too much insulin can lower blood sugar to dangerous levels, and too little insulin can lead to diabetes,” says Matthew Merrins, a professor of medicine at the UW School of Medicine and Public Health. “The question we’re asking here is: How do nutrients like glucose and amino acids turn on beta cells in the pancreas to release just the right amount of insulin?”

According to the team, the commonly held belief over the past few decades has been that mitochondria are responsible for initiating the secretion of insulin. Often described as the powerhouse of cells, mitochondria break down nutrients and generate energy-rich molecules such as ATP, which at the same time depletes stocks of a low-energy molecule called ADP. It was thought that this see-sawing of molecules was what led to the triggering of stored insulin.

But the UW-Madison team suspected something else might be at play, because they knew mitochondria to be most active after insulin secretion has kicked off, rather than before. Turning to studies from the 1980s on heart muscle cells, the team learned how an enzyme called pyruvate kinase, entirely unrelated to mitochondria, can also convert sugar into energy and severely deplete ADP.

This process takes place close to proteins in the pancreas that can sense ADP and are involved in insulin release themselves, so the team suspected that pyruvate kinase could be implicated in the secretion of insulin. To start with, they ran experiments where sugar and ADP molecules were fed to parts of pancreatic cells containing the pyruvate kinase enzyme, which promptly gobbled them up and depleted the ADP. They found that as this happened, the nearby ADP-sensing protein responded by triggering insulin secretion.

“That’s one of the important concepts in our paper: the location of metabolism is critical to its function,” says Merrins.

Further experiments followed on mice and human cells, in which drugs were used to stimulate pyruvate kinase activity, which led to a quadrupling in the release of insulin. Interestingly, this only happened when there were appropriate levels of sugar around, which bodes well for the potential of this technique to translate into a safe form of therapy.

“Pyruvate kinase doesn’t change how much fuel comes into the cell, it just changes how that fuel is used,” says Merrins. “Drugs that active pyruvate kinase strongly boost insulin secretion without causing too much insulin release that can lead to hypoglycemia.”

In a companion study led by scientists at Yale University, researchers examined these mechanisms in healthy and obese rats. Here they found that by activating pyruvate kinase, they could boost insulin secretion and insulin sensitivity, which also had the effect of improving sugar metabolism in the rodents’ livers and red blood cells.

“The therapeutic idea here is we could rewire metabolism to more efficiently trigger insulin secretion while improving the function of other organs at the same time,” says Merrins.

The two papers detailing the research were published in the journal Cell (1, 2).

Source: University of Wisconsin-Madison

2 comments
Lawdog
Or, you know, just exercise.
Karmudjun
In other words biochemists and medical personnel are on the same page now.

Back in the day when I learned biochemistry, pyruvate kinase was considered a gateway step for fueling the mitochondria 'powerhouse'. An increase in ADP/ATP ratio (ATP depletion) was said to prompt glucose release from the liver and a rise in mitochondrial function - insulin is the key required to unlock the glucose transport into muscle cells. So the presence of blood sugar in blood through the pancreas leads to a release of insulin. Pyruvate Kinase yields Pyruvate which is THEN transported into the mitochondria as Acetyl-CoA, the fuel of the mitochondria's energy pathways. Why would anyone say the mitochondria signals Insulin release???? Maybe if a signalling molecule were released by the mitochondria - but we knew the pancreas responds to precurser molecules like glucose......So this is news? It only sounds confirmatory...I'm lost on this 'breakthrough'.