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MADISON, Wis. Researchers have discovered a previously unknown way in which pancreatic cells decide how much insulin they secrete. It could provide a promising new target for drug development to increase insulin production in people with type 2 diabetes.
In a couple of articles recently published in Cell metabolism, scientists from the University of Wisconsin-Madison and their colleagues point to a neglected enzyme known as pyruvate kinase as the primary way pancreatic beta cells detect sugar levels and release the appropriate amount of insulin.
From several proof-of-concept experiments on rodents and human pancreatic cells, the team found that drugs that stimulate pyruvate kinase not only increase insulin secretion, but have other metabolically protective effects in the liver, muscles and red blood cells. . The findings suggest that pyruvate kinase activation could be a new way to increase insulin secretion to tackle type 2 diabetes, but more research would be needed before new treatments are available.
“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 who led the work. “The question we’re asking here is: how do nutrients like glucose and amino acids activate beta cells in the pancreas to release the right amount of insulin?”
The work was accomplished by carefully analyzing the paradoxical timing of key biochemical events in the prevailing understanding of how pancreatic beta cells respond to nutrients in the blood. Researchers point to a new and richer model for understanding how this important process that resolves these inconsistencies is controlled.
For decades, scientists have believed that mitochondria, the energy generators in cells, initiate insulin secretion. It was a natural explanation, because mitochondria produce the high-energy molecule ATP, in the process that depletes the low-energy version of ATP, ADP. The drop in ADP stimulates calcium, the ultimate trigger for the release of stored insulin.
But the timing didn’t make sense. Mitochondria are most active after insulin secretion has already started, not before. Furthermore, the mitochondria would stop short before running out of enough ADP to trigger insulin secretion.
A clue to these apparent paradoxes came from studies of heart muscle cells in the 1980s. At the time, scientists found that the pyruvate kinase enzyme, which converts sugar into energy, independent of mitochondria, could also severely reduce ADP. This process occurs near the ADP-sensitive proteins involved in the release of insulin in the pancreas. Perhaps, the Merrins team thought, the pancreas took advantage of this proximity to fine-tune insulin release.
In the initial experiments, the researchers supplied sugar and ADP to sections of pancreatic cells containing pyruvate kinase. The enzyme absorbed both components, reducing the ADP. Since the pyruvate kinase was located next to the ADP-sensitive protein that triggers insulin secretion, it had a great effect.
“This is one of the important concepts in our article: the location of the metabolism is critical to its function,” says Merrins.
Using mouse and human pancreatic islets, the insulin-releasing clusters of cells, the researchers tried to stimulate pyruvate kinase activity. Drugs that activate the enzyme quadrupled insulin release, but only when there was enough sugar around – a sign that the pyruvate kinase can’t 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,” says Merrins. “Drugs that activate pyruvate kinase strongly increase insulin secretion without causing excessive insulin release which can lead to hypoglycemia.”
In all, they uncovered evidence of a more complex way in which pancreatic beta cells decide when and how much insulin to release, similar to a two-stroke engine. In the first cycle, blood sugar is processed by pyruvate kinase, reducing ADP. The mitochondria maintain the process by feeding the pyruvate kinase even more material, which causes ADP levels to drop, eventually stimulating enough calcium to enter the cell to release insulin.
In the second cycle, the mitochondria move from feeding the pyruvate kinase with the material to producing the high-energy molecule ATP, which is needed to fully release insulin. The process then resets.
In the complementary study, led by Merrins colleagues at Yale University, the researchers examined how pyruvate kinase activators affected metabolism in healthy and obese rats. In a series of experiments, they found that pyruvate kinase activation increases both insulin secretion and insulin sensitivity, improving sugar metabolism in the liver and red blood cells. Such treatments could be useful for people with type 2 diabetes, who do not produce enough insulin and consequently have dysfunctional sugar metabolism.
“The therapeutic idea here is that we could rewire the metabolism to more efficiently trigger insulin secretion while improving the function of other organs,” says Merrins.
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This work was supported in part by the National Institutes of Health (grants R01DK092606, R01DK110181, K08DK080142, UL1RR-0024139, P30DK045735, K01DK101683, R01DK113103, R21AG050135, T01AG062H32.
– Eric Hamilton,
(608) 263-1986,
[email protected]
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