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Pyruvate kinase enzyme could be new target for treating T2DM

Mon, 11/16/2020 - 12:03
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Researchers have discovered a previously unknown way that pancreatic cells decide how much insulin to secrete, which could provide a promising new target to develop drugs for boosting insulin production in people with T2DM. In two papers published in Cell Metabolism, scientists from the University of Wisconsin-Madison and their colleagues point to an overlooked enzyme known as pyruvate kinase as the primary way pancreatic beta cells sense sugar levels and release the appropriate amount of insulin.


"Too much insulin can lower blood sugar to dangerous levels, and too little insulin can lead to diabetes," explained Dr 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 turn on beta cells in the pancreas to release just the right amount of insulin?"



However, the timing did not make sense - mitochondria are most active after insulin secretion has already begun, not before. Plus, mitochondria would stall out before exhausting enough ADP to trigger insulin secretion.

A clue to solving these apparent paradoxes came from studies in the 1980s on heart muscle cells. At the time, scientists found that the enzyme pyruvate kinase (which converts sugar into energy, independently of mitochondria) could also severely deplete ADP. This process happens near ADP-sensing proteins involved in insulin release in the pancreas. Maybe, Merrins' team thought, the pancreas took advantage of this proximity to fine-tune the release of insulin.


"That's one of the important concepts in our paper, the location of metabolism is critical to its function," added Merrins.

In the study, ‘Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway’, using mouse and human pancreatic islets, the clusters of cells that release insulin, the researchers tried stimulating pyruvate kinase activity. Drugs that activate the enzyme quadrupled the release of insulin, but only when there was enough sugar around, a sign that pyruvate kinase cannot be forced to release too much insulin.

"Pyruvate kinase does not change how much fuel comes into the cell, it just changes how that fuel is used," explained Merrins. "Drugs that active pyruvate kinase strongly boost insulin secretion without causing too much insulin release that can lead to hypoglycaemia."



In the second study, ‘Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health’, 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 activating pyruvate kinase increased both insulin secretion and insulin sensitivity while improving sugar metabolism in liver and red blood cells. Such treatments could be helpful for people with Type 2 diabetes, who do not produce enough insulin and have dysfunctional sugar metabolism as a result.
