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• W2079915433 abstract "<h3>SUMMARY</h3> Pancreatic β-cells couple nutrient metabolism with appropriate insulin secretion. Here, we show that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) into ATP and pyruvate, underlies β-cell sensing of both glycolytic and mitochondrial fuels. PK present at the plasma membrane is sufficient to close K_ATP channels and initiate calcium influx. Small-molecule PK activators increase β-cell oscillation frequency and potently amplify insulin secretion. By cyclically depriving mitochondria of ADP, PK restricts oxidative phosphorylation in favor of the mitochondrial PEP cycle with no net impact on glucose oxidation. Our findings support a compartmentalized model of β-cell metabolism in which PK locally generates the ATP/ADP threshold required for insulin secretion, and identify a potential therapeutic route for diabetes based on PK activation that would not be predicted by the β-cell consensus model. <h3>GRAPHICAL ABSTRACT</h3> The consensus model for β-cell glucose sensing supports a dominant role for OxPhos. This model doesn’t fully explain the observed metabolic and electrophysiologic oscillations associated with glucose-stimulated insulin secretion. Lewandowski <i>et al</i>. challenge this model by mechanistically connecting the anaplerotic PEP cycle to the electrically silent triggering phase, and OxPhos to the electrically active secretory phase. Here, the allosteric recruitment of pyruvate kinase directs metabolic traffic between the two cycles and identifies potential therapeutic strategies for diabetes based on pharmacologic pyruvate kinase activation. <h3>HIGHLIGHTS</h3> Compartmentalized pyruvate kinase (PK) activity underlies β-cell fuel sensing Membrane-associated PK closes K_ATP channels and controls calcium influx By lowering ADP, PK toggles mitochondria between OxPhos and PEP biosynthesis Pharmacologic PK activation increases oscillatory frequency and amplifies secretion" @default.
• W2079915433 created "2016-06-24" @default.
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• W2079915433 date "1983-07-01" @default.
• W2079915433 modified "2023-10-10" @default.
• W2079915433 title "The bronchial response to cold air challenge: evidence for different mechanisms in normal and asthmatic subjects." @default.
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• W2079915433 doi "https://doi.org/10.1136/thx.38.7.506" @default.
• W2079915433 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/459596" @default.
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