[PDF][PDF] Pyruvate kinase controls signal strength in the insulin secretory pathway

SL Lewandowski, RL Cardone, HR Foster, T Ho… - Cell metabolism, 2020 - cell.com
SL Lewandowski, RL Cardone, HR Foster, T Ho, E Potapenko, C Poudel, HR VanDeusen…
Cell metabolism, 2020cell.com
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.
Plasma membrane-localized PK is sufficient to close K ATP channels and initiate calcium
influx. Small-molecule PK activators increase the frequency of ATP/ADP and calcium
oscillations and potently amplify insulin secretion. PK restricts respiration by cyclically …
Summary
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. Plasma membrane-localized PK is sufficient to close KATP channels and initiate calcium influx. Small-molecule PK activators increase the frequency of ATP/ADP and calcium oscillations and potently amplify insulin secretion. PK restricts respiration by cyclically depriving mitochondria of ADP, which accelerates PEP cycling until membrane depolarization restores ADP and oxidative phosphorylation. Our findings support a compartmentalized model of β cell metabolism in which PK locally generates the ATP/ADP required for insulin secretion. Oscillatory PK activity allows mitochondria to perform synthetic and oxidative functions without any net impact on glucose oxidation. These findings suggest a potential therapeutic route for diabetes based on PK activation that would not be predicted by the current consensus single-state model of β cell function.
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