Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway

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. [Display omitted] •Pyruvate kinase (PK) is a highly compartmentalized β cell fuel sensor•Membrane-associated PK closes KATP channels and controls calcium influx•By lowering ADP, PK toggles mitochondria between OxPhos and PEP biosynthesis•PK activation increases oscillatory frequency and amplifies insulin secretion Lewandowski et al. demonstrate that pyruvate kinase, rather than oxidative phosphorylation, is the ATP/ADP generator that closes β cell KATP channels to initiate insulin secretion. Small-molecule activators of pyruvate kinase potently amplify insulin secretion by switching mitochondria from oxidative phosphorylation to anaplerotic phosphoenolpyruvate biosynthesis.