RT Journal Article
SR Electronic
T1 Pyruvate kinase controls signal strength in the insulin secretory pathway
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.01.15.907790
DO 10.1101/2020.01.15.907790
A1 Sophie L. Lewandowski
A1 Rebecca L. Cardone
A1 Hannah R. Foster
A1 Thuong Ho
A1 Evgeniy Potapenko
A1 Chetan Poudel
A1 Halena R. VanDeusen
A1 Tiago C. Alves
A1 Xiaojian Zhao
A1 Megan E. Capozzi
A1 Ishrat Jahan
A1 Craig S. Nunemaker
A1 Jonathan E. Campbell
A1 Craig J. Thomas
A1 Richard G. Kibbey
A1 Matthew J. Merrins
YR 2020
UL http://biorxiv.org/content/early/2020/01/15/2020.01.15.907790.abstract
AB 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 KATP 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.GRAPHICAL ABSTRACTThe 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 et al. 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.HIGHLIGHTSCompartmentalized pyruvate kinase (PK) activity underlies β-cell fuel sensingMembrane-associated PK closes KATP channels and controls calcium influxBy lowering ADP, PK toggles mitochondria between OxPhos and PEP biosynthesisPharmacologic PK activation increases oscillatory frequency and amplifies secretion