2022
β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channel
Foster HR, Ho T, Potapenko E, Sdao SM, Huang SM, Lewandowski SL, VanDeusen HR, Davidson SM, Cardone RL, Prentki M, Kibbey RG, Merrins MJ. β-cell deletion of the PKm1 and PKm2 isoforms of pyruvate kinase in mice reveals their essential role as nutrient sensors for the KATP channel. ELife 2022, 11: e79422. PMID: 35997256, PMCID: PMC9444242, DOI: 10.7554/elife.79422.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine DiphosphateAdenosine TriphosphateAmino AcidsAnimalsMiceNutrientsProtein IsoformsPyruvate KinaseConceptsPyruvate kinaseATP/ADPCytosolic ATP/ADPAmino acidsPKM2 isoformPK isoformsPlasma membraneNutrient sensorNutrient responsesPEP carboxykinasePKM1Mitochondrial sourcesPKM2Channel closureEssential roleInsulin secretionDifferential responsePK activityKinaseMembrane depolarizationIsoformsDeletionATPKey roleADP
2020
Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health
Abulizi A, Cardone RL, Stark R, Lewandowski SL, Zhao X, Hillion J, Ma L, Sehgal R, Alves TC, Thomas C, Kung C, Wang B, Siebel S, Andrews ZB, Mason GF, Rinehart J, Merrins MJ, Kibbey RG. Multi-Tissue Acceleration of the Mitochondrial Phosphoenolpyruvate Cycle Improves Whole-Body Metabolic Health. Cell Metabolism 2020, 32: 751-766.e11. PMID: 33147485, PMCID: PMC7679013, DOI: 10.1016/j.cmet.2020.10.006.Peer-Reviewed Original ResearchConceptsInsulin secretionInsulin sensitivityPK activatorWhole-body metabolic healthPK activationMetabolic homeostasisPeripheral insulin sensitivityHFD-fed ratsEndogenous glucose productionPreclinical rodent modelsHigher insulin contentPreclinical rationaleLiver fatMetabolic healthMarkers of differentiationIslet functionRodent modelsGlucose homeostasisInsulin contentPancreatic isletsGlucose productionGlucose turnoverMitochondrial PEPCKSecretionHomeostasisPyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway
Lewandowski SL, Cardone RL, Foster HR, Ho T, Potapenko E, Poudel C, VanDeusen HR, Sdao SM, Alves TC, Zhao X, Capozzi ME, de Souza AH, Jahan I, Thomas CJ, Nunemaker CS, Davis DB, Campbell JE, Kibbey RG, Merrins MJ. Pyruvate Kinase Controls Signal Strength in the Insulin Secretory Pathway. Cell Metabolism 2020, 32: 736-750.e5. PMID: 33147484, PMCID: PMC7685238, DOI: 10.1016/j.cmet.2020.10.007.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell LineHumansInsulinInsulin SecretionMaleMiceMice, Inbred C57BLPyruvate KinaseConceptsPyruvate kinaseATP/ADPΒ-cell metabolismAppropriate insulin secretionPotential therapeutic routeSecretory pathwayMitochondrial fuelsPancreatic β-cellsInsulin secretory pathwayOxidative phosphorylationCell metabolismNutrient metabolismPhosphoenolpyruvateCell sensingPK activatorΒ-cellsCell functionInsulin secretionPK activityOxidative functionMembrane depolarizationMitochondriaPK activationΒ-cell functionADP
2019
Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
Gassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production. Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinasesMetabolic control pointPhosphorylation sitesNuclear retentionCDK activityPKL activityDays high-fat dietKinase phosphorylationImportant enzymePyruvate kinaseHigh-fat dietS113KinaseEnzyme kineticsPhosphorylationAdditional control pointsRegulationGlucose productionHepatic glucose productionInsulin resistanceGlycolysisEnzymePKAPathwayActivity