2025
1823-P: The Beta-Cell Secretagogue Glyceraldehyde Induces Mitochondrial Leak Respiration, Not OXPHOS
CARDONE R, KIBBEY R, ZHAO X. 1823-P: The Beta-Cell Secretagogue Glyceraldehyde Induces Mitochondrial Leak Respiration, Not OXPHOS. Diabetes 2025, 74 DOI: 10.2337/db25-1823-p.Peer-Reviewed Original ResearchIncreased respirationSn-glycerol-3-phosphateMitochondrial leak respirationPlasma membrane permeabilizationMitochondria in situOligomycin-sensitive respirationMembrane permeabilizationATP synthesisMitochondrial respirationIN cellsDLGALeak respirationOXPHOSNADH oxidationGlyceraldehydeG3PStimulated respirationRespirationMitochondriaNADHPre-incubationInsulin releaseCells pre-incubatedSuccinateRotenone1824-P: Bioenergetic Advantage of Pyruvate Kinase Overcomes Mitochondrial OXPHOS in Beta-Cells to Initiate Insulin Secretion
RUZ-MALDONADO I, CARDONE R, MERRINS M, KIBBEY R. 1824-P: Bioenergetic Advantage of Pyruvate Kinase Overcomes Mitochondrial OXPHOS in Beta-Cells to Initiate Insulin Secretion. Diabetes 2025, 74 DOI: 10.2337/db25-1824-p.Peer-Reviewed Original ResearchPyruvate kinaseATP/ADP ratioMitochondrial OXPHOSHuman isletsBeta-cellsIntact miceOxygen consumption rateKATP channel closureInsulin secretionMitochondrial membrane potentialPlasma membrane depolarizationDose-dependent mannerIntramitochondrial ADPADP availabilityHyperpolarized mitochondriaInitial insulin secretionKATP channelsMitochondrial hyperpolarizationOXPHOS inhibitionINS-1Pyruvate metabolismETC complexesMembrane depolarizationATP synthesisOXPHOS1840-P: Pyruvate Kinase Bioenergetically Restricts OXPHOS in Beta Cells and Myotubules by Inducing Mitochondrial Membrane Hyperpolarization
DAVIDSON E, KIBBEY R. 1840-P: Pyruvate Kinase Bioenergetically Restricts OXPHOS in Beta Cells and Myotubules by Inducing Mitochondrial Membrane Hyperpolarization. Diabetes 2025, 74 DOI: 10.2337/db25-1840-p.Peer-Reviewed Original ResearchMitochondrial membrane potentialPyruvate kinaseHyperpolarization of mitochondrial membrane potentialRespiratory suppressionMitochondrial membrane potential differenceMitochondrial membrane hyperpolarizationCytosolic ATP/ADP ratioComplex V activityDigestive and Kidney DiseasesINS-1ATP hydrolysisATP synthesisPhosphoenolpyruvateMembrane hyperpolarizationPK substratesBlocking electron transportOXPHOSKidney diseaseATP/ADP ratioBeta cellsHyperpolarizationMembrane potentialPK activityState 3Oligos83-OR: GLP-1RA Efficacy Doubled with Small Molecule Modulators of Pyruvate Kinase for Obesity Treatment
KIBBEY R, CARDONE R, RUZ-MALDONADO I, ZHAO X, BROWN S, FOSTER H, MERRINS M. 83-OR: GLP-1RA Efficacy Doubled with Small Molecule Modulators of Pyruvate Kinase for Obesity Treatment. Diabetes 2025, 74 DOI: 10.2337/db25-83-or.Peer-Reviewed Original ResearchGLP-1 RAsLean massCombo groupInsulin secretionOptimal treatment of obesityPreservation of lean massObesity treatmentTreatment groupsIslet healthCa2+ oscillationsCa2+ imagingFasting glucose levelsC57BL/6J male miceTreatment of obesityImproved insulin sensitivityGLP-1RAAUC glucoseOptimal treatmentDIO miceMale miceStudy endPlaceboGLP-1Body compositionInsulin sensitivity
2024
Phosphoenolpyruvate carboxykinase-2 (PCK2) is a therapeutic target in triple-negative breast cancer
Gunasekharan V, Lin H, Marczyk M, Rios-Hoyo A, Campos G, Shan N, Ahmed M, Umlauf S, Gareiss P, Raaisa R, Williams R, Cardone R, Siebel S, Kibbey R, Surovtseva Y, Pusztai L. Phosphoenolpyruvate carboxykinase-2 (PCK2) is a therapeutic target in triple-negative breast cancer. Breast Cancer Research And Treatment 2024, 208: 657-671. PMID: 39177932, DOI: 10.1007/s10549-024-07462-z.Peer-Reviewed Original ResearchMetabolic fluxTriple-negative breast cancerReduced metabolic fluxMDA-MB-231 cellsCell growth in vitroEnzyme assays in vitroMDA-MB-231Potential small molecule inhibitorsPyruvate carboxylaseGrowth in vitroSmall molecule inhibitorsIn silico screeningEnzyme assaysAssay in vitroEnzymatic assayCell lines in vitroEnzyme activityGrowth inhibitory activityBT-549Breast cancerIn vitro screeningBreast cell lines in vitroPhosphoenolpyruvateSignificant growth inhibitory activityLines in vitro1583-P: Measuring Mitochondrial Metabolism In Vivo with [1,2-13C2]-L-Glutamine Mass Isotopomers
SIEBEL S, CARDONE R, MASON G, KIBBEY R. 1583-P: Measuring Mitochondrial Metabolism In Vivo with [1,2-13C2]-L-Glutamine Mass Isotopomers. Diabetes 2024, 73 DOI: 10.2337/db24-1583-p.Peer-Reviewed Original Research1734-P: ADP Privation of Human Beta-Cell Mitochondria by Pyruvate Kinase
RUZ-MALDONADO I, CARDONE R, KIBBEY R. 1734-P: ADP Privation of Human Beta-Cell Mitochondria by Pyruvate Kinase. Diabetes 2024, 73 DOI: 10.2337/db24-1734-p.Peer-Reviewed Original ResearchPyruvate kinaseBeta-cell mitochondriaInhibition of OxPhosBeta-cellsHuman beta-cellsModulation of enzymesIntramitochondrial ADPPhosphoenolpyruvate inhibitionADP availabilityADP/ATP exchangeKATP channelsPhosphoenolpyruvate metabolismOxidative phosphorylationPhosphoenolpyruvateMitochondrial functionOXPHOSSubstrate transportComplex IATP/ADP ratioHuman isletsMitochondrial couplingOxygen consumption ratePyruvateMitochondriaDose-dependent mannerGlucose Regulation of β-Cell KATP Channels: It Is Time for a New Model!
Merrins M, Kibbey R. Glucose Regulation of β-Cell KATP Channels: It Is Time for a New Model! Diabetes 2024, 73: 856-863. PMID: 38768366, PMCID: PMC11109790, DOI: 10.2337/dbi23-0032.Peer-Reviewed Original ResearchConceptsB-cell metabolismInsulin secretionEfficiency of mitochondrial ATP productionModel of glucose-stimulated insulin secretionGlucose-stimulated insulin secretionMitochondrial ATP productionNADPH productionGenetic evidenceInitial insulin secretionATP productionGlycolytic enzymesOXPHOSPyruvate kinaseATP/ADP ratioHealthy B cellsKATP channel closureB cellsDiabetes pathophysiologyGlycolysisStoichiometric yieldKATP channelsBioenergeticsATP/ADPMembrane depolarizationMetabolismHeterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage
Ruz-Maldonado I, Gonzalez J, Zhang H, Sun J, Bort A, Kabir I, Kibbey R, Suárez Y, Greif D, Fernández-Hernando C. Heterogeneity of hepatocyte dynamics restores liver architecture after chemical, physical or viral damage. Nature Communications 2024, 15: 1247. PMID: 38341404, PMCID: PMC10858916, DOI: 10.1038/s41467-024-45439-0.Peer-Reviewed Original Research
2023
Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis
Chaube B, Citrin K, Sahraei M, Singh A, de Urturi D, Ding W, Pierce R, Raaisa R, Cardone R, Kibbey R, Fernández-Hernando C, Suárez Y. Suppression of angiopoietin-like 4 reprograms endothelial cell metabolism and inhibits angiogenesis. Nature Communications 2023, 14: 8251. PMID: 38086791, PMCID: PMC10716292, DOI: 10.1038/s41467-023-43900-0.Peer-Reviewed Original ResearchALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control
Gao Y, Zimmer J, Vasic R, Liu C, Gbyli R, Zheng S, Patel A, Liu W, Qi Z, Li Y, Nelakanti R, Song Y, Biancon G, Xiao A, Slavoff S, Kibbey R, Flavell R, Simon M, Tebaldi T, Li H, Halene S. ALKBH5 modulates hematopoietic stem and progenitor cell energy metabolism through m6A modification-mediated RNA stability control. Cell Reports 2023, 42: 113163. PMID: 37742191, PMCID: PMC10636609, DOI: 10.1016/j.celrep.2023.113163.Peer-Reviewed Original ResearchConceptsAlkB homolog 5Post-transcriptional regulatory mechanismsHematopoietic stemNumerous cellular processesProgenitor cell fitnessEnergy metabolismMitochondrial ATP productionMethyladenosine (m<sup>6</sup>A) RNA modificationTricarboxylic acid cycleCell energy metabolismHuman hematopoietic cellsMitochondrial energy productionCell fitnessCellular processesRNA modificationsRNA methylationRegulatory mechanismsEnzyme transcriptsATP productionHomolog 5Acid cycleΑ-ketoglutarateHematopoietic cellsMessenger RNAΑ-KGTNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes
Boutagy N, Fowler J, Grabinska K, Cardone R, Sun Q, Vazquez K, Whalen M, Zhu X, Chakraborty R, Martin K, Simons M, Romanoski C, Kibbey R, Sessa W. TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2218150120. PMID: 37695914, PMCID: PMC10515159, DOI: 10.1073/pnas.2218150120.Peer-Reviewed Original ResearchConceptsPyruvate dehydrogenase kinase 4Dehydrogenase kinase 4Lon proteasePyruvate dehydrogenase activityHistone acetylationMitochondrial metabolismKinase 4Specific gene lociPDH fluxEndothelial cellsSiRNA-mediated knockdownAcetyl-CoA generationLysine 27Gene transcriptionTCA fluxRNA sequencingHuman umbilical vein endothelial cellsProtein degradationHistone 3Gene locusUmbilical vein endothelial cellsNF-κB-dependent mechanismTricarboxylic acid cycle fluxVein endothelial cellsActive subunitLoss of ZNF148 enhances insulin secretion in human pancreatic β cells
de Klerk E, Xiao Y, Emfinger C, Keller M, Berrios D, Loconte V, Ekman A, White K, Cardone R, Kibbey R, Attie A, Hebrok M. Loss of ZNF148 enhances insulin secretion in human pancreatic β cells. JCI Insight 2023, 8: e157572. PMID: 37288664, PMCID: PMC10393241, DOI: 10.1172/jci.insight.157572.Peer-Reviewed Original ResearchConceptsPancreatic β-cellsΒ-cellsSC-β cellsHuman pancreatic β-cellsInsulin secretionHuman β-cellsVesicle traffickingGenetic regulatorsStem cell-derived β cellsDirect repressionS100 genesCells identifiesZNF148Annexin A2Tetrameric complexCell membraneNovel therapeutic targetNovel therapeutic strategiesHuman isletsRegulatorTherapeutic targetCellsS100A16 expressionGlucose homeostasisTherapeutic strategiesLoss of ZNF148 enhances insulin secretion in human pancreatic ß cells.
71. de Klerk E, Xiao Y, Emfinger C, Keller MP,Berrios DI, Loconte V, Ekman A, White KL, Cardone RL, Kibbey RG, Attie A, Hebrok M, Loss of ZNF148 enhances insulin secretion in human pancreatic ß cells. JCI Insights, 2023 (in press)Peer-Reviewed Original Research
2022
UCP2-dependent redox sensing in POMC neurons regulates feeding
Yoon N, Jin S, Kim J, Liu Z, Sun Q, Cardone R, Kibbey R, Diano S. UCP2-dependent redox sensing in POMC neurons regulates feeding. Cell Reports 2022, 41: 111894. PMID: 36577374, PMCID: PMC9885759, DOI: 10.1016/j.celrep.2022.111894.Peer-Reviewed Original ResearchConceptsPOMC neuronsGlucose metabolismPOMC neuronal activityAnorexigenic pro-opiomelanocortin (POMC) neuronsPro-opiomelanocortin (POMC) neuronsHigh-fat dietFatty acid metabolismMitochondrial respirationLactate levelsCerebrospinal fluidNeuronal activityGlucose utilizationFed stateNeuronsPyruvate levelsExtracellular pyruvate levelsAcid metabolismMalate-aspartate shuttleMetabolismAddition of lactateMitochondrial pyruvate carrierInhibitionObesityPyruvate carrierSatietyBiomarkers of autoimmunity and beta cell metabolism in type 1 diabetes
Yang M, Kibbey R, Mamula M. Biomarkers of autoimmunity and beta cell metabolism in type 1 diabetes. Frontiers In Immunology 2022, 13: 1028130. PMID: 36389721, PMCID: PMC9647083, DOI: 10.3389/fimmu.2022.1028130.Peer-Reviewed Original ResearchConceptsPosttranslational protein modificationMetabolic pathwaysType 1 diabetesCellular metabolic pathwaysImportant biological functionsAutoimmune diseasesBeta cellsCellular metabolic dysfunctionPancreatic isletsProtein modificationBiological functionsProtein structureInsulin-producing beta cellsBiomarkers of autoimmunityChronic autoimmune diseaseCell metabolismBeta-cell metabolismNumerous autoimmune diseasesPancreatic beta cellsPotential pathological consequencesNormal metabolic pathwaysDisease activityPathological consequencesSpecific autoantigensSpecific autoimmunityKetones: the double-edged sword of SGLT2 inhibitors?
Lupsa BC, Kibbey RG, Inzucchi SE. Ketones: the double-edged sword of SGLT2 inhibitors? Diabetologia 2022, 66: 23-32. PMID: 36255460, DOI: 10.1007/s00125-022-05815-1.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSGLT2 inhibitorsDrug categoriesSodium-glucose cotransporter 2 inhibitorsCardio-renal benefitsNormal blood glucose concentrationsCotransporter 2 inhibitorsClasses of medicationsAnti-inflammatory effectsSerious adverse effectsType 1 diabetesBlood glucose levelsBlood glucose concentrationKidney outcomesRare complicationBlood pressureSGLT2 inhibitionGlucose levelsKetone levelsBody weightType 2Ketone bodiesAdverse effectsGlucose concentrationInhibitorsEdged swordOverexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo
Codella R, Alves TC, Befroy DE, Choi CS, Luzi L, Rothman DL, Kibbey RG, Shulman GI. Overexpression of UCP3 decreases mitochondrial efficiency in mouse skeletal muscle in vivo. FEBS Letters 2022, 597: 309-319. PMID: 36114012, DOI: 10.1002/1873-3468.14494.Peer-Reviewed Original ResearchConceptsOverexpression of UCP3ATP synthesisMitochondrial oxidationMitochondrial transmembrane proteinInner mitochondrial membraneSkeletal muscleMitochondrial oxidative phosphorylationMitochondrial oxidative metabolismMuscle-specific overexpressionMouse skeletal muscleTransmembrane proteinMitochondrial membraneProton leakPrecise functionOxidative phosphorylationMitochondrial efficiencyUCP3 expressionMitochondrial inefficiencyOverexpressionProtein 3UCP3Oxidative metabolismVivoMagnetic resonance spectroscopyPhosphorylationβ-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 ResearchConceptsPyruvate kinaseATP/ADPCytosolic ATP/ADPAmino acidsPKM2 isoformPK isoformsPlasma membraneNutrient sensorNutrient responsesPEP carboxykinasePKM1Mitochondrial sourcesPKM2Channel closureEssential roleInsulin secretionDifferential responsePK activityKinaseMembrane depolarizationIsoformsDeletionATPKey roleADPMetabolic cycles and signals for insulin secretion
Merrins MJ, Corkey BE, Kibbey RG, Prentki M. Metabolic cycles and signals for insulin secretion. Cell Metabolism 2022, 34: 947-968. PMID: 35728586, PMCID: PMC9262871, DOI: 10.1016/j.cmet.2022.06.003.Peer-Reviewed Original Research
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