2024
Glucose 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-KG
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 carrierSatietyOverexpression 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 roleADPβ Cell–specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses
Emfinger CH, de Klerk E, Schueler KL, Rabaglia ME, Stapleton DS, Simonett SP, Mitok KA, Wang Z, Liu X, Paulo JA, Yu Q, Cardone RL, Foster HR, Lewandowski SL, Perales JC, Kendziorski CM, Gygi SP, Kibbey RG, Keller MP, Hebrok M, Merrins MJ, Attie AD. β Cell–specific deletion of Zfp148 improves nutrient-stimulated β cell Ca2+ responses. JCI Insight 2022, 7: e154198. PMID: 35603790, PMCID: PMC9220824, DOI: 10.1172/jci.insight.154198.Peer-Reviewed Original ResearchConceptsCell-specific deletionΒ-cell Ca2Insulin secretionAmino acid metabolismLow glucose conditionsRNA-seqPancreatic β-cellsLevels of enzymesZfp148Glutamate dehydrogenaseIntermediary metabolismChannel closureEnhanced insulin secretionWestern-style dietControl mice fedElevated glucose levelsAcid metabolismΒ-cellsCell functionGlucose toleranceCell Ca2Elevated sensitivityGlucose conditionsMetabolic challengesMice fedCitrullination of glucokinase is linked to autoimmune diabetes
Yang ML, Horstman S, Gee R, Guyer P, Lam TT, Kanyo J, Perdigoto AL, Speake C, Greenbaum CJ, Callebaut A, Overbergh L, Kibbey RG, Herold KC, James EA, Mamula MJ. Citrullination of glucokinase is linked to autoimmune diabetes. Nature Communications 2022, 13: 1870. PMID: 35388005, PMCID: PMC8986778, DOI: 10.1038/s41467-022-29512-0.Peer-Reviewed Original ResearchConceptsGlucose-stimulated insulin secretionResult of inflammationType 1 diabetesBeta-cell metabolismPancreatic beta cellsAutoimmune diabetesNOD miceAutoreactive CD4Inflammatory cytokinesAutoimmune biomarkersInsulin secretionT cellsBeta cellsType 1InflammationBiologic activityReactive oxygen speciesDiabetesPost-translational modificationsDiabetes biomarkersGlycogen synthesisBiomarkersCitrullinationGlucokinaseOxygen speciesDyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice
Bhat N, Narayanan A, Fathzadeh M, Kahn M, Zhang D, Goedeke L, Neogi A, Cardone RL, Kibbey RG, Fernandez-Hernando C, Ginsberg HN, Jain D, Shulman G, Mani A. Dyrk1b promotes hepatic lipogenesis by bypassing canonical insulin signaling and directly activating mTORC2 in mice. Journal Of Clinical Investigation 2022, 132: e153724. PMID: 34855620, PMCID: PMC8803348, DOI: 10.1172/jci153724.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisNonalcoholic steatohepatitisInsulin resistanceHepatic lipogenesisElevated de novo lipogenesisNonalcoholic fatty liver diseaseFatty liver diseaseLiver of patientsHepatic glycogen storageHigh-sucrose dietHepatic insulin resistanceFatty acid uptakeMetabolic syndromeLiver diseaseHepatic steatosisTriacylglycerol secretionNovo lipogenesisHepatic insulinTherapeutic targetImpaired activationAcid uptakeGlycogen storageMouse liverLiverLipogenesis
2020
NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart
Zhang H, Xiao Y, Nederlof R, Bakker D, Zhang P, Girardin SE, Hollmann MW, Weber NC, Houten SM, van Weeghel M, Kibbey RG, Zuurbier CJ. NLRX1 Deletion Increases Ischemia-Reperfusion Damage and Activates Glucose Metabolism in Mouse Heart. Frontiers In Immunology 2020, 11: 591815. PMID: 33362773, PMCID: PMC7759503, DOI: 10.3389/fimmu.2020.591815.Peer-Reviewed Original ResearchConceptsIschemia-reperfusion injuryNOD-like receptorsMouse heartsKO heartsGlucose metabolismCardiac ischemia-reperfusion injuryIschemia-reperfusion damageMin of reperfusionCardiac IR injurySurvival pathwaysPro-inflammatory memberCardiac glucose metabolismInnate immune systemCardiac oxygen consumptionFatty acid oxidationInflammatory parametersPyruvate dehydrogenase fluxIR injuryEarly reperfusionInflammatory mediatorsMin reperfusionSevere ischemiaC-palmitateImmune systemReperfusionMulti-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 functionADPGlucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis
Davis JC, Alves TC, Helman A, Chen JC, Kenty JH, Cardone RL, Liu DR, Kibbey RG, Melton DA. Glucose Response by Stem Cell-Derived β Cells In Vitro Is Inhibited by a Bottleneck in Glycolysis. Cell Reports 2020, 31: 107623. PMID: 32402282, PMCID: PMC7433758, DOI: 10.1016/j.celrep.2020.107623.Peer-Reviewed Original ResearchConceptsSC-β cellsΒ-cellsHuman isletsReduced glucose-stimulated insulin secretionGlucose-stimulated insulin secretionStem cell-derived β cellsHuman β-cellsEnzyme glyceraldehydeTCA cycleGlucose challengeInsulin secretionInsulin releaseDiabetes treatmentGlucose responseCadaveric isletsBottleneck resultsEarly glycolysisTransplantable isletsCell functionIsletsIntermediate metabolitesConsistency of responsesGlycolysisCellsKinaseEndocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma
Chung KM, Singh J, Lawres L, Dorans KJ, Garcia C, Burkhardt DB, Robbins R, Bhutkar A, Cardone R, Zhao X, Babic A, Vayrynen SA, Dias Costa A, Nowak JA, Chang DT, Dunne RF, Hezel AF, Koong AC, Wilhelm JJ, Bellin MD, Nylander V, Gloyn AL, McCarthy MI, Kibbey RG, Krishnaswamy S, Wolpin BM, Jacks T, Fuchs CS, Muzumdar MD. Endocrine-Exocrine Signaling Drives Obesity-Associated Pancreatic Ductal Adenocarcinoma. Cell 2020, 181: 832-847.e18. PMID: 32304665, PMCID: PMC7266008, DOI: 10.1016/j.cell.2020.03.062.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarcinogenesisCarcinoma, Pancreatic DuctalCell LineCell Line, TumorCell Transformation, NeoplasticDisease Models, AnimalDisease ProgressionEndocrine CellsExocrine GlandsFemaleGene Expression Regulation, NeoplasticHumansMaleMiceMice, Inbred C57BLMutationObesityPancreatic NeoplasmsSignal TransductionTumor MicroenvironmentConceptsPancreatic ductal adenocarcinomaPDAC progressionDuctal adenocarcinomaMajor modifiable risk factorModifiable risk factorsBeta cell expressionObesity-associated changesAutochthonous mouse modelPancreatic ductal tumorigenesisDriver gene mutationsPeptide hormone cholecystokininRisk factorsPDAC developmentMouse modelObesityHormone cholecystokininOncogenic KrasCell expressionTumor microenvironmentDietary inductionCancer developmentGene mutationsReversible roleMurine samplesProgression
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 resistanceGlycolysisEnzymePKAPathwayActivityMitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels
Taddeo EP, Alsabeeh N, Baghdasarian S, Wikstrom JD, Ritou E, Sereda S, Erion K, Li J, Stiles L, Abdulla M, Swanson Z, Wilhelm J, Bellin MD, Kibbey RG, Liesa M, Shirihai O. Mitochondrial Proton Leak Regulated by Cyclophilin D Elevates Insulin Secretion in Islets at Nonstimulatory Glucose Levels. Diabetes 2019, 69: 131-145. PMID: 31740442, PMCID: PMC6971491, DOI: 10.2337/db19-0379.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin secretionInsulin resistanceFree fatty acidsNonesterified free fatty acidsGlucose-stimulated insulin secretionPrediabetic stateInsulin hypersecretionObese subjectsFatty acidsObese miceLean miceGlucose levelsHuman isletsPancreatic isletsΒ-cellsIsletsProton leakSecretionHyperinsulinemiaProgressive increaseDiabetesMiceMitochondrial proton leakLeakN-acyl taurines are endogenous lipid messengers that improve glucose homeostasis
Grevengoed TJ, Trammell SAJ, McKinney MK, Petersen N, Cardone RL, Svenningsen JS, Ogasawara D, Nexøe-Larsen CC, Knop FK, Schwartz TW, Kibbey RG, Cravatt BF, Gillum MP. N-acyl taurines are endogenous lipid messengers that improve glucose homeostasis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2019, 116: 24770-24778. PMID: 31740614, PMCID: PMC6900532, DOI: 10.1073/pnas.1916288116.Peer-Reviewed Original ResearchMeSH KeywordsAmidohydrolasesAmino Acid SubstitutionAnimalsBlood GlucoseDisease Models, AnimalEatingEthanolaminesFemaleGlucagonGlucagon-Like Peptide 1Glucose Tolerance TestHumansInjections, IntravenousInsulinIslets of LangerhansMaleMetabolic SyndromeMiceMice, TransgenicMiddle AgedOleic AcidsPostprandial PeriodReceptors, G-Protein-CoupledTaurineConceptsFatty acid amide hydrolaseGLP-1 secretionPostprandial glucose regulationN-acyl taurinesBioactive fatty acid amidesEndogenous lipid messengersGlucagon secretionGlucose toleranceInsulin sensitivityUnique metabolic profileFood intakeGLP-1Peripheral tissuesMouse modelGlucose homeostasisLipid messengersGlucose regulationMetabolic diseasesAmide hydrolaseFunctional polymorphismsConcurrent elevationSubstantial elevationMetabolic profileFatty acid amidesMice
2017
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e9172-e9180. PMID: 29073114, PMCID: PMC5664516, DOI: 10.1073/pnas.1707797114.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisAdipose tissue lipolysisHepatic insulin resistanceThyroid hormonesHypothyroid miceImpaired suppressionInsulin resistanceTissue lipolysisInsulin secretionHigh thyroid-stimulating hormone levelsRegulation of THThyroid-stimulating hormone levelsLipid utilizationFatty liver diseaseSerum glucose levelsEndogenous glucose productionLow thyroid hormoneFatty acidsHepatic lipid utilizationLiver diseaseSevere hypothyroidismHormone levelsProfound suppressionGlucose levels