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 depolarizationMetabolism
2023
ALKBH5 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 strategies
2022
Biomarkers 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 swordCitrullination 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 speciesComprehensive Analysis of Metabolic Isozyme Targets in Cancer
Marczyk M, Gunasekharan V, Casadevall D, Qing T, Foldi J, Sehgal R, Shan NL, Blenman KRM, O'Meara TA, Umlauf S, Surovtseva YV, Muthusamy V, Rinehart J, Perry RJ, Kibbey R, Hatzis C, Pusztai L. Comprehensive Analysis of Metabolic Isozyme Targets in Cancer. Cancer Research 2022, 82: 1698-1711. PMID: 35247885, PMCID: PMC10883296, DOI: 10.1158/0008-5472.can-21-3983.Peer-Reviewed Original ResearchConceptsPotential therapeutic targetAcetyl-CoA carboxylase 1Therapeutic targetCancer typesCell linesBreast cancer viabilityPatient-derived xenograftsNovel metabolic targetsCorresponding cell linesExpression patternsDrug treatmentMatching normal tissuesRelated commentaryTumor growthMalignant transformationSmall molecule inhibitionCancer viabilityCancer Cell Line EncyclopediaNormal tissuesMetabolic vulnerabilitiesCarboxylase 1Anticancer therapyCellular changesCell proliferationMetabolic reprogrammingDyrk1b 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
Pyruvate 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 ResearchConceptsPyruvate 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
Mitochondrial 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 amidesMiceChildhood Pancreatitis and Risk for Incident Diabetes in Adulthood
Bendor CD, Bardugo A, Zucker I, Cukierman-Yaffe T, Lutski M, Derazne E, Shohat T, Mosenzon O, Tzur D, Sapir A, Pinhas-Hamiel O, Kibbey RG, Raz I, Afek A, Gerstein HC, Tirosh A, Twig G. Childhood Pancreatitis and Risk for Incident Diabetes in Adulthood. Diabetes Care 2019, 43: 145-151. PMID: 31694859, PMCID: PMC7011197, DOI: 10.2337/dc19-1562.Peer-Reviewed Original ResearchConceptsIsraeli National Diabetes RegistryIncident diabetesAcute pancreatitisNormal pancreatic functionUnexposed groupPancreatic functionOdds ratioChildhood pancreatitisIncident type 2 diabetesNational Diabetes RegistryPopulation-based studyType 2 diabetesDiagnosis of diabetesLogistic regression analysisYears of ageBaseline BMINormal BMIDiabetes RegistryRisk factorsPancreatitisCase subjectsSociodemographic confoundersDiabetesYounger ageFurther adjustment