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
Loss 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
Metabolic 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 ResearchCitrullination 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
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
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 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