2021
FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance
Stöhr O, Tao R, Miao J, Copps K, White M. FoxO1 suppresses Fgf21 during hepatic insulin resistance to impair peripheral glucose utilization and acute cold tolerance. Cell Reports 2021, 34: 108893. PMID: 33761350, PMCID: PMC8529953, DOI: 10.1016/j.celrep.2021.108893.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAdipocytes, BrownAdipose Tissue, BrownAnimalsBlood GlucoseBody WeightCold TemperatureDiet, High-FatFibroblast Growth FactorsForkhead Box Protein O1Gene Expression RegulationGlucoseHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverMice, KnockoutOrgan SpecificityOxidation-ReductionThermogenesisConceptsHepatic insulin resistanceInsulin resistanceGlucose utilizationHigher plasma Fgf21 levelsSevere hepatic insulin resistanceFGF21 knockout micePlasma FGF21 levelsPeripheral glucose utilizationInsulin-resistant miceThermogenic gene expressionFGF21 resistancePharmacologic formsFGF21 levelsCold intoleranceFGF21 functionMetabolic healthBAT functionGlucose homeostasisKnockout miceFGF21Adenoviral infectionMiceWeight lossSkeletal muscleAcute cold tolerance
2011
Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways
Long Y, Cheng Z, Copps K, White M. Insulin Receptor Substrates Irs1 and Irs2 Coordinate Skeletal Muscle Growth and Metabolism via the Akt and AMPK Pathways. Molecular And Cellular Biology 2011, 31: 430-441. PMID: 21135130, PMCID: PMC3028618, DOI: 10.1128/mcb.00983-10.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsBody CompositionBody WeightEnzyme ActivationForkhead Transcription FactorsGlucoseHomeostasisIn Vitro TechniquesInsulinInsulin Receptor Substrate ProteinsLactic AcidMiceMice, KnockoutModels, BiologicalMuscle, SkeletalMyocardiumOrgan SizeOrgan SpecificityProto-Oncogene Proteins c-aktSignal TransductionUp-RegulationConceptsSkeletal muscle growthMdKO miceMuscle growthElevated AMP/ATP ratioInsulin-receptor substrate IRS1AMP/ATP ratioSkeletal muscleInsulin receptor substrateMuscle creatine kinaseSubstrates IRS1Insulin-stimulated glucose uptakeProtein kinaseNutrient availabilityReceptor substrateCarboxylase phosphorylationFatty acid oxidationAMPK pathwayMetabolic homeostasisATP ratioIRS1Impaired growthKinaseAmino acid releaseSkeletal muscle massAtrogene expression
2005
Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth
Dong X, Park S, Lin X, Copps K, Yi X, White M. Irs1 and Irs2 signaling is essential for hepatic glucose homeostasis and systemic growth. Journal Of Clinical Investigation 2005, 116: 101-114. PMID: 16374520, PMCID: PMC1319221, DOI: 10.1172/jci25735.Peer-Reviewed Original ResearchConceptsSystemic growthHundreds of genesInsulin receptor substrateHepatic nutrient homeostasisHepatic glucose homeostasisHeterologous pathwaysNutrient homeostasisReceptor substrateGene expressionGSK3beta phosphorylationReceptor signalsHepatic gene expressionLKO miceInsulin receptorGlucose homeostasisIRS2IRS1Hepatic genesHepatic insulin receptorAkt-FoxO1 pathwayHomeostasisGenesHepatic glycogen storesLKO liversPathwayReduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. Journal Of Clinical Investigation 2005, 115: 3587-3593. PMID: 16284649, PMCID: PMC1280967, DOI: 10.1172/jci25151.Peer-Reviewed Original ResearchMeSH KeywordsBiopsyBlood GlucoseBlotting, WesternBody Mass IndexBody WeightDiabetes Mellitus, Type 2DNA, MitochondrialFamily HealthFemaleGene Expression RegulationGlucose Clamp TechniqueGlucose Tolerance TestHumansHyperinsulinismImmunoprecipitationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipidsMaleMicroscopy, ElectronMicroscopy, Electron, TransmissionMitochondriaMusclesPhosphoproteinsPhosphorylationProtein Serine-Threonine KinasesReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSerineSignal TransductionTime FactorsTranscription, GeneticTriglyceridesConceptsInsulin-resistant offspringIR offspringType 2 diabetesInsulin-stimulated muscle glucose uptakeType 2 diabetic parentsIntramyocellular lipid contentHyperinsulinemic-euglycemic clampMuscle glucose uptakeIRS-1 serine phosphorylationMuscle mitochondrial densityMitochondrial densityMuscle biopsy samplesSerine kinase cascadeInsulin-stimulated Akt activationDiabetic parentsInsulin resistanceControl subjectsBiopsy samplesGlucose uptakeLipid accumulationMitochondrial dysfunctionInsulin signalingAkt activationEarly defectsMuscle
2004
Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes
Lin X, Taguchi A, Park S, Kushner J, Li F, Li Y, White M. Dysregulation of insulin receptor substrate 2 in β cells and brain causes obesity and diabetes. Journal Of Clinical Investigation 2004, 114: 908-916. PMID: 15467829, PMCID: PMC518668, DOI: 10.1172/jci22217.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBody WeightBrainDiabetes Mellitus, Type 2DietEatingGene DeletionGene Expression RegulationGlucoseHomeostasisHumansHypothalamusInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansMaleMiceMice, Inbred C57BLMice, KnockoutObesityPhosphoproteinsRandom AllocationSignal TransductionConceptsInsulin receptor substrate 2Beta cellsInsulin resistanceSufficient beta cell functionPancreas beta cellsBeta-cell failureBeta-cell functionFunctional beta cellsMonths of ageAdult beta cellsFat body massSubstrate 2Obese miceDiabetesΒ-cellsObesityPromotes RegenerationConditional knockoutCell functionMiceBrainBody massMolecular linkCell failureCells
2003
Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation
Schubert M, Brazil D, Burks D, Kushner J, Ye J, Flint C, Farhang-Fallah J, Dikkes P, Warot X, Rio C, Corfas G, White M. Insulin Receptor Substrate-2 Deficiency Impairs Brain Growth and Promotes Tau Phosphorylation. Journal Of Neuroscience 2003, 23: 7084-7092. PMID: 12904469, PMCID: PMC6740672, DOI: 10.1523/jneurosci.23-18-07084.2003.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsApoptosisBody WeightBrainCell CountCell DivisionCell SurvivalCells, CulturedCerebellumCrosses, GeneticEnzyme InhibitorsHeterozygoteIn Situ Nick-End LabelingInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutNeuronsOrgan SizePhosphoproteinsPhosphorylationReceptor, IGF Type 1Signal TransductionTau ProteinsConceptsMolecular linkInsulin receptor substrate (IRS) proteinsBrain growthNeurodegenerative diseasesPancreatic beta-cell functionPeripheral insulin actionSubstrate proteinsBeta-cell functionTyrosine phosphorylationLike growth factorIrs2 branchInsulin resistanceTau phosphorylationIRS2 geneNeuronal proliferationInsulin actionMouse brainInsulin-IGFGrowth factorPhosphorylationIRS2DiabetesBody growthDiseaseMice
2002
Pdx1 restores β cell function in Irs2 knockout mice
Kushner J, Ye J, Schubert M, Burks D, Dow M, Flint C, Dutta S, Wright C, Montminy M, White M. Pdx1 restores β cell function in Irs2 knockout mice. Journal Of Clinical Investigation 2002, 109: 1193-1201. PMID: 11994408, PMCID: PMC150960, DOI: 10.1172/jci14439.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornBlood GlucoseBody WeightDiabetes Mellitus, Type 2FemaleHomeodomain ProteinsInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsIslets of LangerhansMaleMiceMice, KnockoutPhosphoproteinsReceptor, InsulinSignal TransductionTrans-ActivatorsConceptsOnset of diabetesPeripheral insulin actionBeta-cell failureType 2 diabetesBeta-cell massEarly-onset diabetesIrs2 knockout micePancreatic beta-cell growthBeta-cell growthWeeks of ageIrs2 branchHepatocyte nuclear factorGlucose toleranceExpression of Pdx1Knockout miceBeta cellsDiabetesInsulin actionInsulin/MiceNuclear factorTranscription factor Pdx1Cell functionIsletsTransgenic expression
1999
Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling
Withers D, Burks D, Towery H, Altamuro S, Flint C, White M. Irs-2 coordinates Igf-1 receptor-mediated β-cell development and peripheral insulin signalling. Nature Genetics 1999, 23: 32-40. PMID: 10471495, DOI: 10.1038/12631.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsApoptosisBlood GlucoseBody WeightFemaleGene Expression Regulation, DevelopmentalGlucose Tolerance TestInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, KnockoutMuscle, SkeletalPancreasPhosphoproteinsReceptor, IGF Type 1Signal TransductionTime FactorsConceptsIGF-1 receptorΒ-cell developmentIGF-1Glucose homeostasisΒ-cellsPeripheral insulin resistancePeripheral target tissuesEffect of insulinPancreatic β-cellsPeripheral insulinInsulin resistanceInsulin receptor substratePost-natal growthGlucose metabolismNull allelesTarget tissuesInsulinMiceReceptor substrateIR-1Carbohydrate metabolismReceptorsSurvivalCell growthPleiotropic effects