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
2018
Metabolic Dysfunction within Brown Adipose Tissue and Skeletal Muscle Caused by Complete Hepatic Insulin Resistance Is Reversible by FGF-21 Treatment
STOEHR O, TAO R, COPPS K, WHITE M. Metabolic Dysfunction within Brown Adipose Tissue and Skeletal Muscle Caused by Complete Hepatic Insulin Resistance Is Reversible by FGF-21 Treatment. Diabetes 2018, 67 DOI: 10.2337/db18-1873-p.Peer-Reviewed Original ResearchHepatic insulin resistanceFGF-21Insulin resistanceGlucose toleranceSkeletal muscleGlucose uptakeAdipose tissue markersFGF-21 treatmentSkeletal muscle dysfunctionSystemic insulin resistanceBetter glucose toleranceSystemic glucose homeostasisDouble knockout miceBrown adipose tissueDeletion of FoxO1Hepatokine secretionThermogenesis markersHepatic infectionBody core temperatureGlucose intoleranceMuscle dysfunctionSevere hyperglycemiaControl miceInsulin sensitivityMetabolic dysfunction
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
2009
Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo *
Lee D, Shi J, Jeoung N, Kim M, Zabolotny J, Lee S, White M, Wei L, Kim Y. Targeted Disruption of ROCK1 Causes Insulin Resistance in Vivo *. Journal Of Biological Chemistry 2009, 284: 11776-11780. PMID: 19276091, PMCID: PMC2673246, DOI: 10.1074/jbc.c900014200.Peer-Reviewed Original ResearchMeSH KeywordsAdiposityAnimalsDiabetes Mellitus, Type 2GlucoseGTPase-Activating ProteinsInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceMiceMice, KnockoutObesityPhosphatidylinositol 3-KinasesPhosphorylationProto-Oncogene Proteins c-aktRho-Associated KinasesRibosomal Protein S6 KinasesSignal TransductionConceptsIRS-1Skeletal muscleWhole-body glucose homeostasisInsulin resistanceBody glucose homeostasisCultured cell linesPhosphorylation of AktPhospho-tyrosinesGlucose homeostasisROCK1-deficient miceSerine phosphorylationNovel regulatorTyrosine phosphorylationS6KRho kinase isoformsInsulin sensitivityPhysiological roleGene ablationAbility of insulinInsulin receptorTargeted disruptionPhosphorylationNormal glucose homeostasisGlucose-induced insulin secretionROCK1
2008
Muscle-Specific IRS-1 Ser→Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle
Morino K, Neschen S, Bilz S, Sono S, Tsirigotis D, Reznick RM, Moore I, Nagai Y, Samuel V, Sebastian D, White M, Philbrick W, Shulman GI. Muscle-Specific IRS-1 Ser→Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle. Diabetes 2008, 57: 2644-2651. PMID: 18633112, PMCID: PMC2551673, DOI: 10.2337/db06-0454.Peer-Reviewed Original ResearchMeSH KeywordsAlanineAmino Acid SubstitutionAnimalsBlotting, WesternDietary FatsFemaleGlucose Clamp TechniqueGlucose Tolerance TestImmunoprecipitationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceMaleMiceMice, Inbred C57BLMice, TransgenicMuscle, SkeletalPhosphorylationSerineTriglyceridesConceptsSerine phosphorylationIRS-1IRS-1-associated phosphatidylinositolSkeletal muscleInsulin-stimulated IRS-1-associated phosphatidylinositolWild-type transgenic miceFat-induced insulin resistanceInsulin receptor substrateTransgenic miceReceptor substrateInsulin signalingAkt phosphorylationPhosphorylationCellular mechanismsCritical roleGlucose uptakeHigh-fat feedingInsulin resistanceMuscle glucose uptakeInsulin actionVivoSerInsulin-stimulated muscle glucose uptakeImportant rolePhosphatidylinositol
2005
Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: Role of IRS phosphorylation
Zhang Q, Carter E, Ma B, White M, Fischman A, Tompkins R. Molecular mechanism(s) of burn-induced insulin resistance in murine skeletal muscle: Role of IRS phosphorylation. Life Sciences 2005, 77: 3068-3077. PMID: 15982669, DOI: 10.1016/j.lfs.2005.02.034.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBurnsDisease Models, AnimalEnzyme ActivationHindlimbInsulin Receptor Substrate ProteinsInsulin ResistanceJNK Mitogen-Activated Protein KinasesMaleMAP Kinase Kinase 4MiceMitogen-Activated Protein Kinase KinasesMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptor, InsulinSignal TransductionConceptsInsulin receptor substrate-1Burn-induced insulin resistanceAkt kinase activityIRS-1 proteinSAPK/JNKSerine 307Kinase activitySkeletal muscleReceptor substrate-1Murine skeletal muscleHind limb skeletal muscleStress kinasesKey proteinsSubstrate-1Biochemical basisPhosphorylationIRS phosphorylationKinase enzymeProteinEnzyme activityJNKLimb skeletal muscleProtein contentInsulin resistanceKinase
2004
Insulin resistance in thermally-injured rats is associated with post-receptor alterations in skeletal muscle, liver and adipose tissue.
Carter E, Burks D, Fischman A, White M, Tompkins R. Insulin resistance in thermally-injured rats is associated with post-receptor alterations in skeletal muscle, liver and adipose tissue. International Journal Of Molecular Medicine 2004, 14: 653-8. PMID: 15375597, DOI: 10.3892/ijmm.14.4.653.Peer-Reviewed Original ResearchConceptsUrinary C-peptide excretionC-peptide excretionPost-receptor alterationsInsulin resistanceInsulin receptor bindingSkeletal muscleInsulin infusionBurn injuryAdipose tissueFull-thickness scald injuryGlucose productionSham-treated control animalsReceptor bindingHepatic glucose productionIRS-1 expressionWestern blot methodBinding of insulinAbsence of changesScald injuryBolus injectionRat modelPossible molecular mechanismsControl animalsInjuryThermal injuryDisruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance
Duan C, Yang H, White M, Rui L. Disruption of the SH2-B Gene Causes Age-Dependent Insulin Resistance and Glucose Intolerance. Molecular And Cellular Biology 2004, 24: 7435-7443. PMID: 15314154, PMCID: PMC506995, DOI: 10.1128/mcb.24.17.7435-7443.2004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAdipose TissueAgingAnimalsBlood GlucoseCarrier ProteinsCell LineDietary FatsGlucose IntoleranceHomeostasisHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred StrainsMice, KnockoutMitogen-Activated Protein KinasesMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptor, InsulinSignal TransductionConceptsSrc homology 2Insulin receptor substrate-1Insulin receptor activationInsulin receptorTyrosine phosphorylationSH2 domain-dependent mannerPleckstrin homology domain-containing adaptor proteinDomain-containing adaptor proteinDomain-dependent mannerReceptor substrate-1Skeletal muscleSH2 domainHomology 2Adaptor proteinReceptor activationSubstrate-1Physiological roleCultured cellsGlucose homeostasisERK1/2 pathwayDependent insulin resistancePhysiological enhancerSystemic deletionPhosphorylationIRS2Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity
Fujii N, Boppart M, Dufresne S, Crowley P, Jozsi A, Sakamoto K, Yu H, Aschenbach W, Kim S, Miyazaki H, Rui L, White M, Hirshman M, Goodyear L. Overexpression or ablation of JNK in skeletal muscle has no effect on glycogen synthase activity. American Journal Of Physiology - Cell Physiology 2004, 287: c200-c208. PMID: 15013949, DOI: 10.1152/ajpcell.00415.2003.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDown-RegulationElectroporationEnzyme ActivationGene Transfer TechniquesGlycogen SynthaseHumansInjections, IntramuscularInsulin Receptor Substrate ProteinsMiceMice, KnockoutMitogen-Activated Protein Kinase 8Mitogen-Activated Protein Kinase 9Mitogen-Activated Protein KinasesMuscle ContractionMuscle ProteinsMuscle, SkeletalPhosphoproteinsPhosphorylationSerineTyrosineConceptsGlycogen synthase activityMouse skeletal muscleS6 kinasePhosphorylation stateJNK signalingSynthase activityJNK activityProtein kinase B/AktJNK overexpressionGlycogen synthase kinase-3Skeletal muscleExtracellular signal-regulated kinase 1/2Signal-regulated kinase 1/2P70 S6 kinaseInsulin-stimulated glycogen synthase activitySynthase kinase-3P90 S6 kinaseBasal phosphorylation stateGlycogen synthase activationSitu muscle contractionBiological functionsTerminal kinaseKinase 3JNK activationKinase 1/2
2002
Insulin Signaling After Exercise in Insulin Receptor Substrate-2-Deficient Mice
Howlett K, Sakamoto K, Hirshman M, Aschenbach W, Dow M, White M, Goodyear L. Insulin Signaling After Exercise in Insulin Receptor Substrate-2-Deficient Mice. Diabetes 2002, 51: 479-483. PMID: 11812758, DOI: 10.2337/diabetes.51.2.479.Peer-Reviewed Original ResearchConceptsPhosphotyrosine-associated phosphatidylinositolIRS-2 tyrosine phosphorylationIRS-2 signalingInsulin receptor substrate-2-deficient (IRS2(-/-)) miceWild-type miceIRS-2-deficient miceEnhanced insulin actionWT miceTyrosine phosphorylationTreadmill exerciseInsulin receptor substrateInsulin actionMiceImmediate periodSkeletal muscleInsulin-stimulated responsesInsulin signalingMarked increaseReceptor substrateExerciseInsulinPresent studySignalingPhosphorylation
2000
Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2
Kido Y, Burks D, Withers D, Bruning J, Kahn C, White M, Accili D. Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. Journal Of Clinical Investigation 2000, 105: 199-205. PMID: 10642598, PMCID: PMC377430, DOI: 10.1172/jci7917.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBlood GlucoseCell SizeDiabetes Mellitus, Type 2Disease Models, AnimalHeterozygoteHomozygoteHyperglycemiaInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, KnockoutMuscle, SkeletalMutationOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphoproteinsReceptor, InsulinConceptsBeta-cell hyperplasiaSevere insulin resistanceInsulin resistanceSkeletal muscleInsulin actionAltered beta-cell functionCompensatory beta-cell hyperplasiaMild insulin resistanceTissue-specific insulin resistanceBeta-cell functionUnderlying metabolic abnormalitiesType 2 diabetesInsulin receptorHeterozygous null mutationsDiabetic miceMetabolic abnormalitiesInsulin receptor substrateAdipose tissueRole of IRSType 2MiceHyperplasiaLiverMuscleIRS-2
1999
Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle*
Higaki Y, Wojtaszewski J, Hirshman M, Withers D, Towery H, White M, Goodyear L. Insulin Receptor Substrate-2 Is Not Necessary for Insulin- and Exercise-stimulated Glucose Transport in Skeletal Muscle*. Journal Of Biological Chemistry 1999, 274: 20791-20795. PMID: 10409618, DOI: 10.1074/jbc.274.30.20791.Peer-Reviewed Original ResearchConceptsExercise-stimulated glucose transportInsulin-stimulated 2DG uptakeBlood glucose concentrationGlucose transportInsulin resistanceSkeletal muscleInsulin receptor substrate 2Glucose concentrationSkeletal muscle glucose transportHigher blood glucose concentrationsInsulin receptor substrate-2-deficient (IRS2(-/-)) miceOnset of diabetesType 2 diabetesWild-type miceMuscle glucose transportIRS2 proteinAbsence of insulinMuscle GLUT4 contentSubstrate 2WT animalsSoleus muscleGLUT4 contentLower basalMiceInsulin
1998
Disruption of IRS-2 causes type 2 diabetes in mice
Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S, Zhang Y, Bernal D, Pons S, Shulman G, Bonner-Weir S, White M. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998, 391: 900-904. PMID: 9495343, DOI: 10.1038/36116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCloning, MolecularDiabetes Mellitus, Type 2FemaleGene TargetingHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationReceptor, InsulinRecombination, GeneticSignal TransductionConceptsType 2 diabetesInsulin resistanceHuman type 2 diabetesPancreatic β-cell functionInsulin secretion increasesSingle molecular abnormalityΒ-cell compensationIRS-2-deficient miceΒ-cell functionHuman type 2Insulin secretionInsulin receptor substrateGlucose homeostasisSecretion increasesInsulin actionType 2DiabetesMolecular abnormalitiesProgressive deteriorationSkeletal muscleIRS-2Insulin signalingIRS-1Mild resistanceMice