2010
Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β?
Carew R, Sadagurski M, Goldschmeding R, Martin F, White M, Brazil D. Deletion of Irs2 causes reduced kidney size in mice: role for inhibition of GSK3β? BMC Developmental Biology 2010, 10: 73. PMID: 20604929, PMCID: PMC2910663, DOI: 10.1186/1471-213x-10-73.Peer-Reviewed Original ResearchConceptsIrs2-/- miceYes-associated proteinKidney sizeΒ-cateninΒ-catenin targetsBody weight ratioImportant novel mediatorType 2 diabetesPostnatal day 5Mouse developmentInhibition of GSK3βOrgan sizeYAP activityYAP phosphorylationPituitary developmentDevelopmental defectsYAP levelsGlomerular densityRenal growthNeuronal proliferationAnalysis of insulinGlomerular numberConcomitant accumulationDay 5Kidney structure
2009
Metformin and Insulin Meet in a Most Atypical Way
White M. Metformin and Insulin Meet in a Most Atypical Way. Cell Metabolism 2009, 9: 485-487. PMID: 19490902, DOI: 10.1016/j.cmet.2009.05.007.Peer-Reviewed Original Research
2008
Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation
Dong X, Copps K, Guo S, Li Y, Kollipara R, DePinho R, White M. Inactivation of Hepatic Foxo1 by Insulin Signaling Is Required for Adaptive Nutrient Homeostasis and Endocrine Growth Regulation. Cell Metabolism 2008, 8: 65-76. PMID: 18590693, PMCID: PMC2929667, DOI: 10.1016/j.cmet.2008.06.006.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAnimalsEndocrine GlandsFoodForkhead Transcription FactorsGrowthHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsLiverMiceMice, KnockoutNerve Tissue ProteinsPhosphoproteinsSignal TransductionConceptsInsulin signalingForkhead transcription factor FOXO1Insulin-regulated glucose homeostasisExpression of genesTranscription factor FOXO1Endocrine growth regulationNutrient homeostasisMetabolic genesStress resistancePerturbed expressionActive FoxO1Growth regulationLiver-specific deletionHepatic FoxO1Hepatic insulin resistanceBody sizePI3KHepatic Irs1FOXO1TranscriptomeSomatic growthDKO miceGenesSignalingHomeostasisStructural and biochemical characterization of the KRLB region in insulin receptor substrate-2
Wu J, Tseng Y, Xu C, Neubert T, White M, Hubbard S. Structural and biochemical characterization of the KRLB region in insulin receptor substrate-2. Nature Structural & Molecular Biology 2008, 15: 251-258. PMID: 18278056, DOI: 10.1038/nsmb.1388.Peer-Reviewed Original ResearchMeSH KeywordsAmino Acid SequenceAnimalsCHO CellsCricetinaeCricetulusCrystallography, X-RayHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceModels, MolecularMolecular Sequence DataMutationPhosphoproteinsPhosphorylationPhosphotyrosineProtein BindingProtein Structure, TertiaryProtein-Tyrosine KinasesReceptor, IGF Type 1Structure-Activity RelationshipSubstrate SpecificityConceptsInsulin receptorPleckstrin homology domainCrucial adaptor proteinTwo-hybrid studiesInsulin receptor kinaseKinase active siteInsulin receptor substrate 2C-terminal regionTyrosine kinase domainPrevious yeastThreonine phosphorylationHomology domainAdaptor proteinReceptor kinaseKinase domainTyrosine phosphorylationBiochemical characterizationRegion functionsSubstrate 2Binding regionsPhosphorylationKinase inhibitionFactor 1IRS2Insulin-like growth factor-1
2007
The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis
Li D, Yin X, Zmuda E, Wolford C, Dong X, White M, Hai T. The Repression of IRS2 Gene by ATF3, a Stress-Inducible Gene, Contributes to Pancreatic β-Cell Apoptosis. Diabetes 2007, 57: 635-644. PMID: 18057093, DOI: 10.2337/db07-0717.Peer-Reviewed Original ResearchMeSH KeywordsActivating Transcription Factor 3AnimalsApoptosisCell LineCells, CulturedDown-RegulationInsulinInsulin Receptor Substrate ProteinsInsulin-Secreting CellsIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutPhosphoproteinsPromoter Regions, GeneticRatsStress, PhysiologicalTime FactorsConceptsStress-inducible genesIRS2 gene expressionIRS2 promoterBinding of ATF3Gene transcriptionGene expressionExpression of IRS2Chromatin immunoprecipitation assaysIRS2 genePancreatic β-cell apoptosisEnvironmental stress factorsΒ-cell apoptosisTranscription factor 3Effect of ATF3Stress signalsImmunoprecipitation assaysBeta-cell survivalTarget genesProapoptotic genesExpression of ATF3GenesTranscriptionIRS2 expressionATF3PromoterBrain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis
Taguchi A, Wartschow L, White M. Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis. Science 2007, 317: 369-372. PMID: 17641201, DOI: 10.1126/science.1142179.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsBrainCircadian RhythmCrosses, GeneticDietFemaleGlucoseHomeostasisInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsLongevityMaleMiceMice, KnockoutMice, TransgenicOverweightOxidation-ReductionOxygen ConsumptionPhosphoproteinsRespirationSignal TransductionSuperoxide DismutasePhosphorylation of Irs1 at SER-522 Inhibits Insulin Signaling
Giraud J, Haas M, Feener E, Copps K, Dong X, Dunn S, White M. Phosphorylation of Irs1 at SER-522 Inhibits Insulin Signaling. Endocrinology 2007, 21: 2294-2302. PMID: 17579213, DOI: 10.1210/me.2007-0159.Peer-Reviewed Original ResearchConceptsTyrosine phosphorylationInsulin-stimulated tyrosine phosphorylationInsulin-stimulated IRS1 tyrosine phosphorylationIRS1 tyrosine phosphorylationInsulin-stimulated phosphorylationPhosphorylation of IRS1Threonine residuesMultisite phosphorylationPhosphorylation sitesPhosphoserine antibodyInhibits InsulinL6 myoblastsPhosphorylationCultured cellsIRS1Akt expressionPhosphatidylinositolFunctional effectsMass spectrometryPD98059WortmanninMyoblastsMyotubesRNASerineInsulin receptor substrate 1 (IRS‐1) plays a unique role in normal epidermal physiology
Sadagurski M, Nofech‐Mozes S, Weingarten G, White M, Kadowaki T, Wertheimer E. Insulin receptor substrate 1 (IRS‐1) plays a unique role in normal epidermal physiology. Journal Of Cellular Physiology 2007, 213: 519-527. PMID: 17508357, DOI: 10.1002/jcp.21131.Peer-Reviewed Original ResearchConceptsNull miceIRS-1IRS-1 null miceIRS-2Skin physiologySkin cellsNormal epidermal physiologyInsulin receptor substrate-1Primary skin cellsSkin differentiationIRS-2 proteinReceptor substrate-1Skin epidermal cellsInsulin actionAdvanced stageExpression of K1Histological analysisNull skinSkin sectionsInsulin receptor substrate (IRS) proteinsEpidermal physiologyMiceSkin keratinocytesMarked decreaseEffects of inactivationAnalysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2
Kim J, Kido Y, Scherer P, White M, Accili D. Analysis of compensatory β-cell response in mice with combined mutations of Insr and Irs2. AJP Endocrinology And Metabolism 2007, 292: e1694-e1701. PMID: 17299086, DOI: 10.1152/ajpendo.00430.2006.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAdiponectinAdipose TissueAnimalsAnimals, NewbornDiabetes MellitusGlucose Tolerance TestGrowth DisordersHyperinsulinismInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceInsulin-Secreting CellsIntracellular Signaling Peptides and ProteinsLeptinLiverMiceMice, Inbred StrainsMice, KnockoutMuscle, SkeletalMutationOrgan SizeOsmolar ConcentrationPhosphatidylinositol 3-KinasesPhosphoproteinsProto-Oncogene Proteins c-aktReceptor, InsulinConceptsBeta-cell dysfunctionBeta-cell massInsulin resistanceInsulin secretionType 2 diabetes resultsCompensatory insulin secretionBeta-cell responseImpaired insulin actionType 2 diabetesΒ-cell responseBeta-cell growthBeta-cell physiologyDiabetes resultsInsulin levelsMetabolic controlInsulin actionProgressive deteriorationDiabetesRobust increaseDysfunctionCompensatory responseMiceSecretionComprehensive treatmentINSRPlasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice.
Gonzalez-Navarro H, Vila-Caballer M, Pastor M, Vinue A, White M, Burks D, Andres V. Plasma insulin levels predict the development of atherosclerosis when IRS2 deficiency is combined with severe hypercholesterolemia in apolipoprotein E-null mice. Frontiers In Bioscience-Landmark 2007, 12: 2291-8. PMID: 17127239, DOI: 10.2741/2231.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApolipoproteins EAtherosclerosisBlood GlucoseDiabetes Mellitus, Type 2Diabetic AngiopathiesFemaleHypercholesterolemiaInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsLipidsMacrophagesMaleMiceMice, KnockoutMuscle, Smooth, VascularPhosphoproteinsConceptsInsulin receptor substrate 2ApoE-/- miceDevelopment of atherosclerosisIrs2-/- miceSevere hypercholesterolemiaInsulin levelsType 2 diabetic patientsAtherosclerotic lesion burdenPre-diabetic patientsPlasma insulin levelsFat-fed miceAbsence of hyperglycaemiaDefective insulin signalingDiabetic patientsLesion burdenClinical manifestationsInsulin resistanceModerate hypercholesterolemiaApolipoprotein EGlucose levelsAtherosclerotic lesionsAtherosclerosisHypercholesterolemiaNull miceImportant modulator
2006
Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis
Ma Z, Gibson S, Byrne M, Zhang J, White M, Shaw L. Suppression of Insulin Receptor Substrate 1 (IRS-1) Promotes Mammary Tumor Metastasis. Molecular And Cellular Biology 2006, 26: 9338-9351. PMID: 17030605, PMCID: PMC1698550, DOI: 10.1128/mcb.01032-06.Peer-Reviewed Original ResearchConceptsIRS-1Insulin receptor substrate (IRS) proteinsInsulin receptor substrate-1Wild-type levelsMetastasis suppressor functionReceptor substrate-1Cell surface receptorsBreast cancerSubstrate proteinsCytoplasmic adaptorAkt/mTOR activityMammary tumor metastasisSignificant homologySerine phosphorylationDistinct functionsSubstrate-1Mammary tumorsIRS-2MTOR activitySuppressor functionMetastatic mammary tumorsTumor cellsIR-1Surface receptorsBreast cancer metastasisThe reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling.
Guo S, Dunn S, White M. The reciprocal stability of FOXO1 and IRS2 creates a regulatory circuit that controls insulin signaling. Endocrinology 2006, 20: 3389-99. PMID: 16916938, DOI: 10.1210/me.2006-0092.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCells, CulturedFibroblastsForkhead Box Protein O1Forkhead Transcription FactorsInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMiceMice, Mutant StrainsPhosphatidylinositol 3-KinasesPhosphoproteinsProtein KinasesProto-Oncogene Proteins c-aktRecombinant ProteinsSignal TransductionTOR Serine-Threonine KinasesTyrosineConceptsInsulin stimulationWild-type mouse embryo fibroblastsInsulin-receptor substrate IRS1Metastatic mammary tumor cellsProlonged insulin stimulationMouse embryo fibroblastsTranscription factor FOXO1Substrates IRS1FoxO phosphorylationRegulatory circuitsNuclear exclusionWT MEFsTyrosine phosphorylationGene expressionMetabolic regulationEmbryo fibroblastsIRS1 expressionMammary tumor cellsIRS2 expressionCell growthIRS2AktIRS1MEFsPancreatic beta cellsRegulating insulin signaling and -cell function through IRS proteinsThis paper is one of a selection of papers published in this Special Issue, entitled Second Messengers and Phosphoproteins12th International Conference.
White M. Regulating insulin signaling and -cell function through IRS proteinsThis paper is one of a selection of papers published in this Special Issue, entitled Second Messengers and Phosphoproteins12th International Conference. Canadian Journal Of Physiology And Pharmacology 2006, 84: 725-737. PMID: 16998536, DOI: 10.1139/y06-008.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceBeta-cell destructionPeripheral insulin resistanceDiabetes mellitusChronic hyperglycemiaSystemic disordersFemale infertilityInsulin secretionCardiovascular diseaseCell functionInevitable progressionComplex disorderDisordersDiabetesGreater frequencyPrevalent formInsulinPhosphoproteins12th International ConferenceAgeSecond messengerDyslipidemiaHypertensionMellitusAutoimmune
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 defectsMuscleExendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function*
Park S, Dong X, Fisher T, Dunn S, Omer A, Weir G, White M. Exendin-4 Uses Irs2 Signaling to Mediate Pancreatic β Cell Growth and Function*. Journal Of Biological Chemistry 2005, 281: 1159-1168. PMID: 16272563, DOI: 10.1074/jbc.m508307200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCell LineCell SurvivalCyclic AMPDose-Response Relationship, DrugElectrophoresis, Polyacrylamide GelExenatideGenotypeGlucagon-Like Peptide-1 ReceptorGlucoseGuinea PigsHumansHyperglycemiaImmunoblottingImmunohistochemistryImmunoprecipitationInsulinInsulin Receptor Substrate ProteinsInsulin SecretionInsulin-Secreting CellsIntracellular Signaling Peptides and ProteinsIslets of LangerhansMiceMice, TransgenicModels, BiologicalModels, ChemicalPancreasPeptidesPhosphoproteinsPhosphorylationReceptor, InsulinReceptors, GlucagonReverse Transcriptase Polymerase Chain ReactionRNA, MessengerRNA, Small InterferingSignal TransductionTime FactorsVenomsConceptsGlucagon-like peptide-1 receptor agonistsPeptide-1 receptor agonistsReceptor agonistExendin-4Beta cellsProgressive beta cell lossShort-term therapeutic effectsInsulin-like growth factorBeta-cell lossProgression of diabetesBeta-cell massBeta-cell replicationBeta-cell growthPancreatic β-cell growthΒ-cell growthIrs2 branchPrevents diabetesInsulin/insulin-like growth factorCell growthInsulin secretionTherapeutic effectIRS2 expressionLong-term effectsFatal diabetesCell lossPhosphatase and Tensin Homolog Regulation of Islet Growth and Glucose Homeostasis*
Kushner J, Simpson L, Wartschow L, Guo S, Rankin M, Parsons R, White M. Phosphatase and Tensin Homolog Regulation of Islet Growth and Glucose Homeostasis*. Journal Of Biological Chemistry 2005, 280: 39388-39393. PMID: 16170201, DOI: 10.1074/jbc.m504155200.Peer-Reviewed Original ResearchConceptsInsulin/insulin-like growth factorWild typeIrs2 branchBeta-cell growthInsulin-like growth factorPhosphatase PTENGrowth factorFoxO1 phosphorylationBeta-cell massPTEN expressionAktPTENCascadeSmall isletsGlucose homeostasisInsulin productionGrowthIslet growthSufficient insulinPhosphatidylinositolTolerancePhosphorylationMiceSignalingHomeostasisMolecular 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 resistanceKinaseAttenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E
Clough M, Schneider D, Sobel B, White M, Wadsworth M, Taatjes D. Attenuation of Accumulation of Neointimal Lipid by Pioglitazone in Mice Genetically Deficient in Insulin Receptor Substrate-2 and Apolipoprotein E. Journal Of Histochemistry & Cytochemistry 2005, 53: 603-610. PMID: 15872053, DOI: 10.1369/jhc.4a6590.2005.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAnimalsAortaApolipoproteins EArteriosclerosisHyperlipidemiasHypoglycemic AgentsInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsLipid MetabolismMiceMice, Inbred C57BLMice, KnockoutPhosphoproteinsPioglitazoneReceptor, InsulinThiazolidinedionesTunica IntimaConceptsInsulin resistanceApolipoprotein EAcute coronary syndromeVulnerable atherosclerotic plaquesInsulin receptor substrate 2Accumulation of lipidsCoronary syndromeProximal aortaInsulin sensitizersNeointimal accumulationAtheroma formationAortic intimaAtherosclerotic lesionsAtherosclerotic plaquesType 2PioglitazoneMiceLesionsCross-sectional areaHeterozygous deficiencyAtherogenesisSubstrate 2TreatmentLipidsAtheromaAlterations in growth and apoptosis of insulin receptor substrate-1-deficient β-cells
Hennige A, Ozcan U, Okada T, Jhala U, Schubert M, White M, Kulkarni R. Alterations in growth and apoptosis of insulin receptor substrate-1-deficient β-cells. AJP Endocrinology And Metabolism 2005, 289: e337-e346. PMID: 15827066, DOI: 10.1152/ajpendo.00032.2004.Peer-Reviewed Original ResearchMeSH KeywordsAdaptation, PhysiologicalAnimalsApoptosisCell ProliferationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansIslets of Langerhans TransplantationKidneyMaleMiceMice, Inbred C57BLMice, KnockoutPhosphoproteinsSignal TransductionConceptsInsulin resistanceInsulin receptor substrateWT recipientsInsulin/IGFIRS-1 knockout miceBeta-cell proliferationBeta-cell apoptosisIslet hypoplasiaIRS-2 expressionEndogenous isletsOvert diabetesKidney capsuleIslet responseIslet functionIslet defectKnockout miceMitotic rateCompensatory increaseIslet growthDysfunctional isletsGrowth retardationTransplantation approachesΒ-cellsAntiapoptotic effectIGF