2020
Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling
Riehle C, Weatherford E, Wende A, Jaishy B, Seei A, McCarty N, Rech M, Shi Q, Reddy G, Kutschke W, Oliveira K, Pires K, Anderson J, Diakos N, Weiss R, White M, Drakos S, Xiang Y, Abel E. Insulin receptor substrates differentially exacerbate insulin-mediated left ventricular remodeling. JCI Insight 2020, 5: e134920. PMID: 32213702, PMCID: PMC7213803, DOI: 10.1172/jci.insight.134920.Peer-Reviewed Original ResearchConceptsTransverse aortic constrictionInsulin receptor substrate-1Left ventricular remodelingHeart failureVentricular remodelingCardiac hypertrophyTAC-induced LV hypertrophyPressure-overload cardiac hypertrophySevere LV dysfunctionInsulin receptor tyrosine kinase activityAkt1 activationReceptor tyrosine kinase activityLV dysfunctionLV hypertrophyWT miceInsulin resistanceLV remodelingAortic constrictionProinflammatory responseProtein kinase GInsulin receptor substrateReceptor substrate-1Kinomic profilingWT controlsTyrosine kinase activity
2019
1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction
TAO R, COPPS K, WHITE M, STOEHR O. 1835-P: Deletion of Insulin Receptor Substrate 2 in AGRP Neurons Causes Beta-Cell Dysfunction. Diabetes 2019, 68 DOI: 10.2337/db19-1835-p.Peer-Reviewed Original ResearchAgRP neuronsArcuate nucleusInsulin resistanceInsulin secretionInsulin receptor substrateType 2 diabetes progressesCompensatory insulin secretionL-arginine treatmentBeta-cell compensationBeta-cell dysfunctionPeripheral insulin resistanceBeta-cell failureBeta-cell functionHigh-fat dietInsulin secretory functionType 2 diabetesSteady-state hyperglycemiaGlucose infusion rateΒ-cell dysfunctionInsulin receptor substrate 2Pancreatic β-cellsGrowth-promoting actionDiabetes progressesFat dietHyperglycemic clamp
2014
Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training
Riehle C, Wende A, Zhu Y, Oliveira K, Pereira R, Jaishy B, Bevins J, Valdez S, Noh J, Kim B, Moreira A, Weatherford E, Manivel R, Rawlings T, Rech M, White M, Abel E. Insulin Receptor Substrates Are Essential for the Bioenergetic and Hypertrophic Response of the Heart to Exercise Training. Molecular And Cellular Biology 2014, 34: 3450-3460. PMID: 25002528, PMCID: PMC4135616, DOI: 10.1128/mcb.00426-14.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEnergy MetabolismGene Expression RegulationGlycogenHeartInsulin Receptor Substrate ProteinsMiceMice, Inbred C57BLMice, KnockoutMitochondriaPeroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alphaPhosphatidylinositol 3-KinasesProtein IsoformsSignal TransductionSwimmingTranscription FactorsConceptsInsulin receptor substrate-1IRS isoformsProtein phosphatase 2AReceptor substrate-1Insulin receptor substrateInsulin-like growth factor 1 receptorGrowth factor 1 receptorSynthase kinase-3βPeroxisome proliferator-activated receptor gamma coactivatorPhosphatase 2AProliferator-activated receptor gamma coactivatorFactor 1 receptorPGC-1α protein contentCardiomyocyte-specific deletionDevelopmental regulationProtein contentHypertrophic responseReceptor substrateReceptor gamma coactivatorFatty acid oxidationSubstrate-1Kinase-3βDivergent rolesMetabolic adaptationNonredundant role
2013
Insulin receptor substrate signaling suppresses neonatal autophagy in the heart
Riehle C, Wende A, Sena S, Pires K, Pereira R, Zhu Y, Bugger H, Frank D, Bevins J, Chen D, Perry C, Dong X, Valdez S, Rech M, Sheng X, Weimer B, Gottlieb R, White M, Abel E. Insulin receptor substrate signaling suppresses neonatal autophagy in the heart. Journal Of Clinical Investigation 2013, 123: 5319-5333. PMID: 24177427, PMCID: PMC3859408, DOI: 10.1172/jci71171.Peer-Reviewed Original ResearchMeSH KeywordsAmino AcidsAnimalsApoptosisApoptosis Regulatory ProteinsAutophagyBeclin-1Cardiomyopathy, DilatedFetal HeartHeartHeart FailureInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IMiceMitochondria, HeartMyocytes, CardiacOxidative PhosphorylationPhosphorylationProtein Processing, Post-TranslationalReceptor, IGF Type 1Signal TransductionTOR Serine-Threonine KinasesConceptsInsulin receptor substrateInduction of autophagyActivation of mTORIGF-1R signalingPostnatal cardiac developmentUnrestrained autophagyCardiomyocyte-specific deletionGenetic suppressionCardiac developmentReceptor substrateIGF-1 receptorEssential adaptationProsurvival signalingAutophagic fluxAutophagy suppressionAutophagyMitochondrial dysfunctionMammalian heartPhysiological suppressionNeonatal starvationAutophagic activationSignalingIRS1IRS2Insulin actionIrs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis
Sadagurski M, Dong X, Myers M, White M. Irs2 and Irs4 synergize in non-LepRb neurons to control energy balance and glucose homeostasis. Molecular Metabolism 2013, 3: 55-63. PMID: 24567904, PMCID: PMC3929908, DOI: 10.1016/j.molmet.2013.10.004.Peer-Reviewed Original ResearchFed blood glucose levelsBlood glucose levelsLepRb neuronsSevere obesityInsulin resistanceInsulin receptor substrateGlucose levelsLeptin receptorGlucose homeostasisBody weightInsulin/IGF1MiceMetabolic homeostasisEnergy expenditureNeuronsWhole bodyReceptor substrateIRS2Metabolic sensingHomeostasisMetabolic regulationHyperglycemiaLepRbObesityHypothalamusInsulin receptor substrate‐2 is expressed in kidney epithelium and up‐regulated in diabetic nephropathy
Hookham M, O'Donovan H, Church R, Mercier‐Zuber A, Luzi L, Curran S, Carew R, Droguett A, Mezzano S, Schubert M, White M, Crean J, Brazil D. Insulin receptor substrate‐2 is expressed in kidney epithelium and up‐regulated in diabetic nephropathy. The FEBS Journal 2013, 280: 3232-3243. PMID: 23617393, PMCID: PMC4022317, DOI: 10.1111/febs.12305.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAnimalsBase SequenceBinding SitesBone Morphogenetic Protein 7Case-Control StudiesCell LineChildDiabetic NephropathiesEpitheliumFemaleGene ExpressionHumansInsulin Receptor Substrate ProteinsKidney TubulesMaleMiceMiddle AgedPhosphorylationProtein Processing, Post-TranslationalSignal TransductionSmad4 ProteinTranscriptional ActivationYoung AdultConceptsDiabetic nephropathyBone morphogenetic protein-7DN patientsInsulin receptor substrateChronic kidney disease severityEnd-stage renal diseaseProgression of DNKidney epitheliumTyrosine/serine phosphorylationHuman kidney proximal tubule epithelial cellsKidney disease severityProximal tubule epithelial cellsKidney proximal tubule epithelial cellsHK-2 cellsRole of insulinInsulin receptor substrate 2Growth factor-β1Tubule epithelial cellsIRS2 transcriptionSDS/PAGEIRS proteinsDN progressionRenal diseaseKidney failureMorphogenetic protein-7
2012
Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2
Copps K, White M. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. Diabetologia 2012, 55: 2565-2582. PMID: 22869320, PMCID: PMC4011499, DOI: 10.1007/s00125-012-2644-8.Peer-Reviewed Original ResearchConceptsInsulin receptor substrateT phosphorylationReceptor substrateSerine/threonine residuesSerine/threonine phosphorylationInsulin receptor tyrosine kinaseInsulin-stimulated kinasesReceptor tyrosine kinasesThreonine phosphorylationThreonine residuesNegative regulationTyrosine kinasePhosphorylationCultured cellsKinaseMetabolic diseasesIRS2IRS1Hormonal controlKey targetAltered patternTail regionComplex mechanismsRegulationDysregulation
2011
Inhibition of Insulin Signaling in Endothelial Cells by Protein Kinase C-induced Phosphorylation of p85 Subunit of Phosphatidylinositol 3-Kinase (PI3K)*
Maeno Y, Li Q, Park K, Rask-Madsen C, Gao B, Matsumoto M, Liu Y, Wu I, White M, Feener E, King G. Inhibition of Insulin Signaling in Endothelial Cells by Protein Kinase C-induced Phosphorylation of p85 Subunit of Phosphatidylinositol 3-Kinase (PI3K)*. Journal Of Biological Chemistry 2011, 287: 4518-4530. PMID: 22158866, PMCID: PMC3281670, DOI: 10.1074/jbc.m111.286591.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCattleCells, CulturedClass Ia Phosphatidylinositol 3-KinaseEndothelial CellsEnzyme ActivationInsulinInsulin Receptor Substrate ProteinsMetabolic DiseasesNitric Oxide Synthase Type IIIPhosphorylationProtein Kinase CProto-Oncogene Proteins c-aktSignal TransductionVascular Endothelial Growth Factor AConceptsP85/PI3KPI3KPKC activationInsulin receptor substrateProtein kinase C activationEndothelial nitric oxide synthaseProtein kinase CAkt/endothelial nitric oxide synthaseKinase C activationPI3K/Akt pathwayP85 subunitDeletion mutantsGeneral activatorTyrosine phosphorylationReceptor substrateEndothelial cellsInsulin signalingInsulin activationKinase CAkt pathwayPhosphorylationC activationThr-86SignalingIRS1Insulin 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
2010
Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models
Cheng Z, White M. Targeting Forkhead Box O1 from the Concept to Metabolic Diseases: Lessons from Mouse Models. Antioxidants & Redox Signaling 2010, 14: 649-661. PMID: 20615072, PMCID: PMC3025764, DOI: 10.1089/ars.2010.3370.Peer-Reviewed Original ResearchConceptsForkhead box O (FOXO) transcription factorsInsulin receptor substratePhosphoenolpyruvate carboxykinaseActivation of FOXO1Β-cellsRegulation of metabolismAkt signal cascadeRole of FoxO1Transcriptional regulationForkhead box O1Β-cell proliferationStress resistanceTranscription factorsDuodenal homeobox 1Mitochondrial metabolismPancreatic β-cellsReceptor substrateSignal cascadeΒ-cell failureLipid switchesCarboxypeptidase E.Mouse modelHomeobox 1Metabolic diseasesInhibition of FOXO1Irs1 Serine 307 Promotes Insulin Sensitivity in Mice
Copps K, Hancer N, Opare-Ado L, Qiu W, Walsh C, White M. Irs1 Serine 307 Promotes Insulin Sensitivity in Mice. Cell Metabolism 2010, 11: 84-92. PMID: 20074531, PMCID: PMC3314336, DOI: 10.1016/j.cmet.2009.11.003.Peer-Reviewed Original Research
2009
The Role of Insulin‐like Signaling for the Central and Peripheral Regulation of Nutrient Homeostasis and Life Span
White M. The Role of Insulin‐like Signaling for the Central and Peripheral Regulation of Nutrient Homeostasis and Life Span. The FASEB Journal 2009, 23: 329.2-329.2. DOI: 10.1096/fasebj.23.1_supplement.329.2.Peer-Reviewed Original ResearchInsulin-like signalingNutrient homeostasisHigher animalsInsulin receptor substrateLife spanAge-related diseasesMammalian lifespanLower metazoansReceptor substrateInsulin resistanceInsulin secretionNutrient storageNarrow physiologic rangeSignalingMetazoansAction of insulinReduced insulin secretionRole of insulinHomeostasisBlood glucose concentrationCompensatory hyperinsulinemiaGlucose intolerancePeripheral regulationPeripheral tissuesGlucose homeostasis
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 rolePhosphatidylinositolThe Relationship Between the Insulin Receptor Substrates and Metabolic Disease
White M. The Relationship Between the Insulin Receptor Substrates and Metabolic Disease. Contemporary Endocrinology 2008, 255-278. DOI: 10.1007/978-1-60327-116-5_14.Peer-Reviewed Original Research
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 liversPathwayAlterations 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 effectIGFInsulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells
Yi X, Schubert M, Peachey N, Suzuma K, Burks D, Kushner J, Suzuma I, Cahill C, Flint C, Dow M, Leshan R, King G, White M. Insulin Receptor Substrate 2 Is Essential for Maturation and Survival of Photoreceptor Cells. Journal Of Neuroscience 2005, 25: 1240-1248. PMID: 15689562, PMCID: PMC6725974, DOI: 10.1523/jneurosci.3664-04.2005.Peer-Reviewed Original ResearchMeSH KeywordsAge FactorsAnimalsAnimals, NewbornApoptosisCell SurvivalDiabetic RetinopathyEye ProteinsGene DeletionHomeodomain ProteinsHyperglycemiaHyperinsulinismInsulin Receptor Substrate ProteinsInsulin ResistanceInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsMiceMice, KnockoutPhosphoproteinsPhosphorylationPhotic StimulationPhotoreceptor CellsProtein Processing, Post-TranslationalProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktRetinal Ganglion CellsSignal TransductionTrans-ActivatorsConceptsIrs2-/- micePhotoreceptor cellsPlexiform layerInsulin receptor substrate 2Insulin receptor substrateInsulin-like growth factor 1 receptorGrowth factor 1 receptorMost photoreceptor cellsInner plexiform layerOuter plexiform layerFactor 1 receptorFinal common pathwaySurvival of photoreceptorsNormal electrical functionMonths of ageWeeks of ageReceptor substrateCellular growthSubstrate 2Akt phosphorylationGanglion cellsIRS2 expressionPharmacological strategiesControl littermatesPhotoreceptor degeneration
2004
Signaling Pathways: The Benefits of Good Communication
Fisher T, White M. Signaling Pathways: The Benefits of Good Communication. Current Biology 2004, 14: r1005-r1007. PMID: 15589136, DOI: 10.1016/j.cub.2004.11.024.Peer-Reviewed Original ResearchIRS‐2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes
Valverde A, Fabregat I, Burks D, White M, Benito M. IRS‐2 mediates the antiapoptotic effect of insulin in neonatal hepatocytes. Hepatology 2004, 40: 1285-1294. PMID: 15565601, DOI: 10.1002/hep.20485.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, NewbornApoptosisApoptosis Regulatory ProteinsBcl-2-Like Protein 11Bcl-X ProteinBlood ProteinsCarrier ProteinsEpidermal Growth FactorFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene ExpressionHepatocytesHypoglycemic AgentsInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMaleMembrane ProteinsMiceMice, Mutant StrainsPhosphatidylinositol 3-KinasesPhosphoproteinsPregnancyProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktProto-Oncogene Proteins c-bcl-2Signal TransductionTranscription FactorsConceptsCaspase-3 activityIRS-2Caspase-3 activationGene expressionWild-type hepatocytesDominant negative FoxO1Wild-type cellsSerum withdrawal-induced apoptosisInsulin receptor substrateWithdrawal-induced apoptosisAnti-apoptotic gene expressionImmortalized hepatocyte cell linesIRS-2 signalingPIP3 generationProapoptotic gene expressionAntiapoptotic gene expressionProlonged insulin treatmentEpidermal growth factorActive FoxO1Receptor substrateNeonatal hepatocytesProapoptotic genesAntiapoptotic genesCaspase-8Serum withdrawalMammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation
Carlson C, White M, Rondinone C. Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation. Biochemical And Biophysical Research Communications 2004, 316: 533-539. PMID: 15020250, DOI: 10.1016/j.bbrc.2004.02.082.Peer-Reviewed Original ResearchConceptsSerine 307 phosphorylationSerine 307Rapamycin-sensitive mannerInsulin receptor substrateRole of mTORAmino acid stimulationActivation of mTORPhosphatase PP2AKinase mTOROkadaic acidReceptor substrateInsulin signalingIRS-1MTOR activityPhosphorylationMammalian targetMTORCytosolic fractionRapamycinPP2AAcid stimulationPKBInhibitorsSignalingJNK