2021
Irs2 deficiency alters hippocampus-associated behaviors during young adulthood
Tanokashira D, Wang W, Maruyama M, Kuroiwa C, White M, Taguchi A. Irs2 deficiency alters hippocampus-associated behaviors during young adulthood. Biochemical And Biophysical Research Communications 2021, 559: 148-154. PMID: 33940386, PMCID: PMC8361845, DOI: 10.1016/j.bbrc.2021.04.101.Peer-Reviewed Original ResearchConceptsYoung adult male miceAdult male miceMale miceAlzheimer's diseaseType 2 diabetes mellitusInsulin-like growth factor-1Brain energy metabolismGrowth factor-1Young adult malesCore body temperatureDiabetes mellitusInsulin resistanceInsulin/insulin-like growth factor-1Risk factorsBehavioral alterationsCognitive impairmentGenetic backgroundPremature deathHippocampusMiceYoung adulthoodAberrant alterationsFactor 1Abnormal changesBody temperatureInsulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice
Takatani T, Shirakawa J, Shibue K, Gupta M, Kim H, Lu S, Hu J, White M, Kennedy R, Kulkarni R. Insulin receptor substrate 1, but not IRS2, plays a dominant role in regulating pancreatic alpha cell function in mice. Journal Of Biological Chemistry 2021, 296: 100646. PMID: 33839150, PMCID: PMC8131928, DOI: 10.1016/j.jbc.2021.100646.Peer-Reviewed Original ResearchConceptsAKT Ser/Thr kinaseInsulin receptor substrate (IRS) proteinsSer/Thr kinaseAlpha-cell functionGlobal protein translationCell functionInsulin receptor substrate-1Pancreatic alpha-cell functionDownstream target genesReceptor substrate-1Alpha cellsAlpha-cell lineGlucagon secretionSubstrate proteinsProtein translationTarget genesSubstrate-1Downstream proteinsDominant regulatorPancreatic alpha cellsMitochondrial dysfunctionCognate receptorsIRS2Normal glucose toleranceCell lines
2020
Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance
Sutton A, Gonzalez I, Sadagurski M, Rajala M, Lu C, Allison M, Adams J, Myers M, White M, Olson D. Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Scientific Reports 2020, 10: 5546. PMID: 32218485, PMCID: PMC7099088, DOI: 10.1038/s41598-020-62468-z.Peer-Reviewed Original ResearchConceptsEnergy expenditureEnergy expenditure regulationAnti-obesity therapiesFeeding-related behaviorsNormal energy balanceInsulin receptor substrate 4Negative energy balancePVH neuronsHypothalamic circuitryHypothalamic sitesEnergy balance controlFeeding suppressionParaventricular nucleusSatiety responseSubstantial obesityNormal feedingPVHNeuronsViral toolsNeural componentsHindbrain regionsObesityRequisite roleBalance controlEnergy balance
2018
Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver
Kalvisa A, Siersbæk M, Præstholm S, Christensen L, Nielsen R, Stohr O, Vettorazzi S, Tuckermann J, White M, Mandrup S, Grøntved L. Insulin signaling and reduced glucocorticoid receptor activity attenuate postprandial gene expression in liver. PLOS Biology 2018, 16: e2006249. PMID: 30532187, PMCID: PMC6301715, DOI: 10.1371/journal.pbio.2006249.Peer-Reviewed Original ResearchConceptsCircadian gene transcriptionGene transcriptionGene expressionCircadian-regulated genesInsulin-regulated genesGenomic approachesGlucocorticoid receptorGene programEnhancer activityCistromic analysisGlucocorticoid receptor activityGenesMechanistic insightsTranscriptionFeeding behaviorSelective disruptionDiet-induced obese animalsEnhancerReceptor activityFeeding responseDiet-induced obesityExpressionDysregulationChromatinFOXO1Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Huang H, Lee S, Sousa-Lima I, Kim S, Hwang W, Dagon Y, Yang W, Cho S, Kang M, Seo J, Shibata M, Cho H, Belew G, Bhin J, Desai B, Ryu M, Shong M, Li P, Meng H, Chung B, Hwang D, Kim M, Park K, Macedo M, White M, Jones J, Kim Y. Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Journal Of Clinical Investigation 2018, 128: 5335-5350. PMID: 30226474, PMCID: PMC6264719, DOI: 10.1172/jci63562.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic lipid accumulationLiver diseaseInsulin resistanceRisk factorsNovo lipogenesisObesity-related metabolic disordersLipid accumulationObesity-induced steatosisChronic liver diseaseObese diabetic miceDiet-induced obesityMajor risk factorSevere hepatic steatosisHigh-fat dietDe novo lipogenesisThermogenic gene expressionRho kinase 1Antidiabetes drugsDiabetic miceHepatic steatosisActivation of AMPKHepatocellular carcinomaMetabolic disorders
2017
Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity
Cao J, Peng J, An H, He Q, Boronina T, Guo S, White M, Cole P, He L. Endotoxemia-mediated activation of acetyltransferase P300 impairs insulin signaling in obesity. Nature Communications 2017, 8: 131. PMID: 28743992, PMCID: PMC5526866, DOI: 10.1038/s41467-017-00163-w.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorE1A-Associated p300 ProteinEndoplasmic Reticulum StressEndotoxemiaGene Expression ProfilingImmunoblottingInsulinInsulin ResistanceLipopolysaccharidesLiverMaleMembrane ProteinsMice, Inbred C57BLMice, ObeseObesityProtein Serine-Threonine KinasesReceptor, InsulinSignal TransductionX-Box Binding Protein 1ConceptsInsulin resistanceP300 acetyltransferase activityHigh-fat diet-fedChronic low-grade inflammationObese ob/ob miceOb/ob miceLow-grade inflammationDiet-induced obesityAcetyltransferase activityElevated plasma concentrationsPromising therapeutic targetCytoplasm of hepatocytesEndoplasmic reticulum stressObese patientsObese miceInsulin sensitivityIntestinal permeabilityOb micePlasma concentrationsDisrupts insulinTherapeutic targetImpairs insulinPharmacological inhibitionGlucose productionObesity
2016
IRS proteins and diabetic complications
Lavin D, White M, Brazil D. IRS proteins and diabetic complications. Diabetologia 2016, 59: 2280-2291. PMID: 27514532, PMCID: PMC5506098, DOI: 10.1007/s00125-016-4072-7.Peer-Reviewed Original ResearchConceptsIRS proteinsType 2 diabetesDiabetic complicationsMitogen-activated protein kinaseElicit cellular responsesCoronary artery diseaseElevated blood glucoseComplications of diabetesProtein kinaseDownstream effectorsAdaptor moleculeInsulin signalingCellular responsesNumber of organsInsulin receptorMacrovascular complicationsMicrovascular complicationsArtery diseasePatient morbidityBlood glucoseProteinMale micePatient outcomesCell proliferationComplicationsInsulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma
Metz H, Kargl J, Busch S, Kim K, Kurland B, Abberbock S, Randolph-Habecker J, Knoblaugh S, Kolls J, White M, Houghton A. Insulin receptor substrate-1 deficiency drives a proinflammatory phenotype in KRAS mutant lung adenocarcinoma. Proceedings Of The National Academy Of Sciences Of The United States Of America 2016, 113: 8795-8800. PMID: 27439864, PMCID: PMC4978299, DOI: 10.1073/pnas.1601989113.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate-1Janus kinase/signal transducerKinase/signal transducerTumor burdenActivator of transcriptionReceptor substrate-1IRS-1 deficiencyKRAS-mutant lung adenocarcinomaInsulin-like growth factor receptorAdenoviral Cre recombinaseIL-22 receptorMutant lung adenocarcinomaTumor-promoting inflammationAdaptor proteinSignificant survival disadvantageGrowth factor receptorSignal transducerSubstrate-1PI3KProinflammatory phenotypeLung cancerLung adenocarcinomaMutant subgroupTissue microarrayCre recombinase
2014
APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor
Ryu J, Galan A, Xin X, Dong F, Abdul-Ghani M, Zhou L, Wang C, Li C, Holmes B, Sloane L, Austad S, Guo S, Musi N, DeFronzo R, Deng C, White M, Liu F, Dong L. APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor. Cell Reports 2014, 7: 1227-1238. PMID: 24813896, PMCID: PMC4380268, DOI: 10.1016/j.celrep.2014.04.006.Peer-Reviewed Original Research
2013
Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells
Park K, Li Q, Rask-Madsen C, Mima A, Mizutani K, Winnay J, Maeda Y, D'Aquino K, White M, Feener E, King G. Serine Phosphorylation Sites on IRS2 Activated by Angiotensin II and Protein Kinase C To Induce Selective Insulin Resistance in Endothelial Cells. Molecular And Cellular Biology 2013, 33: 3227-3241. PMID: 23775122, PMCID: PMC3753901, DOI: 10.1128/mcb.00506-13.Peer-Reviewed Original ResearchMeSH KeywordsAngiotensin IIAnimalsCattleCell LineEndothelial CellsEnzyme ActivationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceMaleMiceMice, TransgenicPhosphatidylinositol 3-KinasesPhosphorylationProtein Kinase CProtein Kinase C betaRatsRats, ZuckerSerineTetradecanoylphorbol AcetateThreonineTyrosineInsulin 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-7Chronic activation of a designer Gq-coupled receptor improves β cell function
Jain S, de Azua I, Lu H, White M, Guettier J, Wess J. Chronic activation of a designer Gq-coupled receptor improves β cell function. Journal Of Clinical Investigation 2013, 123: 1750-1762. PMID: 23478411, PMCID: PMC3613926, DOI: 10.1172/jci66432.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Line, TumorCell ProliferationClozapineDiabetes Mellitus, ExperimentalDrug Evaluation, PreclinicalFemaleGene ExpressionGTP-Binding Protein alpha Subunits, Gq-G11Hypoglycemic AgentsInsulin Receptor Substrate ProteinsInsulin-Secreting CellsMaleMAP Kinase Signaling SystemMiceMice, Inbred C57BLMice, TransgenicMolecular Targeted TherapyMuscarinic AgonistsProtein EngineeringReceptor, Muscarinic M3Receptors, G-Protein-CoupledRecombinant ProteinsConceptsΒ-cell functionΒ-cellsCell functionPancreatic β-cell functionStreptozotocin-induced diabetesBeneficial metabolic effectsTreatment of T2D.High-fat dietType 2 diabetesNovel antidiabetic drugsType G proteinsClasses of receptorsChronic stimulationMetabolic deficitsAntidiabetic drugsMetabolic effectsChronic activationGlucose homeostasisTherapeutic strategiesCell pathwaysEnhanced expressionReceptorsNumerous receptorsCellular effectsDiabetes
2012
Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling
Matveyenko A, Liuwantara D, Gurlo T, Kirakossian D, Man C, Cobelli C, White M, Copps K, Volpi E, Fujita S, Butler P. Pulsatile Portal Vein Insulin Delivery Enhances Hepatic Insulin Action and Signaling. Diabetes 2012, 61: 2269-2279. PMID: 22688333, PMCID: PMC3425431, DOI: 10.2337/db11-1462.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2DogsForkhead Transcription FactorsGlucokinaseInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceInsulin SecretionLiverMaleNerve Tissue ProteinsPortal VeinProto-Oncogene Proteins c-aktRatsRats, Sprague-DawleySignal TransductionConceptsPulsatile insulin secretionHepatic insulin actionInsulin secretionHepatic insulinPortal veinInsulin deliveryPulsatile patternInsulin actionDiscrete insulin secretory burstsHepatic insulin receptor substrateImpaired activationType 2 diabetes mellitusSequential liver biopsiesIntraportal insulin infusionInsulin secretory burstsHepatic insulin resistanceHepatic portal veinExpression of glucokinaseGlycemic controlDiabetes mellitusLiver biopsyInsulin resistanceInsulin infusionSecretory burstsRat modelIRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action
Sadagurski M, Leshan R, Patterson C, Rozzo A, Kuznetsova A, Skorupski J, Jones J, Depinho R, Myers M, White M. IRS2 Signaling in LepR-b Neurons Suppresses FoxO1 to Control Energy Balance Independently of Leptin Action. Cell Metabolism 2012, 15: 703-712. PMID: 22560222, PMCID: PMC3361909, DOI: 10.1016/j.cmet.2012.04.011.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBrainCytoskeletal ProteinsEnergy MetabolismFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene ExpressionGlucoseGlucose IntoleranceHomeostasisInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLeptinMaleMiceMice, TransgenicNerve Tissue ProteinsNeuronsObesityReceptors, LeptinSignal TransductionConceptsLeptin actionGlucose homeostasisGlucose intoleranceInsulin resistanceHormone leptinFoxO1 nuclear exclusionIRS2 expressionLeptin receptorMetabolic actionsNeuronsMiceEnergy balanceFOXO1Metabolic sensingIRS2HomeostasisGene expressionNuclear exclusionObesityLeptinExpressionCNSInsulinIntoleranceBrainThe AKTion in non-canonical insulin signaling
Cheng Z, White M. The AKTion in non-canonical insulin signaling. Nature Medicine 2012, 18: 351-353. PMID: 22395698, PMCID: PMC3982803, DOI: 10.1038/nm.2694.Peer-Reviewed Original Research
2011
IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease
Sadagurski M, Cheng Z, Rozzo A, Palazzolo I, Kelley G, Dong X, Krainc D, White M. IRS2 increases mitochondrial dysfunction and oxidative stress in a mouse model of Huntington disease. Journal Of Clinical Investigation 2011, 121: 4070-4081. PMID: 21926467, PMCID: PMC3195462, DOI: 10.1172/jci46305.Peer-Reviewed Original ResearchMeSH KeywordsAgingAnimalsBrainDisease Models, AnimalDisease ProgressionFemaleForkhead Box Protein O1Forkhead Transcription FactorsGene ExpressionHumansHuntington DiseaseInsulin Receptor Substrate ProteinsLongevityMaleMiceMice, KnockoutMice, Mutant StrainsMice, TransgenicMitochondriaOxidative StressSignal TransductionConceptsHuntington's diseaseOxidative stressMouse modelProgression of HDMitochondrial dysfunctionMajor risk factorR6/2 mouse modelNeuronal oxidative stressMitochondrial functionHD-like symptomsHD patientsNumber of autophagosomesTranscription factor FOXO1Risk factorsR6/2 miceSlow progressionTherapeutic approachesExpression of IRS2HD progressionLife spanNeurodegenerative diseasesIRS2 levelsProgressionDiseaseMice
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
Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis
Liang L, Guo W, Esquiliano D, Asai M, Rodriguez S, Giraud J, Kushner J, White M, Lopez M. Insulin-Like Growth Factor 2 and the Insulin Receptor, But Not Insulin, Regulate Fetal Hepatic Glycogen Synthesis. Endocrinology 2009, 151: 741-747. PMID: 20032056, PMCID: PMC2817628, DOI: 10.1210/en.2009-0705.Peer-Reviewed Original ResearchConceptsGlycogen synthesisInsulin receptorFetal liverInsulin receptor substrate 2Insulin-like growth factor 2Knockout mouse strainIR-A isoformGlycogen synthaseMajor regulatorGrowth factor 2Akt proteinSubstrate 2Insulin receptor isoformsGlycogen metabolismIgf2 deficiencyPDX-1Factor 2Receptor isoformsHepatic glycogen synthesisHepatic glycogen metabolismINSRIGF2Fetal hepatocytesIsoformsMouse strainsThe IRS2 Gly1057Asp Variant Is Associated With Human Longevity
Barbieri M, Rizzo M, Papa M, Boccardi V, Esposito A, White M, Paolisso G. The IRS2 Gly1057Asp Variant Is Associated With Human Longevity. The Journals Of Gerontology Series A 2009, 65A: 282-286. PMID: 19887537, DOI: 10.1093/gerona/glp154.Peer-Reviewed Original ResearchConceptsInsulin receptor substrate 2Gene polymorphismsYears of ageIGF-1 signalingSs-cell functionInsulin-like growth factor-1 signalingIrs2 branchInsulin resistanceInsulin sensitivityMetabolic covariatesGly1057Asp variantIRS2 geneExtreme old ageLarge population groupsInternal medicineC participantsOlder ageHuman longevityCommon polymorphismsIGF signalingInsulinFurther studiesPopulation groupsAgeWhole population
2008
Irs2 Inactivation Suppresses Tumor Progression in Pten +/− Mice
Szabolcs M, Keniry M, Simpson L, Reid L, Koujak S, Schiff S, Davidian G, Licata S, Gruvberger-Saal S, Murty V, Nandula S, Efstratiadis A, Kushner J, White M, Parsons R. Irs2 Inactivation Suppresses Tumor Progression in Pten +/− Mice. American Journal Of Pathology 2008, 174: 276-286. PMID: 19095950, PMCID: PMC2631340, DOI: 10.2353/ajpath.2009.080086.Peer-Reviewed Original ResearchConceptsPI3KInsulin receptor substrate-2 expressionProstatic intraepithelial neoplasiaHuman prostate cancerCancer cell growthSuppresses tumor progressionIntraepithelial neoplasiaInitiation of neoplasiaProstate cancerIRS2 expressionMultiple organsExpression of MYCTumor progressionTumor samplesMiceHuman cancersMYC expressionProgressionExpression levelsPTEN levelsBasement membraneIRS2NeoplasiaTumorsCancer