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
2008
Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance
Tanabe K, Liu Z, Patel S, Doble B, Li L, Cras-Méneur C, Martinez S, Welling C, White M, Bernal-Mizrachi E, Woodgett J, Permutt M. Genetic Deficiency of Glycogen Synthase Kinase-3β Corrects Diabetes in Mouse Models of Insulin Resistance. PLOS Biology 2008, 6: e37. PMID: 18288891, PMCID: PMC2245985, DOI: 10.1371/journal.pbio.0060037.Peer-Reviewed Original ResearchConceptsBeta-cell massIrs2-/- miceInsulin resistanceMouse modelType 2 diabetes mellitusObese insulin-resistant individualsWhole-body glucose disposalOnset of diabetesPdx1 levelsBeta-cell functionBeta-cell lossInsulin-resistant individualsBeta-cell replicationGSK-3betaBeta-cell proliferationInsulin receptor substrate 2Cyclin-dependent kinase inhibitorDiabetes mellitusDiabetes onsetEarly diabetesPI-3K/Akt pathwayGlucose disposalGSK-3beta activityDiabetesInsulin action
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 failureCellsIslet-Sparing Effects of Protein Tyrosine Phosphatase-1b Deficiency Delays Onset of Diabetes in IRS2 Knockout Mice
Kushner J, Haj F, Klaman L, Dow M, Kahn B, Neel B, White M. Islet-Sparing Effects of Protein Tyrosine Phosphatase-1b Deficiency Delays Onset of Diabetes in IRS2 Knockout Mice. Diabetes 2004, 53: 61-66. PMID: 14693698, DOI: 10.2337/diabetes.53.1.61.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCrosses, GeneticDiabetes Mellitus, Type 1Glucose Tolerance TestInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsIslets of LangerhansKineticsLeptinMaleMiceMice, KnockoutModels, AnimalPhosphoproteinsProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine PhosphatasesSignal TransductionConceptsPeripheral insulin sensitivityBeta-cell areaBeta-cell functionInsulin sensitivityPancreatic beta cell areaPancreatic beta-cell functionDecreased insulin requirementIrs2 knockout miceBeta cell homeostasisMonths of ageInsulin requirementsPeripheral actionsGlucose toleranceGlucose homeostasisKnockout miceDelay onsetMiceInsulin receptorPTP1B deficiencyDiabetesReceptor complexIRS2Novel roleInsulinDownstream targets
2003
Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes
Hennige A, Burks D, Ozcan U, Kulkarni R, Ye J, Park S, Schubert M, Fisher T, Dow M, Leshan R, Zakaria M, Mossa-Basha M, White M. Upregulation of insulin receptor substrate-2 in pancreatic β cells prevents diabetes. Journal Of Clinical Investigation 2003, 112: 1521-1532. PMID: 14617753, PMCID: PMC259126, DOI: 10.1172/jci18581.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisCell SizeDiabetes Mellitus, ExperimentalDiabetes Mellitus, Type 2Dietary FatsGene Expression RegulationHumansInsulinInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansIslets of Langerhans TransplantationMaleMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicPhosphoproteinsReceptor, InsulinSignal TransductionSurvival RateUp-RegulationConceptsPancreatic beta-cell functionPeripheral insulin actionBeta-cell failureBeta-cell functionType 2 diabetesIrs2-/- miceInsulin receptor substrate 2Beta-cell growthBeta cell-specific expressionPrevents diabetesObese miceTransgenic isletsInsulin secretionWT isletsIRS2 expressionPharmacological approachesBeta cellsPhysiologic responsesInsulin actionRational treatmentDiabetesInsulin/IGFCell functionMiceCell-specific expressionInsulin 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
2001
IRS proteins and beta-cell function.
Burks D, White M. IRS proteins and beta-cell function. Diabetes 2001, 50: s140. PMID: 11272176, DOI: 10.2337/diabetes.50.2007.s140.Peer-Reviewed Original ResearchConceptsInsulin receptor substrateIRS proteinsIRS protein familyBeta-cell functionBeta-cell massClassical insulin target tissuesDownstream effector pathwaysPeripheral insulin resistanceIRS-2 geneInsulin resistanceProtein familyInsulin target tissuesReceptor substrateIRS-1Effector pathwaysPancreatic beta-cell massInsulin secretory reserveGrowth-promoting actionProteinBeta-cell dysfunctionSomatic growthType 2 diabetesCritical roleDiabetic phenotypeRegulation
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 action and type 2 diabetes: lessons from knockout mice
Withers D, White M. Insulin action and type 2 diabetes: lessons from knockout mice. Current Opinion In Endocrinology Diabetes And Obesity 1999, 6: 141-145. DOI: 10.1097/00060793-199904000-00010.Peer-Reviewed Original ResearchBeta-cell functionType 2 diabetesInsulin signal transduction pathwayInsulin receptor resultsSignal transduction pathwaysGlucose homeostasisInsulin receptor substrateClassical insulin target tissuesInsulin actionBeta cell-specific deletionCell functionPancreatic beta-cell functionPeripheral insulin actionKnockout mouse modelInsulin target tissuesCell-specific deletionTransduction pathwaysReceptor substrateSignaling pathwaysUnsuspected roleNew experimental modelInsulin resistanceNovel insightsNovel mechanismGlucose disposal