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
2016
Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice
Kuznetsova A, Yu Y, Hollister-Lock J, Opare-Addo L, Rozzo A, Sadagurski M, Norquay L, Reed J, Khattabi I, Bonner-Weir S, Weir G, Sharma A, White M. Trimeprazine increases IRS2 in human islets and promotes pancreatic β cell growth and function in mice. JCI Insight 2016, 1: e80749. PMID: 27152363, PMCID: PMC4854304, DOI: 10.1172/jci.insight.80749.Peer-Reviewed Original ResearchInsulin receptor substrate 2Progression of diabetesΒ-cell growthHuman isletsΒ-cellsHuman islet transplantsIsolated human pancreatic isletsAdverse systemic effectsFirst-generation antihistaminesHistamine H1 receptorsΒ-cell replicationPancreatic β-cell growthAnti-CD3 AbPancreatic β-cellsHuman pancreatic isletsNuclear Pdx1NOD miceIslet transplantsDiabetic miceCell growthH1 receptorsIslet massIRS2 expressionDownstream signaling cascadesGlucose homeostasis
2013
Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling
Ersoy B, Tarun A, D’Aquino K, Hancer N, Ukomadu C, White M, Michel T, Manning B, Cohen D. Phosphatidylcholine Transfer Protein Interacts with Thioesterase Superfamily Member 2 to Attenuate Insulin Signaling. Science Signaling 2013, 6: ra64. PMID: 23901139, PMCID: PMC3959124, DOI: 10.1126/scisignal.2004111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGlucoseHEK293 CellsHomeostasisHumansInhibitory Concentration 50InsulinLiverMechanistic Target of Rapamycin Complex 1MiceMice, TransgenicMultiprotein ComplexesPhospholipid Transfer ProteinsPhosphorylationSignal TransductionThiolester HydrolasesTOR Serine-Threonine KinasesTuberous Sclerosis Complex 2 ProteinTumor Suppressor ProteinsConceptsThioesterase superfamily member 2Insulin receptor substrate 2Phosphatidylcholine transfer proteinTSC1-TSC2 complexGenetic ablationRapamycin complex 1Transfer proteinSteady-state amountsMember 2Hepatic glucose homeostasisPhospholipid-binding proteinProtein exhibitInsulin signalingChemical inhibitionKey effectorsSubstrate 2Mammalian targetDiet-induced diabetesProteinTSC2KnockdownGlucose homeostasisPhospholipid-dependent mechanismsActivationComplexes 1Insulin 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
2011
IRS-2 Deficiency Impairs NMDA Receptor-Dependent Long-term Potentiation
Martín E, Sánchez-Perez A, Trejo J, Martin-Aldana J, Jaimez M, Pons S, Umanzor C, Menes L, White M, Burks D. IRS-2 Deficiency Impairs NMDA Receptor-Dependent Long-term Potentiation. Cerebral Cortex 2011, 22: 1717-1727. PMID: 21955917, PMCID: PMC3388895, DOI: 10.1093/cercor/bhr216.Peer-Reviewed Original ResearchConceptsLong-term potentiationInduction of LTPInsulin receptor substrate 2Activation of FynPotential new componentSynaptic transmissionSynaptic plasticityWild-type controlsSubstrate 2Alzheimer's diseasePostsynaptic N-methyl-D-aspartate receptorsIRS2 expressionN-methyl-D-aspartate receptorsImpairs long-term potentiationInsulin-like growth factor IMechanistic linkNMDA receptor-dependent long-term potentiationType 2 diabeticsBasal synaptic transmissionExpression of NR2AGroups of miceGrowth factor IPaired-pulse facilitationNeurodegenerative disordersTetanus stimulation
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 populationInsulin Receptor Substrate-2 in β-Cells Decreases Diabetes in Nonobese Diabetic Mice
Norquay L, D'Aquino K, Opare-Addo L, Kuznetsova A, Haas M, Bluestone J, White M. Insulin Receptor Substrate-2 in β-Cells Decreases Diabetes in Nonobese Diabetic Mice. Endocrinology 2009, 150: 4531-4540. PMID: 19574401, PMCID: PMC2754683, DOI: 10.1210/en.2009-0395.Peer-Reviewed Original ResearchConceptsNonobese diabetic (NOD) miceBeta-cell destructionNOD miceInsulin receptor substrate 2Glucose toleranceDiabetes incidenceDiabetic miceIslet massAnti-CD3 antibody injectionNondiabetic NOD miceReduced diabetes incidenceRisk of diabetesBeta-cell massType 1 diabetesBetter glucose toleranceAnti-CD3 antibodyBeta-cell growthWk of ageDiabetic NODSevere insulitisOvert diabetesSubstrate 2C57BL/6 miceBeta-cell mitogenesisAntibody injection
2008
Response to Comment on "Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis"
Taguchi A, White M. Response to Comment on "Brain IRS2 Signaling Coordinates Life Span and Nutrient Homeostasis". Science 2008, 320: 1012-1012. DOI: 10.1126/science.1152620.Peer-Reviewed Original ResearchGenetic 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 actionStructural 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
Brain 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 DismutasePlasma 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
2005
Attenuation 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 2TreatmentLipidsAtheromaInsulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport*
Sadagurski M, Weingarten G, Rhodes C, White M, Wertheimer E. Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport*. Journal Of Biological Chemistry 2005, 280: 14536-14544. PMID: 15705592, DOI: 10.1074/jbc.m410227200.Peer-Reviewed Original ResearchMeSH KeywordsAdenoviridaeAnimalsBiological TransportDeoxyglucoseEpidermisFibroblastsGenotypeGlucoseHomozygoteImmunoblottingImmunoprecipitationInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsKeratinocytesMiceMice, KnockoutPhosphatidylinositol 3-KinasesPhosphoproteinsSkinThymidineTime FactorsConceptsIRS-2Glucose transportInsulin receptor substrate-2 proteinInsulin-induced glucose transportInsulin receptor substrate 2Insulin-stimulated glucose transportIRS-1 proteinCell specific associationIRS-2 proteinClassical insulin target tissuesCell-specific mannerSkin epidermal keratinocytesIRS-PICell-specific rolePositive regulatorInsulin target tissuesCell physiologyDermal fibroblastsKO cellsEpidermal keratinocytesAkt activationPhosphatidylinositolSubstrate 2Insulin receptorProteinInsulin 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 degenerationDeletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice
Uchida T, Nakamura T, Hashimoto N, Matsuda T, Kotani K, Sakaue H, Kido Y, Hayashi Y, Nakayama K, White M, Kasuga M. Deletion of Cdkn1b ameliorates hyperglycemia by maintaining compensatory hyperinsulinemia in diabetic mice. Nature Medicine 2005, 11: 175-182. PMID: 15685168, DOI: 10.1038/nm1187.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCell Cycle ProteinsCell NucleusCyclin-Dependent Kinase Inhibitor p27Diabetes Mellitus, Type 2Disease Models, AnimalEnzyme InhibitorsHyperglycemiaHyperinsulinismInsulin Receptor Substrate ProteinsInsulin-Like Growth Factor IIntracellular Signaling Peptides and ProteinsIslets of LangerhansLeptinMiceMice, KnockoutPhosphoproteinsProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktReceptors, Cell SurfaceReceptors, LeptinSignal TransductionTumor Suppressor ProteinsConceptsCyclin-dependent kinasesInsulin receptor substrate 2Cell cycle progressionPancreatic beta cell proliferationPotential new targetsCompensatory hyperinsulinemiaCycle progressionProtein p27Kip1Substrate 2Type 2 diabetes mellitusPancreatic beta cellsP27Kip1Beta-cell failureBeta-cell proliferationType 2 diabetesLong formNew targetsDeletionDiabetes mellitusDiabetic miceIslet massLeptin receptorBeta cellsAnimal modelsMice
2004
Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis
Nagle J, Ma Z, Byrne M, White M, Shaw L. Involvement of Insulin Receptor Substrate 2 in Mammary Tumor Metastasis. Molecular And Cellular Biology 2004, 24: 9726-9735. PMID: 15509777, PMCID: PMC525494, DOI: 10.1128/mcb.24.22.9726-9735.2004.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsApoptosisBase SequenceBreast NeoplasmsCell Line, TumorDNA, NeoplasmFemaleHumansInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsMammary Neoplasms, ExperimentalMiceMice, Inbred C57BLMice, KnockoutMice, TransgenicMitosisNeoplasm InvasivenessPhosphoproteinsPhosphorylationConceptsIRS-2Insulin receptor substrate (IRS) proteinsMammary tumor cellsPolyoma virus middle T antigenInsulin receptor substrate 2Middle T antigenGrowth factor deprivationTumor cellsIRS-2 expressionSubstrate proteinsPyV mTMammary tumor metastasisApoptotic stimuliFactor deprivationAdaptor moleculeIncidence of metastasisMitotic cellsMammary fat padMammary tumor progressionBreast cancer metastasisHuman breast cancerSubstrate 2T antigenTumor initiationCancer metastasisDysregulation 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 failureCells
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 expression