2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammation
2001
Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes
Zhang C, Baffy G, Perret P, Krauss S, Peroni O, Grujic D, Hagen T, Vidal-Puig A, Boss O, Kim Y, Zheng X, Wheeler M, Shulman G, Chan C, Lowell B. Uncoupling Protein-2 Negatively Regulates Insulin Secretion and Is a Major Link between Obesity, β Cell Dysfunction, and Type 2 Diabetes. Cell 2001, 105: 745-755. PMID: 11440717, DOI: 10.1016/s0092-8674(01)00378-6.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAnimalsBlood GlucoseBody WeightDiabetes MellitusDiabetes Mellitus, Type 2Disease Models, AnimalGene TargetingHomeostasisHumansHyperglycemiaInsulinInsulin SecretionIon ChannelsIslets of LangerhansMaleMembrane Transport ProteinsMiceMice, KnockoutMice, ObeseMitochondrial ProteinsModels, BiologicalObesityProteinsRNA, MessengerThermogenesisUncoupling AgentsUncoupling Protein 2ConceptsOb/ob miceInsulin secretionOb miceCell dysfunctionFirst-phase insulin secretionIslet ATP levelsGlucose-stimulated insulin secretionLevel of glycemiaSerum insulin levelsBeta-cell dysfunctionType 2 diabetesObesity-induced diabetesΒ-cell dysfunctionBeta-cell glucose sensingProtein 2UCP2-deficient miceInsulin levelsPathophysiologic significanceBeta cellsType 2SecretionMiceObesityATP levelsDiabetesInsulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ)
Cho H, Mu J, Kim J, Thorvaldsen J, Chu Q, Crenshaw E, Kaestner K, Bartolomei M, Shulman G, Birnbaum M. Insulin Resistance and a Diabetes Mellitus-Like Syndrome in Mice Lacking the Protein Kinase Akt2 (PKBβ). Science 2001, 292: 1728-1731. PMID: 11387480, DOI: 10.1126/science.292.5522.1728.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseDeoxyglucoseDiabetes Mellitus, Type 2FemaleGene TargetingGlucoseGlucose Clamp TechniqueGlucose Tolerance TestHomeostasisInsulinInsulin ResistanceIslets of LangerhansLiverMaleMiceMice, Inbred C57BLMice, TransgenicMuscle, SkeletalProtein Serine-Threonine KinasesProto-Oncogene ProteinsProto-Oncogene Proteins c-aktSignal TransductionConceptsSerine-threonine protein kinase AktProtein kinase Akt2Protein kinase AktProtein kinase B.Activation of phosphatidylinositolEssential genesKinase Akt2Kinase AktAbility of insulinGlucose homeostasisNormal glucose homeostasisAkt2Critical initial stepEarly eventsSkeletal muscleHomeostasisInsulin actionMice LackingInsulin responsivenessInitial stepActivationInsulin resistancePhosphatidylinositolBlood glucoseGenesAdipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver
Abel E, Peroni O, Kim J, Kim Y, Boss O, Hadro E, Minnemann T, Shulman G, Kahn B. Adipose-selective targeting of the GLUT4 gene impairs insulin action in muscle and liver. Nature 2001, 409: 729-733. PMID: 11217863, DOI: 10.1038/35055575.Peer-Reviewed Original ResearchConceptsInsulin-stimulated glucose uptakeType 2 diabetesInsulin resistanceGlucose uptakeAdipose tissueGLUT4 expressionInsulin-resistant statesDownregulation of GLUT4Glucose intoleranceGlucose transportAdipose massIntracellular storage sitesGlucose homeostasisInsulin actionDiabetesPhosphoinositide-3-OH kinaseImpaired activationSkeletal muscleMuscleMicePlasma membrane4Early defectsLiverMain siteAdipocytes
1998
Disruption of IRS-2 causes type 2 diabetes in mice
Withers D, Gutierrez J, Towery H, Burks D, Ren J, Previs S, Zhang Y, Bernal D, Pons S, Shulman G, Bonner-Weir S, White M. Disruption of IRS-2 causes type 2 diabetes in mice. Nature 1998, 391: 900-904. PMID: 9495343, DOI: 10.1038/36116.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseCloning, MolecularDiabetes Mellitus, Type 2FemaleGene TargetingHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceIntracellular Signaling Peptides and ProteinsIslets of LangerhansLiverMaleMiceMice, Inbred C57BLMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsPhosphorylationReceptor, InsulinRecombination, GeneticSignal TransductionConceptsType 2 diabetesInsulin resistanceHuman type 2 diabetesPancreatic β-cell functionInsulin secretion increasesSingle molecular abnormalityΒ-cell compensationIRS-2-deficient miceΒ-cell functionHuman type 2Insulin secretionInsulin receptor substrateGlucose homeostasisSecretion increasesInsulin actionType 2DiabetesMolecular abnormalitiesProgressive deteriorationSkeletal muscleIRS-2Insulin signalingIRS-1Mild resistanceMice