2023
MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis.
Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J, Haeusler R, Accili D, Shulman G, Yu H, Choi E. MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis. Diabetes 2023, 72: 1781-1794. PMID: 37725942, PMCID: PMC10658066, DOI: 10.2337/db23-0314.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndocytosisGlucoseHomeostasisInsulinInsulin ResistanceLiverMad2 ProteinsMaleMiceReceptor, InsulinConceptsIR endocytosisInsulin receptor endocytosisCell division regulatorsInsulin receptorProlongs insulin actionReceptor endocytosisTranscriptomic profilesInsulin stimulationEndocytosisMetabolic homeostasisCell surfaceGenetic ablationMetabolic functionsInsulin actionP31cometMad2BubR1DisruptionSignalingRegulatorHomeostasisAdipose tissueInteractionHepatic fat accumulationMetabolism
2022
Bioactive lipids and metabolic syndrome—a symposium report
DeVito LM, Dennis EA, Kahn BB, Shulman GI, Witztum JL, Sadhu S, Nickels J, Spite M, Smyth S, Spiegel S. Bioactive lipids and metabolic syndrome—a symposium report. Annals Of The New York Academy Of Sciences 2022, 1511: 87-106. PMID: 35218041, PMCID: PMC9219555, DOI: 10.1111/nyas.14752.Peer-Reviewed Original ResearchConceptsBioactive lipidsMetabolic syndromeCardiometabolic conditionsCardiovascular diseaseAnimal modelsDietary lipidsLipid metabolismMetabolic homeostasisMultitude of functionsLipidomic approachLipid pathwaysContinued investigationSyndromeMolecular functionsSymposium reportGenetic studiesLipidsPathwayInflammationGreater understandingDiseaseLiverMacrophagesLipogenesis
2021
MMAB promotes negative feedback control of cholesterol homeostasis
Goedeke L, Canfrán-Duque A, Rotllan N, Chaube B, Thompson BM, Lee RG, Cline GW, McDonald JG, Shulman GI, Lasunción MA, Suárez Y, Fernández-Hernando C. MMAB promotes negative feedback control of cholesterol homeostasis. Nature Communications 2021, 12: 6448. PMID: 34750386, PMCID: PMC8575900, DOI: 10.1038/s41467-021-26787-7.Peer-Reviewed Original ResearchMeSH KeywordsAlkyl and Aryl TransferasesAnimalsCell Line, TumorCholesterolCholesterol, LDLFeedback, PhysiologicalGene Expression ProfilingHeLa CellsHep G2 CellsHomeostasisHumansHydroxymethylglutaryl CoA ReductasesLiverMice, Inbred C57BLMice, KnockoutPromoter Regions, GeneticReceptors, LDLRNA InterferenceSterol Regulatory Element Binding Protein 2ConceptsCholesterol biosynthesisCholesterol homeostasisMouse hepatic cell lineIntegrative genomic strategyIntricate regulatory networkMaster transcriptional regulatorCellular cholesterol levelsHMGCR activityLDL-cholesterol uptakeCholesterol levelsHuman hepatic cellsSterol contentGenomic strategiesTranscriptional regulatorsRegulatory networksIntracellular cholesterol levelsGene expressionUnexpected roleHepatic cell linesBiosynthesisMMABIntracellular levelsCell linesHomeostasisExpression of SREBP2
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 pathwayInflammationA MicroRNA Linking Human Positive Selection and Metabolic Disorders
Wang L, Sinnott-Armstrong N, Wagschal A, Wark AR, Camporez JP, Perry RJ, Ji F, Sohn Y, Oh J, Wu S, Chery J, Moud BN, Saadat A, Dankel SN, Mellgren G, Tallapragada DSP, Strobel SM, Lee MJ, Tewhey R, Sabeti PC, Schaefer A, Petri A, Kauppinen S, Chung RT, Soukas A, Avruch J, Fried SK, Hauner H, Sadreyev RI, Shulman GI, Claussnitzer M, Näär AM. A MicroRNA Linking Human Positive Selection and Metabolic Disorders. Cell 2020, 183: 684-701.e14. PMID: 33058756, PMCID: PMC8092355, DOI: 10.1016/j.cell.2020.09.017.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytes, BrownAdiposityAllelesAnimalsCell DifferentiationCell LineCells, CulturedDiet, High-FatEnergy MetabolismEpigenesis, GeneticGenetic LociGlucoseHomeostasisHumansHypertrophyInsulin ResistanceLeptinMaleMammalsMetabolic DiseasesMice, Inbred C57BLMice, ObeseMicroRNAsObesityOligonucleotidesSpecies SpecificityConceptsPositive selectionMiR-128Additional genetic elementsCrucial metabolic regulatorAncient adaptationEvolutionary adaptationGenetic elementsMetabolic regulatorGenetic ablationLociMetabolic maladaptationLactase geneAntisense targetingMetabolic disease modelsThrifty phenotypeDisease modelsDiet-induced obesityMetabolic diseasesAbility of adultsMammalsAdaptationGenesMicroRNAsRegulatorSelection
2010
Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice
Ayala JE, Consortium F, Samuel V, Morton G, Obici S, Croniger C, Shulman G, Wasserman D, McGuinness O. Standard operating procedures for describing and performing metabolic tests of glucose homeostasis in mice. Disease Models & Mechanisms 2010, 3: 525-534. PMID: 20713647, PMCID: PMC2938392, DOI: 10.1242/dmm.006239.Peer-Reviewed Original Research
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 glucoseGenes
2000
Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice
Klaman L, Boss O, Peroni O, Kim J, Martino J, Zabolotny J, Moghal N, Lubkin M, Kim Y, Sharpe A, Stricker-Krongrad A, Shulman G, Neel B, Kahn B. Increased Energy Expenditure, Decreased Adiposity, and Tissue-Specific Insulin Sensitivity in Protein-Tyrosine Phosphatase 1B-Deficient Mice. Molecular And Cellular Biology 2000, 20: 5479-5489. PMID: 10891488, PMCID: PMC85999, DOI: 10.1128/mcb.20.15.5479-5489.2000.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBody WeightCarrier ProteinsEnergy MetabolismFemaleGlucoseGlucose Tolerance TestHomeostasisHyperinsulinismInsulin ResistanceIon ChannelsLeptinMaleMembrane ProteinsMembrane Transport ProteinsMiceMice, Inbred C57BLMice, Mutant StrainsMitochondrial ProteinsMuscle, SkeletalProtein Tyrosine Phosphatase, Non-Receptor Type 1Protein Tyrosine PhosphatasesProteinsRNA, MessengerUncoupling Protein 1Uncoupling Protein 2Uncoupling Protein 3ConceptsProtein tyrosine phosphatasePTP-1BMajor protein tyrosine phosphataseProtein tyrosine phosphatase 1BSignal transduction pathwaysTargeted gene disruptionInsulin-stimulated glucose uptakeGene disruptionTransduction pathwaysFat cell massPhosphatase 1BMajor regulatorProtein mRNA expressionCell massNull miceSkeletal muscleDeficient miceGlucose uptakeBasal metabolic rateInsulin actionMetabolic ratePhosphataseFat storesDiet-induced obesityAdipocyte numberLoss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction
Michael M, Kulkarni R, Postic C, Previs S, Shulman G, Magnuson M, Kahn C. Loss of Insulin Signaling in Hepatocytes Leads to Severe Insulin Resistance and Progressive Hepatic Dysfunction. Molecular Cell 2000, 6: 87-97. PMID: 10949030, DOI: 10.1016/s1097-2765(05)00015-8.Peer-Reviewed Original ResearchConceptsInsulin resistanceGlucose homeostasisInsulin receptor knockout miceLiver-specific insulin receptor knockout miceDirect insulin actionNormal hepatic functionProgressive hepatic dysfunctionReceptor knockout miceSevere glucose intoleranceSevere insulin resistanceHepatic glucose productionFailure of insulinLoss of insulinHepatic gene expressionHepatic dysfunctionGlucose intoleranceMarked hyperinsulinemiaCre-loxP systemInsulin clearanceHepatic functionInsulin secretionInsulin receptor geneKnockout miceInsulin actionGlucose productionMechanism of muscle glycogen autoregulation in humans
Laurent D, Hundal R, Dresner A, Price T, Vogel S, Petersen K, Shulman G. Mechanism of muscle glycogen autoregulation in humans. AJP Endocrinology And Metabolism 2000, 278: e663-e668. PMID: 10751200, DOI: 10.1152/ajpendo.2000.278.4.e663.Peer-Reviewed Original ResearchConceptsInsulin-stimulated ratesWhole body glucose oxidation ratesMuscle glycogenGlycogen loadingPlasma free fatty acid concentrationsWhole-body glucose uptakeFree fatty acid concentrationsMuscle glycogen contentGlucose oxidation ratesMuscle glycogen synthesisPlasma lactate concentrationTwofold increaseHyperinsulinemic clampGlycogen synthase activityFatty acid concentrationsLoading protocolGlucose infusionHealthy volunteersLactate concentrationGlycogen contentGlucose uptakeAnaerobic glycolysisGlycogen synthesisUnlabeled glucose infusionGlycogen
1995
Local Ventromedial Hypothalamus Glucopenia Triggers Counterregulatory Hormone Release
Borg W, Sherwin R, During M, Borg M, Shulman G. Local Ventromedial Hypothalamus Glucopenia Triggers Counterregulatory Hormone Release. Diabetes 1995, 44: 180-184. PMID: 7859938, DOI: 10.2337/diab.44.2.180.Peer-Reviewed Original ResearchConceptsVentromedial hypothalamusFrontal lobeMicrodialysis probeCounterregulatory hormone releaseCellular glucopeniaCounterregulatory hormonesCounterregulatory responsesPlasma glucagonPlasma glucoseLocal perfusionHormone releaseCerebral tissueStriking elevationControl groupGlucopeniaBrain tissueGlucopenic agentHypoglycemiaRatsTwofold increaseLobeTissueNorepinephrineHypothalamusEpinephrine