2024
O-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice
Ohgaku S, Ida S, Ohashi N, Morino K, Ishikado A, Yanagimachi T, Murata K, Sato D, Ugi S, Nasiri A, Shulman G, Maegawa H, Kume S, Fujita Y. O-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice. Heliyon 2024, 10: e34490. PMID: 39130439, PMCID: PMC11315187, DOI: 10.1016/j.heliyon.2024.e34490.Peer-Reviewed Original ResearchEndothelial cellsHigh-fat dietControl miceLipid absorptionExpression of VEGFR3Body weightNitric oxide donorReduced body weightKnockout miceTherapeutic strategiesOxide donorDecreased expressionIntercellular junctionsMiceHigh-fatNutrient-sensing mechanismsFat absorptionO-GlcNAcylationGlucose metabolismVE-cadherinMorphological alterationsMetabolic regulatory mechanismsJunction morphologyLipid metabolismO-GlcNAc transferase899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice
VIJAYAKUMAR A, SRODA N, MURAKAMI E, WENG S, MYERS R, SUBRAMANIAN M, SHULMAN G. 899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice. Diabetes 2024, 73 DOI: 10.2337/db24-899-p.Peer-Reviewed Original ResearchOral glucose tolerance testGLP-1R agonistsDb/db miceIncremental AUCGlucose tolerance testMale db/db miceImproved glucose toleranceSemaglutide groupGlycemic parametersSemaglutideTolerance testFood intakeGlucose toleranceGLP-1RLiver-targeted mitochondrial uncouplerDb/dbMiceGlucose bolusVEHAgonistsEvaluation of combinationsHbA1cDiabetesMitochondrial uncouplingAssess effects
2023
Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2021
Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation
Lyu K, Zhang D, Song J, Li X, Perry RJ, Samuel VT, Shulman GI. Short-term overnutrition induces white adipose tissue insulin resistance through sn-1,2-diacylglycerol – PKCε – insulin receptorT1160 phosphorylation. JCI Insight 2021, 6: e139946. PMID: 33411692, PMCID: PMC7934919, DOI: 10.1172/jci.insight.139946.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin actionAdipose tissue insulin resistanceTissue insulin resistanceWT control miceHyperinsulinemic-euglycemic clampShort-term HFDTissue insulin actionAdipose tissue insulin actionDiet-fed ratsPotential therapeutic targetHFD feedingControl miceInsulin sensitivityTherapeutic targetLipolysis suppressionImpairs insulinHFDPKCε activationGlucose uptakeΕ activationMiceDiacylglycerol accumulationRecent evidenceProtein kinase C
2020
Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3
Hall JA, Ramachandran D, Roh HC, DiSpirito JR, Belchior T, Zushin PH, Palmer C, Hong S, Mina AI, Liu B, Deng Z, Aryal P, Jacobs C, Tenen D, Brown CW, Charles JF, Shulman GI, Kahn BB, Tsai LTY, Rosen ED, Spiegelman BM, Banks AS. Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3. Cell Metabolism 2020, 32: 665-675.e6. PMID: 32941798, PMCID: PMC7543662, DOI: 10.1016/j.cmet.2020.08.016.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin sensitivitySide effectsObesity-linked phosphorylationSignificant side effectsLigands of PPARγHyperinsulinemic-euglycemic clamp experimentsPromotes Insulin ResistanceDiabetogenic roleReceptor agonismGrowth differentiation factor 3Healthy miceBody weightMice revealsThiazolidinedionesClamp experimentsPPARγMiceInhibits BMPFamily membersFactor 3Putative targetsSerine 273Ectopic expressionBMP family membersMembrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotypingSlc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival
Chande S, Caballero D, Ho BB, Fetene J, Serna J, Pesta D, Nasiri A, Jurczak M, Chavkin NW, Hernando N, Giachelli CM, Wagner CA, Zeiss C, Shulman GI, Bergwitz C. Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival. Scientific Reports 2020, 10: 3069. PMID: 32080237, PMCID: PMC7033257, DOI: 10.1038/s41598-020-59430-4.Peer-Reviewed Original ResearchConceptsHyp miceMuscle functionSkeletal muscleMyofiber functionNormal body weightSkeletal muscle atrophyGene dose-dependent reductionConditional knockout miceReduced oxygen consumption rateStimulation of AMP kinaseKnockout miceHypophosphatemic disordersMuscle atrophyERK1/2 activationGrip strengthConditional deletionHormonal changesLow bloodBody weightC2C12 myoblastsMiceFurther evaluationBlood phosphateDependent reductionAMP kinase
2014
The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510: 84-91. PMID: 24899308, PMCID: PMC4489847, DOI: 10.1038/nature13478.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsType 2 diabetesHepatic insulin resistanceNon-alcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseHepatic lipidsHealth care costsInflammatory signalingTherapeutic approachesMortality rateDiabetesRelated epidemicsProtein kinase CεDiseaseCellular modificationsEpidemicLipid speciesMorbidityLipidsDiacylglycerol activationMice
2011
Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice
Birkenfeld A, Lee H, Guebre-Egziabher F, Alves T, Jurczak M, Jornayvaz F, Zhang D, Hsiao J, Martin-Montalvo A, Fischer-Rosinsky A, Spranger J, Pfeiffer A, Jordan J, Fromm M, König J, Lieske S, Carmean C, Frederick D, Weismann D, Knauf F, Irusta P, De Cabo R, Helfand S, Samuel V, Shulman G. Deletion of the Mammalian INDY Homolog Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice. Cell Metabolism 2011, 14: 567. DOI: 10.1016/j.cmet.2011.09.005.Peer-Reviewed Original Research
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
2008
Correction: A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice
Savage D, Zhai L, Ravikumar B, Choi C, Snaar J, McGuire A, Wou S, Medina-Gomez G, Kim S, Bock C, Segvich D, Solanky B, Deelchand D, Vidal-Puig A, Wareham N, Shulman G, Karpe F, Taylor R, Pederson B, Roach P, O'Rahilly S, DePaoli-Roach A. Correction: A Prevalent Variant in PPP1R3A Impairs Glycogen Synthesis and Reduces Muscle Glycogen Content in Humans and Mice. PLOS Medicine 2008, 5: e246. PMCID: PMC2605894, DOI: 10.1371/journal.pmed.0050246.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 levelsDiabetesAdipose-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
2000
Contrasting Effects of IRS-1 Versus IRS-2 Gene Disruption on Carbohydrate and Lipid Metabolism in Vivo *
Previs S, Withers D, Ren J, White M, Shulman G. Contrasting Effects of IRS-1 Versus IRS-2 Gene Disruption on Carbohydrate and Lipid Metabolism in Vivo *. Journal Of Biological Chemistry 2000, 275: 38990-38994. PMID: 10995761, DOI: 10.1074/jbc.m006490200.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsCarbohydrate MetabolismFatty Acids, NonesterifiedFood DeprivationGas Chromatography-Mass SpectrometryGlucoseGlycerolInsulinInsulin Receptor Substrate ProteinsIntracellular Signaling Peptides and ProteinsLipid MetabolismLiverMaleMiceMusclesMutationPhenotypePhosphoproteinsRadioimmunoassayTime FactorsConceptsLipid metabolismInsulin resistanceIRS-2Glucose utilizationPlasma free fatty acid concentrationsWhole-body glucose utilizationGlycerol turnoverFree fatty acid concentrationsMarked insulin resistancePeripheral glucose metabolismPeripheral glucose utilizationHyperinsulinemic-euglycemic clampEndogenous glucose productionIRS-1Effect of insulinHepatic glycogen synthesisWT miceFatty acid concentrationsInsulin receptor substrateGlucose metabolismFasted miceAdipose tissueReduced suppressionGlucose productionMiceRedistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle
Kim J, Michael M, Previs S, Peroni O, Mauvais-Jarvis F, Neschen S, Kahn B, Kahn C, Shulman G. Redistribution of substrates to adipose tissue promotes obesity in mice with selective insulin resistance in muscle. Journal Of Clinical Investigation 2000, 105: 1791-1797. PMID: 10862794, PMCID: PMC378504, DOI: 10.1172/jci8305.Peer-Reviewed Original ResearchConceptsInsulin resistanceSelective insulin resistanceMIRKO miceType 2 diabetesHyperinsulinemic-euglycemic conditionsInsulin-stimulated muscle glucose transportMuscle glucose transportMuscle-specific inactivationPrediabetic syndromeGlucose transportControl miceFat massInsulin receptor geneInsulin actionMiceRedistribution of substratesSkeletal muscleImportant associationPotential mechanismsReceptor geneObesityGlycogen synthesisTissueMuscleAdiposityTransgenic mice overexpressing GLUT-1 protein in muscle exhibit increased muscle glycogenesis after exercise
Ren J, Barucci N, Marshall B, Hansen P, Mueckler M, Shulman G. Transgenic mice overexpressing GLUT-1 protein in muscle exhibit increased muscle glycogenesis after exercise. AJP Endocrinology And Metabolism 2000, 278: e588-e592. PMID: 10751190, DOI: 10.1152/ajpendo.2000.278.4.e588.Peer-Reviewed Original ResearchConceptsTg miceMuscle glycogen concentrationNT miceTransgenic miceGlycogen concentrationH postexerciseEDL musclesGastrocnemius muscleMuscle glycogenExtensor digitorum longus muscleMale transgenic miceIsolated EDL musclesAge-matched littermatesDigitorum longus muscleMuscle glycogen synthase activationMuscle glycogenesisLongus muscleMuscle glycogenolysisGLUT-1 proteinSynthase activationMicePostexerciseHuman GLUT-1GLUT-1Glycogen synthase activationMechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice*
Kim J, Gavrilova O, Chen Y, Reitman M, Shulman G. Mechanism of Insulin Resistance in A-ZIP/F-1 Fatless Mice*. Journal Of Biological Chemistry 2000, 275: 8456-8460. PMID: 10722680, DOI: 10.1074/jbc.275.12.8456.Peer-Reviewed Original ResearchConceptsType 2 diabetesInsulin resistanceFatless miceInsulin actionTriglyceride contentA-ZIP/FDevelopment of diabetesLiver triglyceride contentHyperinsulinemic-euglycemic clampAccumulation of triglyceridesMuscle/liverWild-type littermatesInsulin receptor substrate-1Receptor substrate-1Partitioning of fatSubsequent impairmentDiabetesFat metabolismMiceFat tissueLiverInsulin signalingMuscleLatter tissueSubstrate-1Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice
Gavrilova O, Marcus-Samuels B, Graham D, Kim J, Shulman G, Castle A, Vinson C, Eckhaus M, Reitman M. Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. Journal Of Clinical Investigation 2000, 105: 271-278. PMID: 10675352, PMCID: PMC377444, DOI: 10.1172/jci7901.Peer-Reviewed Original ResearchConceptsA-ZIP/FLipoatrophic diabetesAdipose tissueNear-physiological amountsMuscle insulin sensitivityLack of fatLipoatrophic miceInsulin levelsHepatic steatosisInsulin resistanceInsulin sensitivitySevere formFFA levelsDiabetesDonor fatTransplantationBeneficial effectsEndocrine communicationSubcutaneous sitesMiceSurgical implantationAdipose physiologyHyperglycemiaFatTissue
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
1997
Human IAPP/amylin overproducing transgenic mice: Characterization of an animal model to study the role of IAPP in the pathogenesis of Type 2 diabetes
Höppener J, Oosterwijk C, Shulman G, Jiménez-Chillarón J, Guinovart J, Chico S, Gómez-Foix A, Ahrén B, Lips C. Human IAPP/amylin overproducing transgenic mice: Characterization of an animal model to study the role of IAPP in the pathogenesis of Type 2 diabetes. Experimental And Clinical Endocrinology & Diabetes 1997, 105: 69-69. DOI: 10.1055/s-0029-1211891.Peer-Reviewed Original Research