2023
O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding
Nakamoto A, Ohashi N, Sugawara L, Morino K, Ida S, Perry R, Sakuma I, Yanagimachi T, Fujita Y, Ugi S, Kume S, Shulman G, Maegawa H. O-linked N-acetylglucosamine modification is essential for physiological adipose expansion induced by high-fat feeding. AJP Endocrinology And Metabolism 2023, 325: e46-e61. PMID: 37224467, PMCID: PMC10292976, DOI: 10.1152/ajpendo.00263.2022.Peer-Reviewed Original ResearchMeSH KeywordsAcetylglucosamineAdipose TissueAnimalsBody WeightFatty Acids, NonesterifiedMiceN-AcetylglucosaminyltransferasesObesityWeight GainConceptsFKO miceAdipose tissueBody weight gainPrimary cultured adipocytesAdipose expansionFree fatty acidsInflammatory genesWeight gainFree fatty acid effluxCultured adipocytesDiet-induced obesityHigh-fat dietHigh-fat feedingLess body weightDe novo lipogenesisAdipose tissue physiologyDe novo lipogenesis genesFatty acid effluxWeeks of ageAdipose inflammationGlucose intoleranceRAW 264.7 macrophagesControl miceFatty acidsSevere fibrosis
2020
Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease
Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtimäki TE, Cline GW, Petersen KF, Shulman GI, Yki-Järvinen H. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 7347-7354. PMID: 32179679, PMCID: PMC7132133, DOI: 10.1073/pnas.1922344117.Peer-Reviewed Original ResearchMeSH KeywordsBody CompositionCitrate (si)-SynthaseDiet, KetogenicFatty AcidsFatty Acids, NonesterifiedFatty LiverFemaleHumansInsulinInsulin ResistanceLipoproteins, VLDLLiverMaleMiddle AgedMitochondriaNon-alcoholic Fatty Liver DiseaseObesityOverweightOxidation-ReductionPyruvate CarboxylaseTriglyceridesConceptsNonalcoholic fatty liver diseaseFatty liver diseaseIntrahepatic triglyceridesKetogenic dietHepatic insulin resistanceNonesterified fatty acidsInsulin resistanceLiver diseaseOverweight/obese subjectsHepatic mitochondrial redox stateSerum insulin concentrationsHepatic mitochondrial metabolismProton magnetic resonance spectroscopyStable isotope infusionKD dietObese subjectsFatty acidsPlasma leptinHepatic steatosisInsulin concentrationsNEFA concentrationsBody weightTriiodothyronine concentrationsIsotope infusionWeight loss
2001
Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance
Kim J, Fillmore J, Chen Y, Yu C, Moore I, Pypaert M, Lutz E, Kako Y, Velez-Carrasco W, Goldberg I, Breslow J, Shulman G. Tissue-specific overexpression of lipoprotein lipase causes tissue-specific insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 7522-7527. PMID: 11390966, PMCID: PMC34701, DOI: 10.1073/pnas.121164498.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseFatty Acids, NonesterifiedGlucagonGlucoseGlucose Clamp TechniqueGlucose Tolerance TestHeterozygoteInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLeptinLipoprotein LipaseLiverMiceMice, KnockoutMice, TransgenicMuscle, SkeletalOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphoproteinsSignal TransductionTriglyceridesConceptsInsulin resistanceFatty acid-derived metabolitesInsulin actionTriglyceride contentType 2 diabetes mellitusInsulin activationLipoprotein lipaseInsulin receptor substrate-1-associated phosphatidylinositolMuscle triglyceride contentSkeletal muscleTissue-specific insulin resistanceLiver triglyceride contentAdipocyte-derived hormoneHyperinsulinemic-euglycemic clampEndogenous glucose productionLiver-specific overexpressionTissue-specific overexpressionInsulin-stimulated glucose uptakeDiabetes mellitusTissue-specific increaseTransgenic miceGlucose productionFat metabolismGlucose uptakeInsulinEffect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats
Bergeron R, Previs S, Cline G, Perret P, Russell III R, Young L, Shulman G. Effect of 5-Aminoimidazole-4-Carboxamide-1-β-d-Ribofuranoside Infusion on In Vivo Glucose and Lipid Metabolism in Lean and Obese Zucker Rats. Diabetes 2001, 50: 1076-1082. PMID: 11334411, DOI: 10.2337/diabetes.50.5.1076.Peer-Reviewed Original ResearchMeSH KeywordsAdenylate KinaseAminoimidazole CarboxamideAnimalsBlood GlucoseBody WeightFatty Acids, NonesterifiedGlucoseGlycerolInfusions, IntravenousInjections, IntravenousInsulinInsulin ResistanceLactatesMaleModels, AnimalMuscle, SkeletalObesityRatsRats, ZuckerReference ValuesRibonucleotidesTriglyceridesConceptsWhole-body glucose disposalInsulin-resistant rat modelObese ratsEndogenous glucose productionObese Zucker ratsRed gastrocnemius muscleInsulin infusion rateLean ratsGlucose disposalInsulin infusionRat modelInfusion rateGastrocnemius muscleZucker ratsLipid metabolismGlucose productionEndogenous glucose production rateGlucose transport activitySkeletal muscle glucose transport activityType 2 diabetesWhole-body carbohydrateInsulin-stimulated glucose uptakeInsulin-independent pathwaySkeletal muscle AMPKGlucose production rateOverexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance
Zabolotny J, Kim Y, Peroni O, Kim J, Pani M, Boss O, Klaman L, Kamatkar S, Shulman G, Kahn B, Neel B. Overexpression of the LAR (leukocyte antigen-related) protein-tyrosine phosphatase in muscle causes insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 5187-5192. PMID: 11309481, PMCID: PMC33185, DOI: 10.1073/pnas.071050398.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseBody CompositionCreatine KinaseCreatine Kinase, MM FormFatty Acids, NonesterifiedHumansInsulinInsulin ResistanceIntracellular Signaling Peptides and ProteinsIsoenzymesMiceMice, TransgenicMusclesOrgan SpecificityPhosphatidylinositol 3-KinasesPhosphorylationPhosphotyrosinePromoter Regions, GeneticProtein Tyrosine Phosphatase, Non-Receptor Type 6Protein Tyrosine PhosphatasesRecombinant Fusion ProteinsSignal TransductionConceptsIRS proteinsLAR protein tyrosine phosphataseKinase activityProtein tyrosine phosphatase LARIRS-2Insulin receptor substrate-1Protein tyrosine phosphatasePI3-kinase activityInsulin-resistant humansReceptor substrate-1Association of p85alphaInsulin resistanceInsulin-responsive tissuesHuman LARTyrosyl phosphorylationInsulin target tissuesTransgenic miceSubstrate-1IRS-1Wild-type controlsInsulin receptorWhole-body glucose disposalWhole-body insulin resistancePhosphotyrosinePhosphorylation
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 productionMiceEffects of Caffeine on Muscle Glycogen Utilization and the Neuroendocrine Axis during Exercise1
Laurent D, Schneider K, Prusaczyk W, Franklin C, Vogel S, Krssak M, Petersen K, Goforth H, Shulman G. Effects of Caffeine on Muscle Glycogen Utilization and the Neuroendocrine Axis during Exercise1. The Journal Of Clinical Endocrinology & Metabolism 2000, 85: 2170-2175. PMID: 10852448, DOI: 10.1210/jcem.85.6.6655.Peer-Reviewed Original ResearchConceptsMuscle glycogen contentMuscle glycogen utilizationGlycogen contentCaffeine ingestionNeuroendocrine axisGlycogen utilizationGlycogen-sparing effectFree fatty acid concentrationsBeta-endorphin levelsCaffeine-treated groupExercise-induced glycogen depletionMaximal oxygen consumptionEffects of caffeineHigher muscle glycogen contentPlacebo groupExercise enduranceFatty acid concentrationsPlasma concentrationsNeuroendocrine hormonesCortisol releaseProlonged exerciseGlycogen depletionPlasma lactateNormal valuesThigh musclesMechanism 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 infusionGlycogenTransgenic 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 activation
1999
Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle
Jucker B, Barucci N, Shulman G. Metabolic control analysis of insulin-stimulated glucose disposal in rat skeletal muscle. American Journal Of Physiology 1999, 277: e505-e512. PMID: 10484363, DOI: 10.1152/ajpendo.1999.277.3.e505.Peer-Reviewed Original ResearchConceptsInsulin-stimulated glucose disposalGlucose transport/phosphorylationGlucose disposalHyperinsulinemic clampAwake ratsInfusion protocolGlycogen synthesisSkeletal muscleGlucose infusion rateMuscle glucose disposalSkeletal muscle glucose disposalProtocol IRat skeletal muscleRate of glycolysisInfusion rateHindlimb musclesMajority of controlsEffects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity
Dresner A, Laurent D, Marcucci M, Griffin M, Dufour S, Cline G, Slezak L, Andersen D, Hundal R, Rothman D, Petersen K, Shulman G. Effects of free fatty acids on glucose transport and IRS-1–associated phosphatidylinositol 3-kinase activity. Journal Of Clinical Investigation 1999, 103: 253-259. PMID: 9916137, PMCID: PMC407880, DOI: 10.1172/jci5001.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultFatty Acids, NonesterifiedFemaleGlucoseGlucose Clamp TechniqueGlucose-6-PhosphateGlycerolGlycogenHumansHyperinsulinismInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismMagnetic Resonance SpectroscopyMaleMuscle, SkeletalPhosphatidylinositol 3-KinasesPhosphoproteinsConceptsFree fatty acidsIRS-1-associated phosphatidylinositolLipid infusionInsulin resistanceGlycerol infusionPlasma free fatty acidsWhole-body glucose uptakeFive-hour infusionLipid/heparinHyperinsulinemic-euglycemic clampGlucose concentrationGlucose transportMuscle glycogen synthesisDiminished glucose transportMuscle biopsy samplesHuman skeletal muscleRate of insulinGlucose-6-phosphate concentrationFatty acidsHealthy subjectsBiopsy samplesInfusion studiesIdentical protocolInfusionIRS-1-associated PIIntramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study
Krssak M, Falk Petersen K, Dresner A, DiPietro L, Vogel SM, Rothman DL, Shulman G, Roden M. Intramyocellular lipid concentrations are correlated with insulin sensitivity in humans: a 1H NMR spectroscopy study. Diabetologia 1999, 42: 113-116. PMID: 10027589, DOI: 10.1007/s001250051123.Peer-Reviewed Original ResearchConceptsIntramyocellular lipid concentrationsIntramyocellular lipid contentInsulin sensitivityLipid concentrationsPlasma non-esterified fatty acid concentrationsNon-esterified fatty acid concentrationsWhole-body insulin sensitivityNon-diabetic adultsNon-esterified fatty acidsBody insulin sensitivityNon-obese humansMuscle biopsy studiesCross-sectional analysisInsulin resistanceIntramuscular lipid contentBiopsy studiesClamp testFatty acid concentrationsLipid contentPlasma concentrationsSoleus muscleLinear regression analysisPmol/Inverse correlationM values
1998
Effect of insulin on glycerol production in obese adolescents
Robinson C, Tamborlane W, Maggs D, Enoksson S, Sherwin R, Silver D, Shulman G, Caprio S. Effect of insulin on glycerol production in obese adolescents. American Journal Of Physiology 1998, 274: e737-e743. PMID: 9575836, DOI: 10.1152/ajpendo.1998.274.4.e737.Peer-Reviewed Original ResearchConceptsNet lipid oxidationObese adolescentsLean adultsGlycerol turnoverTwo-step euglycemic-hyperinsulinemic clampFree fatty acid concentrationsBody fat massEuglycemic hyperinsulinemic clampSensitivity of adipocytesEffect of insulinAction of insulinObese groupLean subjectsInsulin resistanceAdipose massPlasma insulinFatty acid concentrationsAdolescent obesityFat massLean adolescentsImpaired stimulationPhysiological incrementsFFA levelsGlucose metabolismIndirect calorimetryEffect of epinephrine on muscle glycogenolysis and insulin-stimulated muscle glycogen synthesis in humans
Laurent D, Petersen K, Russell R, Cline G, Shulman G. Effect of epinephrine on muscle glycogenolysis and insulin-stimulated muscle glycogen synthesis in humans. American Journal Of Physiology 1998, 274: e130-e138. PMID: 9458758, DOI: 10.1152/ajpendo.1998.274.1.e130.Peer-Reviewed Original ResearchConceptsInsulin-stimulated muscle glycogen synthesisMuscle glycogen synthesisMuscle glycogenolysisEpinephrine infusionPhysiological increaseWhole-body glucose oxidationMuscle glycogen synthesis ratesPlasma epinephrine concentrationEuglycemic hyperinsulinemic clampGlucose infusion rateEffect of epinephrineGlycogen synthesisInsulin-stimulated glycogenesisBasal insulinControl subjectsPlasma glucoseEpinephrine concentrationsFree fatty acidsBasal valuesInfusion rateGlycogen synthesis rateMuscle glycogenEpinephrineGlycogenolysisMajor impairment
1997
13C and 31P NMR Studies on the Effects of Increased Plasma Free Fatty Acids on Intramuscular Glucose Metabolism in the Awake Rat*
Jucker B, Rennings A, Cline G, Shulman G. 13C and 31P NMR Studies on the Effects of Increased Plasma Free Fatty Acids on Intramuscular Glucose Metabolism in the Awake Rat*. Journal Of Biological Chemistry 1997, 272: 10464-10473. PMID: 9099689, DOI: 10.1074/jbc.272.16.10464.Peer-Reviewed Original ResearchMeSH KeywordsAlanineAnimalsCarbon IsotopesFatty Acids, NonesterifiedGlucoseGlucose Clamp TechniqueGlucose-6-PhosphateGlycogenGlycolysisHyperinsulinismInfusions, IntravenousInsulinKetonesKineticsLactatesMagnetic Resonance SpectroscopyModels, BiologicalMuscle, SkeletalPhosphorusPyruvatesRatsRats, Sprague-DawleyWakefulnessConceptsPlasma free fatty acids
1980
Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog
Shulman G, Williams P, Liljenquist J, Lacy W, Keller U, Cherrington A. Effect of hyperglycemia independent of changes in insulin or glucagon on lipolysis in the conscious dog. Metabolism 1980, 29: 317-320. PMID: 6103495, DOI: 10.1016/0026-0495(80)90004-9.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseDogsFatty Acids, NonesterifiedFemaleGlucagonGlucoseGlycerolHyperglycemiaInsulinLipolysisLiverMaleSomatostatinConceptsArterial plasma glucose concentrationDirect antilipolytic effectHepatic glycerol uptakeFree fatty acid concentrationsInfusion of somatostatinContinuous glucose infusionPlasma glucose concentrationBlood glycerol levelsHyperglycemia independentConscious dogsBlood glycerolFatty acid concentrationsPancreatic hormonesAntilipolytic effectGlucose infusionBasal levelsSignificant decreaseGlycerol levelsGlucose concentrationHyperglycemiaInfusionGlucagonInsulinFractional extraction