2005
Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents
Morino K, Petersen KF, Dufour S, Befroy D, Frattini J, Shatzkes N, Neschen S, White MF, Bilz S, Sono S, Pypaert M, Shulman GI. Reduced mitochondrial density and increased IRS-1 serine phosphorylation in muscle of insulin-resistant offspring of type 2 diabetic parents. Journal Of Clinical Investigation 2005, 115: 3587-3593. PMID: 16284649, PMCID: PMC1280967, DOI: 10.1172/jci25151.Peer-Reviewed Original ResearchMeSH KeywordsBiopsyBlood GlucoseBlotting, WesternBody Mass IndexBody WeightDiabetes Mellitus, Type 2DNA, MitochondrialFamily HealthFemaleGene Expression RegulationGlucose Clamp TechniqueGlucose Tolerance TestHumansHyperinsulinismImmunoprecipitationInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipidsMaleMicroscopy, ElectronMicroscopy, Electron, TransmissionMitochondriaMusclesPhosphoproteinsPhosphorylationProtein Serine-Threonine KinasesReverse Transcriptase Polymerase Chain ReactionRNA, MessengerSerineSignal TransductionTime FactorsTranscription, GeneticTriglyceridesConceptsInsulin-resistant offspringIR offspringType 2 diabetesInsulin-stimulated muscle glucose uptakeType 2 diabetic parentsIntramyocellular lipid contentHyperinsulinemic-euglycemic clampMuscle glucose uptakeIRS-1 serine phosphorylationMuscle mitochondrial densityMitochondrial densityMuscle biopsy samplesSerine kinase cascadeInsulin-stimulated Akt activationDiabetic parentsInsulin resistanceControl subjectsBiopsy samplesGlucose uptakeLipid accumulationMitochondrial dysfunctionInsulin signalingAkt activationEarly defectsMuscle
2004
Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes. New England Journal Of Medicine 2004, 350: 664-671. PMID: 14960743, PMCID: PMC2995502, DOI: 10.1056/nejmoa031314.Peer-Reviewed Original ResearchMeSH KeywordsAdenosine TriphosphateAdipose TissueBlood GlucoseDiabetes Mellitus, Type 2Fatty AcidsFemaleGlucoseGlucose Clamp TechniqueGlucose Tolerance TestGlycerolHumansInsulinInsulin ResistanceLipolysisMagnetic Resonance SpectroscopyMaleMitochondriaMuscle, SkeletalOxidative PhosphorylationTriglyceridesConceptsInsulin-resistant offspringType 2 diabetesIntramyocellular lipid contentInsulin-sensitive control subjectsMagnetic resonance spectroscopy studyInsulin resistanceControl subjectsProton magnetic resonance spectroscopy studyHyperinsulinemic-euglycemic clamp studiesTumor necrosis factor alphaImpaired mitochondrial activityIntrahepatic triglyceride contentDevelopment of diabetesChildren of patientsInsulin-resistant subjectsNecrosis factor alphaSensitivity of liverInsulin-stimulated ratesFatty acid metabolismMitochondrial oxidative phosphorylation activityInterleukin-6Intramyocellular lipidsPlasma concentrationsFactor alphaClamp studies
2001
Prevention of fat-induced insulin resistance by salicylate
Kim J, Kim Y, Fillmore J, Chen Y, Moore I, Lee J, Yuan M, Li Z, Karin M, Perret P, Shoelson S, Shulman G. Prevention of fat-induced insulin resistance by salicylate. Journal Of Clinical Investigation 2001, 108: 437-446. PMID: 11489937, PMCID: PMC209353, DOI: 10.1172/jci11559.Peer-Reviewed Original ResearchConceptsType 2 diabetesLipid infusionInsulin resistanceGlucose uptakeInsulin actionWhole-body glucose uptakeFat-induced insulin resistanceSkeletal muscleHigh-dose salicylatesHyperinsulinemic-euglycemic clampWild-type miceInsulin-stimulated glucose uptakeSkeletal muscle insulinIRS-1-associated PISerine kinase cascadeLipid-induced effectsAwake ratsAwake miceKnockout miceMuscle insulinInfusionTherapeutic agentsSalicylate actionKinase cascadeIKK betaTissue-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 uptakeInsulinInsulin 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 glucoseGenesSyntaxin 4 heterozygous knockout mice develop muscle insulin resistance
Yang C, Coker K, Kim J, Mora S, Thurmond D, Davis A, Yang B, Williamson R, Shulman G, Pessin J. Syntaxin 4 heterozygous knockout mice develop muscle insulin resistance. Journal Of Clinical Investigation 2001, 107: 1311-1318. PMID: 11375421, PMCID: PMC209300, DOI: 10.1172/jci12274.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose Tissue, BrownAnimalsBiological TransportGlucoseGlucose Clamp TechniqueGlucose Tolerance TestGlucose Transporter Type 4GlycogenGlycolysisHeterozygoteInsulin ResistanceLiverMembrane ProteinsMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsMuscle, SkeletalQa-SNARE ProteinsConceptsHeterozygous knockout miceInsulin-stimulated glucose uptakeGlucose uptakeKnockout miceNormal insulin-stimulated glucose uptakeWhole-body glucose uptakeHyperinsulinemic-euglycemic clamp procedureInsulin-stimulated glucose metabolismInsulin-stimulated GLUT4 translocationSkeletal muscleGLUT4 vesicle traffickingImpaired glucose toleranceMuscle insulin resistanceEarly embryonic lethalitySkeletal muscle glucose transportMuscle glucose transportCritical physiological roleGlucose toleranceInsulin resistanceClamp procedureVesicle traffickingSyntaxin 4Embryonic lethalityGlucose metabolismAnimal models
2000
Redistribution 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 synthesisTissueMuscleAdiposityMechanism 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 infusionGlycogenMechanism 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-1
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 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
Effects of insulin-like growth factor I on glucose metabolism in rats with liver cirrhosis
Petersen K, Jacob R, West A, Sherwin R, Shulman G. Effects of insulin-like growth factor I on glucose metabolism in rats with liver cirrhosis. American Journal Of Physiology 1997, 273: e1189-e1193. PMID: 9435535, DOI: 10.1152/ajpendo.1997.273.6.e1189.Peer-Reviewed Original ResearchConceptsMuscle glycogen synthesisInsulin-like growth factor ICirrhotic ratsGrowth factor IGlucose metabolismLiver cirrhosisGlycogen synthesisFactor IInsulin-stimulated muscle glycogen synthesisIGF-I therapyPeripheral glucose metabolismWhole-body glucose turnoverEndogenous glucose productionAbility of IGFEuglycemic clampInsulin resistanceControl ratsAwake ratsCirrhosisDiminished suppressionControl groupIGFRatsGlucose productionGlucose turnoverMetabolic Defects in Lean Nondiabetic Offspring of NIDDM Parents: A Cross-Sectional Study
Perseghin G, Ghosh S, Gerow K, Shulman G. Metabolic Defects in Lean Nondiabetic Offspring of NIDDM Parents: A Cross-Sectional Study. Diabetes 1997, 46: 1001-1009. PMID: 9166672, DOI: 10.2337/diab.46.6.1001.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin sensitivityControl subjectsInsulin secretionNIDDM parentsNIDDM patientsFFA metabolismFFA concentrationsAbove confounding factorsInsulin-resistant offspringFree fatty acid levelsInverse correlationLDL cholesterol levelsHealthy control subjectsNormal insulin sensitivityIntravenous glucose bolusLower insulin sensitivityPlasma FFA concentrationEuglycemic hyperinsulinemic clampCross-sectional studyFirst-degree relativesPathogenesis of NIDDMDefective insulin secretionFatty acid levelsHigh free fatty acid levels13C 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
1994
Progesterone administration induced impairment of insulin suppression of hepatic glucose production
Nelson T, Shulman G, Grainger D, Diamond M. Progesterone administration induced impairment of insulin suppression of hepatic glucose production. Fertility And Sterility 1994, 62: 491-496. PMID: 8062943, DOI: 10.1016/s0015-0282(16)56936-2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseFemaleGlucoseGlucose Clamp TechniqueInsulinLiverProgesteroneRatsRats, Sprague-Dawley
1992
Simultaneous Insulinlike Growth Factor I and Insulin Resistance in Obese Zucker Rats
Jacob R, Sherwin R, Greenawalt K, Shulman G. Simultaneous Insulinlike Growth Factor I and Insulin Resistance in Obese Zucker Rats. Diabetes 1992, 41: 691-697. PMID: 1587396, DOI: 10.2337/diab.41.6.691.Peer-Reviewed Original ResearchMeSH KeywordsAgingAmino AcidsAnimalsBlood GlucoseBody WeightGlucose Clamp TechniqueInsulinInsulin ResistanceInsulin-Like Growth Factor IObesityRatsRats, ZuckerConceptsInsulinlike growth factor IGrowth factor IObese Zucker ratsObese ratsLean ratsZucker ratsChain amino acid concentrationsFactor IGlucose uptakeIGF-I infusionDiabetic BB ratsIGF-I levelsEffects of IGFEuglycemic insulin clampLean control ratsObese groupBB ratsInsulin clampInsulin resistanceLean controlsControl ratsRats 6Amino acid concentrationsVivo effectsIGF
1991
The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats
Bowen L, Stein P, Stevenson R, Shulman G. The effect of CP 68,722, a thiozolidinedione derivative, on insulin sensitivity in lean and obese Zucker rats. Metabolism 1991, 40: 1025-1030. PMID: 1943727, DOI: 10.1016/0026-0495(91)90124-f.Peer-Reviewed Original ResearchConceptsHepatic glucose productionInsulin-induced suppressionObese animalsObese Zucker ratsGlucose disposalInsulin sensitivityDrug treatmentFree fatty acidsZucker ratsHigher insulin infusion ratesEuglycemic hyperinsulinemic clamp techniqueInsulin-resistant animal modelsPeripheral glucose disposalHyperinsulinemic clamp techniquePeripheral glucose uptakeInsulin infusion rateInsulin clampInsulin suppressionKetone levelsInfusion rateAnimal modelsClamp techniqueEffect of CPLean animalsLipid metabolism