2025
215-OR: Increased White Adipose Tissue Oxidative Capacity and Insulin Resistance Are Early Changes upon High-Fat Diet in Healthy Humans
XOURAFA G, GRANATA C, TRENKAMP S, KORZEKWA B, SCHRAUWEN-HINDERLING V, PETERSEN K, SHULMAN G, KAHL S, RODEN M. 215-OR: Increased White Adipose Tissue Oxidative Capacity and Insulin Resistance Are Early Changes upon High-Fat Diet in Healthy Humans. Diabetes 2025, 74 DOI: 10.2337/db25-215-or.Peer-Reviewed Original ResearchWhite adipose tissueFat mass indexInsulin resistanceHigh-fat dietLipid contentEuropean Association for the StudyNon-esterified fatty acidsInsulin sensitivityLiver lipid contentParallel-group studyEuropean Association for the Study of DiabetesNon-obese individualsAdipose tissue insulin resistanceWhole-body insulin sensitivityPromote insulin resistanceTissue insulin resistanceHepatic ATP levelsHigh-resolution respirometryHyperinsulinemic-euglycemic clampMitochondrial respirationStudy of DiabetesWhole-body insulin resistanceInsulin stimulationHepatic lipid contentHypercaloric high-fat dietATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Slusher A, Santoro N, Vash-Margita A, Galderisi A, Hu P, Tokoglu F, Li Z, Tarabra E, Strober J, Vatner D, Shulman G, Caprio S. ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis. Journal Of Clinical Investigation 2025, 135: e184740. PMID: 40091831, PMCID: PMC11910223, DOI: 10.1172/jci184740.Peer-Reviewed Original ResearchConceptsHyperinsulinemic-euglycemic clampSubcutaneous adipose tissueInsulin resistanceAdipose triglyceride lipaseInsulin infusionOral glucose tolerance testAbdominal fat distributionGlucose tolerance testMeasuring abdominal fat distributionLower liver fatActivating adipose triglyceride lipaseMetabolic disease riskLiver fat contentEctopic lipid storageFUNDINGThis workAdipose tissue lipolysisInhibition of adipose tissue lipolysisSubcutaneous adipose tissue samplesFat distributionTolerance testInsulin exposureLiver fatInfusionGlycerol turnoverAdipose tissue
2023
1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo
HUBBARD B, GASPAR R, ZHANG D, KAHN M, NASIRI A, SHULMAN G. 1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo. Diabetes 2023, 72 DOI: 10.2337/db23-1510-p.Peer-Reviewed Original ResearchInsulin receptor kinasePyruvate carboxylaseHyperinsulinemic-euglycemic clampMitochondrial pyruvate oxidationInsulin resistanceOxidative metabolismMitochondrial pyruvate carboxylaseReceptor kinaseInhibitory phosphorylationAktS473 phosphorylationKinase axisChow fed miceImpairs insulinPyruvate oxidationKnockin micePhosphorylationKey targetFortress BiotechFed micePKCεDiacylglycerolRenal cortexHFDMetabolismBasal conditions192-OR: Lipid-Induced Insulin Resistance in Brown Adipose Tissue Is Mediated by the sn-1,2 DAG-PKCe-IRKT1150 Phosphorylation Pathway
GASPAR R, HUBBARD B, SAKUMA I, LAMOIA T, ZHANG D, SHULMAN G. 192-OR: Lipid-Induced Insulin Resistance in Brown Adipose Tissue Is Mediated by the sn-1,2 DAG-PKCe-IRKT1150 Phosphorylation Pathway. Diabetes 2023, 72 DOI: 10.2337/db23-192-or.Peer-Reviewed Original ResearchRegular chow dietBrown adipose tissueHyperinsulinemic-euglycemic clampInsulin resistanceWild-type miceChow dietType miceAdipose tissue191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice
EL-AGROUDY N, SCHUMANN T, KURZBACH A, SANCAR G, SANDFORTH L, HERRMANN C, SHULMAN G, BIRKENFELD A. 191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice. Diabetes 2023, 72 DOI: 10.2337/db23-191-or.Peer-Reviewed Original ResearchDb/db miceOb/obInsulin sensitivityDb miceMRNA expressionWhole-body insulin sensitivitySkeletal muscle insulin sensitivitySkeletal muscle insulin resistanceSkeletal musclePeripheral insulin sensitivityTreatment of T2D.Hyperinsulinemic-euglycemic clampLiver fat contentGlucose infusion rateMuscle insulin sensitivityMuscle insulin resistanceHepatic glucose productionHepatic mitochondrial functionWT littermate mice849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats
VIJAYAKUMAR A, MURAKAMI E, HUSS R, SRODA N, SHIMAZAKI A, KASHIWAGI Y, MYERS R, SUBRAMANIAN M, SHULMAN G. 849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats. Diabetes 2023, 72 DOI: 10.2337/db23-849-p.Peer-Reviewed Original ResearchZucker diabetic fattyZDF ratsInsulin sensitivityAcetyl-CoA carboxylase 2T2D progressionAntidiabetic effectsClamp glucose infusion rateIntramyocellular lipid contentImproved insulin sensitivityHyperinsulinemic-euglycemic clampType 2 diabetesGlucose infusion rateNovel therapeutic approachesΒ-cell failureFatty acid oxidationFortress BiotechCardiac lipidsInsulin resistanceInfusion rateTherapeutic approachesStrong rationaleRatsGilead SciencesJanssen ResearchIMCL
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
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.
Ter Horst KW, Vatner DF, Zhang D, Cline GW, Ackermans MT, Nederveen AJ, Verheij J, Demirkiran A, van Wagensveld BA, Dallinga-Thie GM, Nieuwdorp M, Romijn JA, Shulman GI, Serlie MJ. Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease. Diabetes Care 2020, 44: 489-498. PMID: 33293347, PMCID: PMC7818337, DOI: 10.2337/dc20-1644.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisFatty liver diseaseBariatric surgeryLiver diseaseImpaired insulin-mediated suppressionGlucose productionHepatic de novo lipogenesisPeripheral glucose metabolismHyperinsulinemic-euglycemic clampType 2 diabetesInsulin-mediated suppressionInsulin-resistant subjectsHepatic insulin resistanceLiver biopsy samplesSuppress glucose productionLipogenic transcription factorsInsulin-mediated regulationObese subjectsInsulin resistanceAcute increaseNovo lipogenesisGlucose metabolismBiopsy samplesParadoxical increaseMembrane-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 phenotyping
2019
266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance
LYU K, ZHANG Y, ZHANG D, KAHN M, NOZAKI Y, BHANOT S, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance. Diabetes 2019, 68 DOI: 10.2337/db19-266-or.Peer-Reviewed Original ResearchHepatic insulin resistanceInsulin resistanceExogenous fatty acidsInsulin actionLipid dropletsHepatic ceramide contentHyperinsulinemic-euglycemic clampHepatic insulin actionBioactive lipid speciesHepatic glucose productionChow-fed ratsHepatic diacylglycerol contentAdvisory PanelFatty acidsHepatic steatosisImpaired suppressionSingle doseSpouse/partnerGlucose productionPKCε activationJanssen ResearchAcute knockdownCeramide contentNational InstituteReceptor kinase activation
2018
Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice
Abulizi A, Camporez JP, Zhang D, Samuel VT, Shulman GI, Vatner DF. Ectopic lipid deposition mediates insulin resistance in adipose specific 11β-hydroxysteroid dehydrogenase type 1 transgenic mice. Metabolism 2018, 93: 1-9. PMID: 30576689, PMCID: PMC6401251, DOI: 10.1016/j.metabol.2018.12.003.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceEctopic lipid depositionInsulin resistanceHepatic lipid contentGlucocorticoid actionTransgenic miceLipid depositionSevere hepatic insulin resistanceTissue-specific insulin actionHepatic triglyceride contentHigh-fat dietHyperinsulinemic-euglycemic clampGlucocorticoid excessAkt serine phosphorylationGlucocorticoid activityHepatic steatosisFat dietLittermate controlsHepatic insulinInsulin actionTriglyceride contentPKCε activationDevelopment of lipidLipid contentMiceEffect of a Controlled-Release Mitochondrial Protonophore (CRMP) on Healthspan and Lifespan in Mice
GOEDEKE L, CAMPOREZ J, NASIRI A, WANG Y, ZHANG X, SHULMAN G. Effect of a Controlled-Release Mitochondrial Protonophore (CRMP) on Healthspan and Lifespan in Mice. Diabetes 2018, 67 DOI: 10.2337/db18-123-lb.Peer-Reviewed Original ResearchControlled-release mitochondrial protonophoreCRMP treatmentHepatic steatosisDiet-induced rodent modelWhole body insulin responsivenessInflammation/fibrosisMale C57BL/6J miceWhole-body energy expenditureHyperinsulinemic-euglycemic clampHigh-fat dietType 2 diabetesGlucose infusion rateMitochondrial protonophorePlasma glucose concentrationWide therapeutic indexStrict dietary regimeSecond-generation compoundsTransaminase levelsFatty liverLiver triglyceridesInsulin resistanceAge-related diseasesC57BL/6J miceHepatic triglyceridesFood intakeMetabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats
SONG J, PERRY R, MUNK A, ZHANG Y, ZHANG D, SHULMAN G. Metabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats. Diabetes 2018, 67 DOI: 10.2337/db18-240-lb.Peer-Reviewed Original ResearchInsulin-resistant ratsMuscle insulin resistanceHigh-fat dietResistant ratsInsulin resistanceNormal ratsSoleus muscleLipid-induced muscle insulin resistanceSkeletal muscle insulin resistancePeripheral glucose metabolismHyperinsulinemic-euglycemic clampPathogenesis of obesityMuscle insulin sensitivityGlucose oxidationMuscle glucose transportAcute infusionPyruvate dehydrogenase fluxSubstrate oxidationFat dietMuscle glucoseInsulin sensitivityAcute modulationGlucose metabolismFat oxidationTissue-specific indices
2017
A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease
Goffredo M, Santoro N, Tricò D, Giannini C, D’Adamo E, Zhao H, Peng G, Yu X, Lam TT, Pierpont B, Caprio S, Herzog RI. A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients 2017, 9: 642. PMID: 28640216, PMCID: PMC5537762, DOI: 10.3390/nu9070642.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseMagnetic resonance imagingBranched-chain amino acidsFatty liver diseaseHepatic fat contentObese adolescentsInsulin resistanceLiver diseaseTwo-step hyperinsulinemic-euglycemic clampOral glucose tolerance testSecond magnetic resonance imagingSubset of patientsGlucose tolerance testHyperinsulinemic-euglycemic clampHigher plasma levelsHepatic insulin sensitivityChain amino acidsPlasma levelsTolerance testInsulin sensitivityMetabolomic signaturePlasma metabolitesResonance imagingValine levelsLipid metabolismMitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation
Lee HY, Lee JS, Alves T, Ladiges W, Rabinovitch PS, Jurczak MJ, Choi CS, Shulman GI, Samuel VT. Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation. Diabetes 2017, 66: db161334. PMID: 28476930, PMCID: PMC5521865, DOI: 10.2337/db16-1334.Peer-Reviewed Original ResearchConceptsHigh-fat dietMuscle insulin resistanceAcute lipid infusionInsulin resistanceRegular chowLipid infusionMCAT miceInsulin actionLipid-induced insulin resistanceDiet-induced insulin resistanceReactive oxygen speciesHyperinsulinemic-euglycemic clampWild-type miceMuscle fat oxidationIntramuscular lipid accumulationROS productionAcute infusionHFD-fedWT miceImpaired insulinPKCθ activationFat oxidationLipid emulsionMuscle insulinMice
2015
Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance
Popov VB, Jornayvaz FR, Akgul EO, Kanda S, Jurczak MJ, Zhang D, Abudukadier A, Majumdar SK, Guigni B, Petersen KF, Manchem VP, Bhanot S, Shulman GI, Samuel VT. Second‐generation antisense oligonucleotides against β‐catenin protect mice against diet‐induced hepatic steatosis and hepatic and peripheral insulin resistance. The FASEB Journal 2015, 30: 1207-1217. PMID: 26644352, PMCID: PMC4750414, DOI: 10.1096/fj.15-271999.Peer-Reviewed Original ResearchConceptsHepatic steatosisInsulin resistanceAntisense oligonucleotideDiet-induced hepatic steatosisWhole-body glucose metabolismLipid-induced insulin resistanceMale C57BL/6 micePeripheral insulin resistanceHyperinsulinemic-euglycemic clampType 2 diabetesHepatic insulin sensitivityΒ-cateninHepatic lipid compositionWhite adipose tissueWnt/β-cateninΒ-catenin expressionMetabolic syndromeProtect miceC57BL/6 miceΒ-catenin mRNAFed miceHepatic triglyceridesInsulin sensitivityAwake miceGlucose metabolism
2013
Validation of HOMA2S in acute phase of myocardial infarction, based on euglycemic-hyperinsulinemic clamp
Carvalho L, Moura F, Gomes N, Sposito A. Validation of HOMA2S in acute phase of myocardial infarction, based on euglycemic-hyperinsulinemic clamp. European Heart Journal 2013, 34: p1272. DOI: 10.1093/eurheartj/eht308.p1272.Peer-Reviewed Original ResearchAcute phase of MIEuglycemic-hyperinsulinemic clampPhase of MIMyocardial infarctionInsulin sensitivityAcute phaseST-segment elevation MIROC curveEvaluate blood glucose levelsArea under the curveAcute phase of myocardial infarctionHomeostasis model assessmentBland-Altman graphsPhase of myocardial infarctionBland-Altman analysisLinear regressionHyperinsulinemic-euglycemic clampHeart StudyGold standard methodBlood glucose levelsNondiabetic patientsStressful situationsCardiovascular eventsElevation MIEndothelial function
2012
The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats
Erion DM, Popov V, Hsiao JJ, Vatner D, Mitchell K, Yonemitsu S, Nagai Y, Kahn M, Gillum MP, Dong J, Murray SF, Manchem VP, Bhanot S, Cline GW, Shulman GI, Samuel VT. The Role of the Carbohydrate Response Element-Binding Protein in Male Fructose-Fed Rats. Endocrinology 2012, 154: 36-44. PMID: 23161873, PMCID: PMC3529388, DOI: 10.1210/en.2012-1725.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisResponse element-binding proteinCarbohydrate response element-binding proteinASO treatmentHepatic expressionNovo lipogenesisElement-binding proteinInsulin-stimulated peripheral glucose uptakeNonalcoholic fatty liver diseaseAntisense oligonucleotideMale Sprague-Dawley ratsHepatic de novo lipogenesisFructose-fed groupHepatic insulin responsivenessFatty liver diseaseFructose fed ratsPeripheral glucose uptakeHyperinsulinemic-euglycemic clampHigh-fat dietHepatic lipid contentHepatic triglyceride secretionHepatic insulin sensitivitySprague-Dawley ratsPlasma triglyceride concentrationsPlasma uric acidReversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes
Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 8236-8240. PMID: 22547801, PMCID: PMC3361376, DOI: 10.1073/pnas.1205675109.Peer-Reviewed Original ResearchConceptsMuscle insulin resistanceInsulin-resistant offspringType 2 diabetesBranched-chain amino acidsInsulin resistanceIR offspringInsulin-stimulated muscle glucose uptakeWeight lossPeripheral insulin responsivenessReduction of IMCLModest weight lossPeripheral glucose metabolismC-reactive proteinHyperinsulinemic-euglycemic clampIntramyocellular lipid accumulationMuscle glucose uptakeAverage weight lossWeight reductionTotal adiponectinHypocaloric dietIL-6IMCL contentPlasma concentrationsWeight stabilizationIMCL accumulation
2011
Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*
Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D, Weismann D, Arafat AM, Pfeiffer AF, Lieske S, Oyadomari S, Ron D, Samuel VT, Shulman GI. Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*. Journal Of Biological Chemistry 2011, 286: 36163-36170. PMID: 21832042, PMCID: PMC3196114, DOI: 10.1074/jbc.m111.228817.Peer-Reviewed Original ResearchConceptsHepatic glucose productionInsulin sensitivityInsulin resistanceCaloric excessER stressHigh-fat diet-fed miceBasal plasma glucose concentrationsGlucose productionIGFBP-3 levelsHepatic ERPeripheral glucose metabolismTissue insulin sensitivityDiet-fed miceHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic clampHepatic insulin sensitivityInfusion of insulinPlasma glucose concentrationEndoplasmic reticulum stress response pathwayEndoplasmic reticulum stressInsulin-stimulated muscleIGFBP-3Fat dietMuscle glucose
This site is protected by hCaptcha and its Privacy Policy and Terms of Service apply