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
2019
Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production
Gassaway BM, Cardone RL, Padyana AK, Petersen MC, Judd ET, Hayes S, Tong S, Barber KW, Apostolidi M, Abulizi A, Sheetz JB, Kshitiz, Aerni HR, Gross S, Kung C, Samuel VT, Shulman GI, Kibbey RG, Rinehart J. Distinct Hepatic PKA and CDK Signaling Pathways Control Activity-Independent Pyruvate Kinase Phosphorylation and Hepatic Glucose Production. Cell Reports 2019, 29: 3394-3404.e9. PMID: 31825824, PMCID: PMC6951436, DOI: 10.1016/j.celrep.2019.11.009.Peer-Reviewed Original ResearchConceptsCyclin-dependent kinasesMetabolic control pointPhosphorylation sitesNuclear retentionCDK activityPKL activityDays high-fat dietKinase phosphorylationImportant enzymePyruvate kinaseHigh-fat dietS113KinaseEnzyme kineticsPhosphorylationAdditional control pointsRegulationGlucose productionHepatic glucose productionInsulin resistanceGlycolysisEnzymePKAPathwayActivity
2018
PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling
Gassaway BM, Petersen MC, Surovtseva YV, Barber KW, Sheetz JB, Aerni HR, Merkel JS, Samuel VT, Shulman GI, Rinehart J. PKCε contributes to lipid-induced insulin resistance through cross talk with p70S6K and through previously unknown regulators of insulin signaling. Proceedings Of The National Academy Of Sciences Of The United States Of America 2018, 115: e8996-e9005. PMID: 30181290, PMCID: PMC6156646, DOI: 10.1073/pnas.1804379115.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAnimals, Genetically ModifiedDiabetes Mellitus, Type 2Diet, High-FatDisease Models, AnimalGene Knockdown TechniquesHumansInsulinInsulin Receptor Substrate ProteinsInsulin ResistanceLipid MetabolismLiverPhosphorylationProtein Kinase C-epsilonProteomicsRatsReceptor, InsulinRibosomal Protein S6Ribosomal Protein S6 Kinases, 70-kDaRNA, Small InterferingSignal TransductionConceptsHigh-fat diet-induced hepatic insulin resistanceDiet-induced hepatic insulin resistanceLipid-induced insulin resistanceProtein phosphorylationSiRNA-based screenProtein kinase C εSet of proteinsCross talkHepatic insulin resistanceQuantitative phosphoproteomicsMotif analysisUnknown regulatorKinase assaysPhosphoproteomic dataCanonical insulinP70S6KInsulin receptorImpact of lipidSystem-level approachPKCεDiacylglycerolPhosphorylationKey mediatorNew therapeutic approachesInsulin resistance
2016
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance
Petersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abulizi A, Zhang XM, Philbrick W, Hubbard SR, Jurczak MJ, Samuel VT, Rinehart J, Shulman GI. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. Journal Of Clinical Investigation 2016, 126: 4361-4371. PMID: 27760050, PMCID: PMC5096902, DOI: 10.1172/jci86013.Peer-Reviewed Original ResearchConceptsInsulin receptorKinase activityHigh-fat diet-induced hepatic insulin resistanceKinase activation loopNonalcoholic fatty liver diseaseLipid-induced hepatic insulin resistanceProtein kinase CHepatic insulin resistanceDiet-induced hepatic insulin resistanceDiacylglycerol-mediated activationActivation loopPKCε inhibitionAlanine mutationsInsulin resistanceMolecular mechanismsKinase CCritical pathophysiological rolePathogenesis of T2DMechanistic linkMutantsGlycogen synthesisConsequent inhibitionPhosphorylationActive configurationPKCεThe Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis
Herman MA, Samuel VT. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis. Trends In Endocrinology And Metabolism 2016, 27: 719-730. PMID: 27387598, PMCID: PMC5035631, DOI: 10.1016/j.tem.2016.06.005.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsFructoseHumansInsulinInsulin ResistanceLipid MetabolismLipogenesisSignal TransductionConceptsFructose consumptionHepatic fructose metabolismHepatic insulin resistanceImpairment of insulinDe novo lipogenesisHepatic steatosisInsulin resistanceEpidemiological studiesNovo lipogenesisMetabolic diseasesFructose metabolismLipogenic enzymesLipogenesisFatty acid synthesisKey transcription factorDiseaseAldolase BLipid synthesisAdditional mechanismHypertriglyceridemiaSteatosisTranscription factorsTherapyInsulinImpairment
2015
Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids
Vatner DF, Majumdar SK, Kumashiro N, Petersen MC, Rahimi Y, Gattu AK, Bears M, Camporez JP, Cline GW, Jurczak MJ, Samuel VT, Shulman GI. Insulin-independent regulation of hepatic triglyceride synthesis by fatty acids. Proceedings Of The National Academy Of Sciences Of The United States Of America 2015, 112: 1143-1148. PMID: 25564660, PMCID: PMC4313795, DOI: 10.1073/pnas.1423952112.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2Enzyme InhibitorsInsulinInsulin ResistanceLiverPalmitic AcidRatsReceptor, InsulinSignal TransductionTriglycerides
2014
The emerging role of oestrogen-related receptor γ as a regulator of energy metabolism
Samuel VT. The emerging role of oestrogen-related receptor γ as a regulator of energy metabolism. Diabetologia 2014, 57: 2440-2443. PMID: 25257097, PMCID: PMC4488899, DOI: 10.1007/s00125-014-3377-7.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsGluconeogenesisInsulinLiverProto-Oncogene Proteins c-aktReceptors, EstrogenSignal Transduction
2013
Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways
Vatner DF, Weismann D, Beddow SA, Kumashiro N, Erion DM, Liao XH, Grover GJ, Webb P, Phillips KJ, Weiss RE, Bogan JS, Baxter J, Shulman GI, Samuel VT. Thyroid hormone receptor-β agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. AJP Endocrinology And Metabolism 2013, 305: e89-e100. PMID: 23651850, PMCID: PMC3725564, DOI: 10.1152/ajpendo.00573.2012.Peer-Reviewed Original ResearchMeSH KeywordsAcetatesAnilidesAnimalsDietary FatsFatty LiverGene ExpressionGluconeogenesisGlucose Transporter Type 4HyperglycemiaHyperinsulinismInsulin ResistanceMaleMuscle, SkeletalNon-alcoholic Fatty Liver DiseasePhenolsRatsRats, Sprague-DawleySignal TransductionThyroid Hormone Receptors betaTriglyceridesConceptsEndogenous glucose productionHepatic insulin sensitivityInsulin sensitivityHepatic steatosisFat-fed ratsInsulin-stimulated peripheral glucose disposalTRβ agonistsInsulin-stimulated skeletal muscle glucose uptakePotent lipid-lowering drugsNonalcoholic fatty liver diseaseWhite adipose tissue lipolysisMale Sprague-Dawley ratsSkeletal muscle glucose uptakeGC-1 treatmentPeripheral glucose disposalFatty liver diseaseImpairs insulin sensitivityLipid-lowering drugsHepatic triglyceride contentAdipose tissue lipolysisMuscle glucose uptakeSprague-Dawley ratsHepatic insulin resistanceSkeletal muscle insulinPotential adverse effects
2012
Mechanisms for Insulin Resistance: Common Threads and Missing Links
Samuel VT, Shulman GI. Mechanisms for Insulin Resistance: Common Threads and Missing Links. Cell 2012, 148: 852-871. PMID: 22385956, PMCID: PMC3294420, DOI: 10.1016/j.cell.2012.02.017.Peer-Reviewed Original ResearchConceptsUnfolded protein response pathwayProtein response pathwayInsulin resistanceFatty acid uptakeResponse pathwaysLipid metabolitesAcid uptakeSpecific lipid metabolitesEctopic lipid depositionImmune pathwaysPathwayImpaired insulinCommon final pathwayCellular changesComplex metabolic disorderSkeletal muscleMetabolic disordersLipid depositionFinal pathwayEnergy expenditureAccumulationEtiological pathwaysMetabolitesMissing linkResistance
2007
Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease
Samuel VT, Liu ZX, Wang A, Beddow SA, Geisler JG, Kahn M, Zhang XM, Monia BP, Bhanot S, Shulman GI. Inhibition of protein kinase Cε prevents hepatic insulin resistance in nonalcoholic fatty liver disease. Journal Of Clinical Investigation 2007, 117: 739-745. PMID: 17318260, PMCID: PMC1797607, DOI: 10.1172/jci30400.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceNonalcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceHigh-fat feedingLiver diseaseFat-induced hepatic insulin resistanceType 2 diabetes mellitusType 2 diabetesHepatic fat accumulationNovel therapeutic targetInsulin receptor kinase activityDiabetes mellitusHepatic steatosisFat accumulationRats resultsTherapeutic targetHepatic insulinReceptor kinase activityProtein kinase CεInsulin receptorCausal roleIsoforms of PKCAntisense oligonucleotideRats
2004
Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*
Samuel VT, Liu ZX, Qu X, Elder BD, Bilz S, Befroy D, Romanelli AJ, Shulman GI. Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*. Journal Of Biological Chemistry 2004, 279: 32345-32353. PMID: 15166226, DOI: 10.1074/jbc.m313478200.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlotting, WesternCell MembraneCytosolDeoxyglucoseEnzyme ActivationFatty AcidsFatty LiverGlycogenGlycogen SynthaseInsulinInsulin ResistanceLipid MetabolismLiverMaleMitogen-Activated Protein Kinase 8Mitogen-Activated Protein KinasesPhosphorylationPrecipitin TestsProtein IsoformsProtein Kinase CProtein Kinase C-epsilonProtein TransportRatsRats, Sprague-DawleyRNA, MessengerSignal TransductionTime FactorsTyrosineConceptsHepatic insulin resistanceNon-alcoholic fatty liver diseaseEndogenous glucose productionFatty liver diseaseInsulin resistanceHepatic fat accumulationFat feedingLiver diseaseFat accumulationFF groupInsulin-stimulated peripheral glucose disposalShort-term fat feedingSkeletal muscle fat contentBasal endogenous glucose productionShort-term high-fat feedingPeripheral glucose disposalHigh-fat feedingIRS-1PKC-epsilonAbility of insulinAcyl-CoA contentInsulin-stimulated IRS-1IRS-2 tyrosine phosphorylationLiver triglyceridesFatty liver
2001
Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle
Chutkow W, Samuel V, Hansen P, Pu J, Valdivia C, Makielski J, Burant C. Disruption of Sur2-containing KATP channels enhances insulin-stimulated glucose uptake in skeletal muscle. Proceedings Of The National Academy Of Sciences Of The United States Of America 2001, 98: 11760-11764. PMID: 11562480, PMCID: PMC58803, DOI: 10.1073/pnas.201390398.Peer-Reviewed Original ResearchMeSH KeywordsAnalysis of VarianceAnimalsATP-Binding Cassette TransportersBiological TransportBlood GlucoseDeoxyglucoseExonsGlucoseGlucose Clamp TechniqueGlucose Tolerance TestGlucose Transporter Type 4InsulinIntronsMiceMice, KnockoutMonosaccharide Transport ProteinsMuscle ProteinsMuscle, SkeletalPolymerase Chain ReactionPotassium ChannelsPotassium Channels, Inwardly RectifyingReceptors, DrugRNA, MessengerSignal TransductionSodium-Potassium-Exchanging ATPaseSulfonylurea ReceptorsTriglyceridesWeight GainConceptsSkeletal muscleInsulin-stimulated glucose transportGene-targeting strategiesGlucose uptake mechanismsInsulin-stimulated glucose uptakeHomozygous null miceRegulatory subunitInsertional mutagenesisWild typeEnhanced glucose useProtection of tissuesDiverse arrayGlucose transportChannel activityUptake mechanismNull miceATP-sensitive potassium channelsPotassium channelsGlucose uptakeMembrane excitabilityFuture therapeutic approachesWild-type littermatesTarget blood glucose levelsInsulin actionPhysiologic function