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
A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCϵDAG contentMembraneFractionation methodKinaseMitochondriaMetabolic control analysis of hepatic glycogen synthesis in vivo
Nozaki Y, Petersen MC, Zhang D, Vatner DF, Perry RJ, Abulizi A, Haedersdal S, Zhang XM, Butrico GM, Samuel VT, Mason GF, Cline GW, Petersen KF, Rothman DL, Shulman GI. Metabolic control analysis of hepatic glycogen synthesis in vivo. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 8166-8176. PMID: 32188779, PMCID: PMC7149488, DOI: 10.1073/pnas.1921694117.Peer-Reviewed Original Research
2019
Considering the Links Between Nonalcoholic Fatty Liver Disease and Insulin Resistance: Revisiting the Role of Protein Kinase C ε
Samuel VT, Petersen MC, Gassaway BM, Vatner DF, Rinehart J, Shulman GI. Considering the Links Between Nonalcoholic Fatty Liver Disease and Insulin Resistance: Revisiting the Role of Protein Kinase C ε. Hepatology 2019, 70: 2217-2220. PMID: 31220350, DOI: 10.1002/hep.30829.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsNonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides. New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/nejmcibr1910023.Peer-Reviewed Original ResearchAdipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action
Abulizi A, Camporez JP, Jurczak MJ, Høyer KF, Zhang D, Cline GW, Samuel VT, Shulman GI, Vatner DF. Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action. The FASEB Journal 2019, 33: 8174-8185. PMID: 30922125, PMCID: PMC6593882, DOI: 10.1096/fj.201802706r.Peer-Reviewed Original ResearchConceptsWhole-body metabolismHepatic insulin actionHepatic insulin resistanceGlucocorticoid actionHepatic steatosisHepatic glycogen synthesisInsulin resistanceAdipose lipolysisFood intakeInsulin actionAdipose triglyceride lipase expressionGlucose-dependent organsReceptor knockout miceOral glucose challengeHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic conditionsGlycogen synthesisProtein kinase B phosphorylationInsulin responseGlucose challengeHepatic insulin responseHepatic insulinMetabolic cagesSteatosis
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 contentMicePEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats
Beddow SA, Gattu AK, Vatner DF, Paolella L, Alqarzaee A, Tashkandi N, Popov V, Church C, Rodeheffer M, Cline G, Geisler J, Bhanot S, Samuel VT. PEPCK1 Antisense Oligonucleotide Prevents Adiposity and Impairs Hepatic Glycogen Synthesis in High-Fat Male Fed Rats. Endocrinology 2018, 160: 205-219. PMID: 30445425, PMCID: PMC6307100, DOI: 10.1210/en.2018-00630.Peer-Reviewed Original ResearchMeSH KeywordsAdipose Tissue, WhiteAdiposityAnimalsDiabetes Mellitus, Type 2Diet, High-FatGlucokinaseHumansInsulinIntracellular Signaling Peptides and ProteinsLipogenesisLiverLiver GlycogenMaleMiceMice, Inbred C57BLOligonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)RatsRats, Sprague-DawleyConceptsHepatic glycogen synthesisAdipose tissueAntisense oligonucleotideType 2 diabetes mellitusWhite adipose tissue massIncreased hepatic gluconeogenesisChow fed ratsHepatic insulin sensitivityMale Sprague-DawleyAdipose tissue massHepatic insulin resistanceWhite adipose tissueHepatic glucose productionDe novo lipogenesisHepatic glucokinase expressionControl antisense oligonucleotideGlycogen synthesisTranscription factor 3HFF ratsDiabetes mellitusHepatic steatosisInsulin resistanceHyperglycemic clampPlasma glucoseInsulin sensitivityPKCε 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 configurationPKCε
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 Research
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 ResearchTargeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats
Cantley JL, Vatner DF, Galbo T, Madiraju A, Petersen M, Perry RJ, Kumashiro N, Guebre-Egziabher F, Gattu AK, Stacy MR, Dione DP, Sinusas AJ, Ragolia L, Hall CE, Manchem VP, Bhanot S, Bogan JS, Samuel VT. Targeting steroid receptor coactivator 1 with antisense oligonucleotides increases insulin-stimulated skeletal muscle glucose uptake in chow-fed and high-fat-fed male rats. AJP Endocrinology And Metabolism 2014, 307: e773-e783. PMID: 25159329, PMCID: PMC4216948, DOI: 10.1152/ajpendo.00148.2014.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAnimalsBiological TransportDiet, High-FatEnzyme InhibitorsGene Expression Regulation, EnzymologicGlucose IntoleranceGlucose Transporter Type 4Insulin ResistanceIntracellular Signaling Peptides and ProteinsIntramolecular OxidoreductasesLipocalinsLiverMaleMuscle, SkeletalNuclear Receptor Coactivator 1Oligodeoxyribonucleotides, AntisensePhosphoenolpyruvate Carboxykinase (GTP)Prostaglandin D2Protein Interaction Domains and MotifsProteolysisRats, Sprague-DawleyConceptsMuscle glucose uptakeSteroid receptor coactivator-1Endogenous glucose productionInsulin-stimulated muscle glucose uptakeReceptor coactivator-1Glucose uptakeGlucose homeostasisInsulin-stimulated skeletal muscle glucose uptakeAntisense oligonucleotideBasal endogenous glucose productionInsulin-stimulated whole-body glucose disposalCoactivator-1Whole-body glucose disposalSkeletal muscle glucose uptakeLipocalin-type prostaglandin D2 synthaseSprage-Dawley ratsGluconeogenic enzymes
2013
Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance
Kumashiro N, Beddow SA, Vatner DF, Majumdar SK, Cantley JL, Guebre-Egziabher F, Fat I, Guigni B, Jurczak MJ, Birkenfeld AL, Kahn M, Perler BK, Puchowicz MA, Manchem VP, Bhanot S, Still CD, Gerhard GS, Petersen KF, Cline GW, Shulman GI, Samuel VT. Targeting Pyruvate Carboxylase Reduces Gluconeogenesis and Adiposity and Improves Insulin Resistance. Diabetes 2013, 62: 2183-2194. PMID: 23423574, PMCID: PMC3712050, DOI: 10.2337/db12-1311.Peer-Reviewed Original ResearchConceptsPyruvate carboxylaseAntisense oligonucleotideHepatocyte fatty acid oxidationInsulin resistanceNonalcoholic fatty liver diseaseZucker diabetic fatty ratsHigh fat-fed ratsFatty liver diseaseLiver biopsy specimensDiabetic fatty ratsPlasma lipid concentrationsType 2 diabetesHepatic insulin sensitivityHuman liver biopsy specimensEndogenous glucose productionHepatic insulin resistancePlasma glucose concentrationPotential therapeutic approachSpecific antisense oligonucleotideFat-fed ratsCarboxylaseFatty acid oxidationDe novo fatty acid synthesisLiver diseaseTissue-specific inhibition
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
2009
Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes
Samuel VT, Beddow SA, Iwasaki T, Zhang XM, Chu X, Still CD, Gerhard GS, Shulman GI. Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2009, 106: 12121-12126. PMID: 19587243, PMCID: PMC2707270, DOI: 10.1073/pnas.0812547106.Peer-Reviewed Original ResearchMeSH KeywordsAdultAnimalsDiabetes Mellitus, Type 2Dietary FatsFastingFeeding BehaviorFemaleGene Expression Regulation, EnzymologicGluconeogenesisGlucose-6-PhosphataseHumansHyperglycemiaHyperinsulinismInsulin Infusion SystemsLiverMaleMiddle AgedPhosphoenolpyruvate Carboxykinase (ATP)RatsRats, Sprague-DawleyStreptozocinConceptsHigh-fat feedingEndogenous glucose productionHFF ratsExpression of PEPCKHepatic expressionType 2 diabetes mellitusBeta-cell compensationBeta-cell responseFirst rat modelPortal vein infusionLiver biopsy samplesHigher plasma glucosePhosphoenolpyruvate carboxykinaseBariatric surgeryT2DM patientsDiabetes mellitusInsulin resistancePlasma insulinPlasma glucosePortal infusionRat modelRodent modelsVein infusionHyperglycemiaKey gluconeogenic enzymes
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