2024
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke L, Strober J, Suh R, Paolella L, Li X, Rogers J, Petersen M, Nasiri A, Casals G, Kahn M, Cline G, Samuel V, Shulman G, Vatner D. High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis. IScience 2024, 27: 111175. PMID: 39524330, PMCID: PMC11550620, DOI: 10.1016/j.isci.2024.111175.Peer-Reviewed Original ResearchDuration of high-fat dietAttenuated insulin signalingHigh-fat dietHepatic insulin resistanceInsulin signalingInsulin stimulationLipogenic substrateStimulation of de novo lipogenesisReduced lipogenesisHFD feedingReduce DNLInsulin resistanceResistance per seLipogenesisInsulin resistance per sePathway selectionGlucose metabolismHepatic IRMiceFat dietSREBP1cINSRCeramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibition1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis
SAKUMA I, GASPAR R, NASIRI A, KAHN M, ZHENG J, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis. Diabetes 2024, 73 DOI: 10.2337/db24-1571-p.Peer-Reviewed Original ResearchLipid droplet sizeCGI-58Choline-deficient l-amino acid-defined high-fat dietGlycerol-3-phosphate acyltransferaseAntisense oligonucleotidesComparative gene identification-58Glycerol-3-phosphateLoss of function mutationsLipid droplet morphologyExpression of CGI-58Liver inflammationCidebCholesterol contentFunction mutationsL-amino acid-defined high-fat dietComplications of type 2 diabetesMolecular mechanismsDevelopment of liver inflammationMacrophage crown-like structuresType 2 diabetesHigh-fat dietCrown-like structuresASO treatmentGPAMKnockdown292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets
SAKUMA I, GASPAR R, NASIRI A, KAHN M, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets. Diabetes 2024, 73 DOI: 10.2337/db24-292-or.Peer-Reviewed Original ResearchCholine-deficient l-amino acid-defined high-fat dietAccumulation of cholesterolMRNA expressionPlasma ALTL-amino acid-defined high-fat dietProtective effectLiver lipid dropletsType 2 diabetesPotential therapeutic approachHigh-fat dietDecreased plasma ALTFibrosis markersFree cholesterol accumulationLipid dropletsLiver inflammationDay 1Macrophage markersHepatic inflammationMouse modelMarker expressionTherapeutic approachesDay 2Day 3Day 7Fibrosis1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway
ZHENG J, NASIRI A, GASPAR R, HUBBARD B, SAKUMA I, MA X, MURRAY S, PERELIS M, BARNES W, SAMUEL V, PETERSEN K, SHULMAN G. 1577-P: CIDEB Knockdown Promotes Increased Hepatic Mitochondrial Fat Oxidation and Reverses Hepatic Steatosis and Hepatic Insulin Resistance by the PKCε-Insulin Receptor Kinase Pathway. Diabetes 2024, 73 DOI: 10.2337/db24-1577-p.Peer-Reviewed Original ResearchReceptor kinase pathwaysMitochondrial fat oxidationHepatic insulin resistanceKinase pathwayExpression of cidebAmeliorated HFD-induced hepatic steatosisHFD-induced hepatic steatosisHFD-induced insulin resistanceSteatotic liver diseasePathogenesis of type 2 diabetesHepatic steatosisCidebHyperinsulinemic-euglycemic clamp studiesHepatic triglyceride accumulationInsulin resistanceReverse hepatic steatosisTriglyceride accumulationHepatic insulin sensitivityInsulin sensitivityPathwayHepatic expressionHigh-fatWhole-body insulin sensitivityLiver diseaseTranslocation
2023
Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition
Sakuma I, Gaspar R, Luukkonen P, Kahn M, Zhang D, Zhang X, Murray S, Golla J, Vatner D, Samuel V, Petersen K, Shulman G. Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2312666120. PMID: 38127985, PMCID: PMC10756285, DOI: 10.1073/pnas.2312666120.Peer-Reviewed Original ResearchAuthor Correction: Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner
Pajvani U, Shawber C, Samuel V, Birkenfeld A, Shulman G, Kitajewski J, Accili D. Author Correction: Inhibition of Notch signaling ameliorates insulin resistance in a FoxO1-dependent manner. Nature Medicine 2023, 30: 604-604. PMID: 38041001, DOI: 10.1038/s41591-023-02695-9.Peer-Reviewed Original Research1569-P: Lysophosphatidic Acid Mediates Inflammation in Liver and White Adipose Tissue in a Rat Model of 1-acyl-sn-glycerol-3-phosphate Acyltransferase 2 Deficiency
SAKUMA I, GASPAR R, LUUKKONEN P, KAHN M, MURRAY S, SAMUEL V, PETERSEN K, SHULMAN G. 1569-P: Lysophosphatidic Acid Mediates Inflammation in Liver and White Adipose Tissue in a Rat Model of 1-acyl-sn-glycerol-3-phosphate Acyltransferase 2 Deficiency. Diabetes 2023, 72 DOI: 10.2337/db23-1569-p.Peer-Reviewed Original ResearchWhite adipose tissueControlled-release mitochondrial protonophoreCongenital generalized lipodystrophyAGPAT2 deficiencyHepatic inflammationASO treatmentAdipose tissueLysophosphatidic acidAdult male SD ratsAntisense oligonucleotideMale SD ratsNovel therapeutic targetNovo NordiskCRMP treatmentFortress BiotechWAT inflammationDohme Corp.SD ratsRat modelAGPAT2 geneGeneralized lipodystrophyInflammationTherapeutic targetIonis PharmaceuticalsDeficient animalsVA/DoD CLINICAL PRACTICE GUIDELINE FOR THE MANAGEMENT OF TYPE 2 DIABETES MELLITUS
VA/DoD Clinical Practice Guideline. (2023). Management of Type 2 Diabetes Mellitus. Washington, DC: U.S. Government Printing Office.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus Statements
2022
Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice
Lee H, Jang H, Li H, Samuel V, Dudek K, Osipovich A, Magnuson M, Sklar J, Shulman G. Deletion of Jazf1 gene causes early growth retardation and insulin resistance in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2022, 119: e2213628119. PMID: 36442127, PMCID: PMC9894197, DOI: 10.1073/pnas.2213628119.Peer-Reviewed Original ResearchConceptsKO miceEarly growth retardationInsulin resistanceFat massGrowth retardationAge-matched wild-type miceHepatic nuclear factor 4 alphaGH-IGF-1 axisHigh-fat diet feedingKO liversHyperinsulinemic-euglycemic clamp techniquePlasma growth hormone concentrationInsulin-like growth factor-1Type 2 diabetesGrowth hormone concentrationsIGF-1 expressionWild-type miceLean body massMuscle insulin resistanceGrowth factor-1Nuclear factor 4 alphaInsulin sensitivityDiet feedingPlasma concentrationsHormone concentrations
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 ResearchNon‐alcoholic Fatty Liver Disease and Insulin Resistance
Petersen M, Samuel V, Petersen K, Shulman G. Non‐alcoholic Fatty Liver Disease and Insulin Resistance. 2020, 455-471. DOI: 10.1002/9781119436812.ch37.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseHepatic insulin resistanceFatty liver diseaseInsulin resistanceLiver diseaseDevelopment of NAFLDLipid-induced muscle insulin resistanceRandle glucose-fatty acid cycleCommon chronic liver diseaseType 2 diabetes mellitusHyperinsulinemic-euglycemic clamp studiesGlucose-fatty acid cycleLiver-related deathSkeletal muscleChronic liver diseaseNon-alcoholic steatohepatitisMajor risk factorLipid-induced hepatic insulin resistanceMuscle insulin resistanceDiabetes mellitusRisk factorsClamp studiesLipoprotein lipaseDiseaseProtein 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 resistanceGlycolysisEnzymePKAPathwayActivityConsidering 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 sensitivity