2023
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
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 animals
2018
PEPCK1 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 sensitivityMembrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo
LYU K, ZHANG D, NOZAKI Y, ZHANG Y, BHANOT S, CLINE G, SAMUEL V, SHULMAN G. Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance In Vivo. Diabetes 2018, 67 DOI: 10.2337/db18-243-lb.Peer-Reviewed Original ResearchHepatic insulin resistanceLipid-induced hepatic insulin resistanceDiglyceride acyltransferase 2Hepatic DAG contentInsulin resistanceHepatic insulin sensitivityInsulin sensitivityImpaired insulin-mediated suppressionActivation/translocationDGAT2 inhibitionAntisense oligonucleotideRegular chow dietInsulin-mediated suppressionHepatic insulin actionHepatic glucose productionInsulin receptor kinaseDAG contentChow dietASO treatmentIonis PharmaceuticalsInsulin actionGlucose productionPKCε activationSREBP-1cGilead SciencesAngptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents
Vatner DF, Goedeke L, Camporez JG, Lyu K, Nasiri AR, Zhang D, Bhanot S, Murray SF, Still CD, Gerhard GS, Shulman GI, Samuel VT. Angptl8 antisense oligonucleotide improves adipose lipid metabolism and prevents diet-induced NAFLD and hepatic insulin resistance in rodents. Diabetologia 2018, 61: 1435-1446. PMID: 29497783, PMCID: PMC5940564, DOI: 10.1007/s00125-018-4579-1.Peer-Reviewed Original ResearchMeSH KeywordsAdipose TissueAngiopoietin-Like Protein 8Angiopoietin-like ProteinsAnimalsBody CompositionCalorimetry, IndirectDiet, High-FatGlucose Tolerance TestInsulin ResistanceLipid MetabolismMaleMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseOligonucleotides, AntisensePeptide HormonesRatsRats, Sprague-DawleyConceptsHepatic insulin resistanceAdipose tissue lipoprotein lipaseInsulin resistanceEctopic lipid accumulationTissue lipoprotein lipaseAdipose tissueLipid uptakeTolerance testFed miceNon-alcoholic fatty liver diseaseAntisense oligonucleotideMixed meal tolerance testLipoprotein lipaseLipid accumulationDiet-induced NAFLDBariatric surgery patientsFatty liver diseaseHyperinsulinaemic euglycaemic clampMeal tolerance testSecond-generation antisense oligonucleotideAmeliorate insulin resistanceType 2 diabetesLipid-induced hepatic insulin resistanceLipoprotein lipase inhibitorWhite adipose tissue
2014
Targeting 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
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