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
2013
Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo
Galbo T, Perry RJ, Jurczak MJ, Camporez J, Alves TC, Kahn M, Guigni BA, Serr J, Zhang D, Bhanot S, Samuel VT, Shulman GI. Saturated and unsaturated fat induce hepatic insulin resistance independently of TLR-4 signaling and ceramide synthesis in vivo. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 12780-12785. PMID: 23840067, PMCID: PMC3732992, DOI: 10.1073/pnas.1311176110.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceFat-induced hepatic insulin resistanceInsulin resistanceToll-like receptor 4 receptorTLR-4 knockout miceFat-induced insulin resistanceTLR-4 activationTLR-4 signalingType 2 diabetesImpairment of insulinInhibition of insulinCeramide synthesisActivation of PKCεTLR-4Hepatic steatosisHepatic accumulationKnockout miceIRS-2 signalingReceptor signalingCeramide accumulationAntisense oligonucleotideInsulinPrimary eventImpairmentFatty acidsTargeting 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
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 acid
2010
Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance
Weismann D, Erion DM, Ignatova-Todorava I, Nagai Y, Stark R, Hsiao JJ, Flannery C, Birkenfeld AL, May T, Kahn M, Zhang D, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Shulman GI, Samuel VT. Knockdown of the gene encoding Drosophila tribbles homologue 3 (Trib3) improves insulin sensitivity through peroxisome proliferator-activated receptor-γ (PPAR-γ) activation in a rat model of insulin resistance. Diabetologia 2010, 54: 935-944. PMID: 21190014, PMCID: PMC4061906, DOI: 10.1007/s00125-010-1984-5.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBenzhydryl CompoundsDiabetes Mellitus, Type 2Disease Models, AnimalEpoxy CompoundsGlucose Clamp TechniqueImmunoblottingInsulin ResistanceMaleOligonucleotides, AntisensePPAR gammaProtein KinasesProtein Serine-Threonine KinasesRatsRats, Sprague-DawleyReverse Transcriptase Polymerase Chain ReactionConceptsTribbles homologue 3Euglycaemic hyperinsulinaemic clampWhite adipose tissueInsulin sensitivityAdipose tissueAntisense oligonucleotideInsulin-stimulated whole-body glucose uptakeWhole-body glucose uptakeConclusions/interpretationThese dataTissue-specific insulin sensitivityGlucose uptakeSkeletal muscle glucose uptakeWhite adipose tissue massPlasma HDL cholesterolRole of PPARAdipose tissue massMuscle glucose uptakeEndogenous glucose productionExpression of PPARInsulin-sensitising effectsDependent mannerViral proto-oncogeneHDL cholesterolAkt2 activityInsulin resistance
2009
Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein
Erion DM, Ignatova ID, Yonemitsu S, Nagai Y, Chatterjee P, Weismann D, Hsiao JJ, Zhang D, Iwasaki T, Stark R, Flannery C, Kahn M, Carmean CM, Yu XX, Murray SF, Bhanot S, Monia BP, Cline GW, Samuel VT, Shulman GI. Prevention of Hepatic Steatosis and Hepatic Insulin Resistance by Knockdown of cAMP Response Element-Binding Protein. Cell Metabolism 2009, 10: 499-506. PMID: 19945407, PMCID: PMC2799933, DOI: 10.1016/j.cmet.2009.10.007.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceNonalcoholic fatty liver diseaseCAMP response element-binding proteinInsulin resistanceResponse element-binding proteinASO treatmentElement-binding proteinCREB expressionType 2 diabetes mellitusOb/ob miceFatty liver diseaseHepatic triglyceride contentPlasma glucose concentrationFed rat modelAttractive therapeutic targetAntisense oligonucleotideDiabetes mellitusLiver diseaseZDF ratsHepatic steatosisOb micePostprandial hyperglycemiaPlasma cholesterolRat modelTriglyceride concentrations
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