2024
Ceramide 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 inhibitorDGAT2DesaturaseInhibition
2020
One-leg inactivity induces a reduction in mitochondrial oxidative capacity, intramyocellular lipid accumulation and reduced insulin signalling upon lipid infusion: a human study with unilateral limb suspension
Bilet L, Phielix E, van de Weijer T, Gemmink A, Bosma M, Moonen-Kornips E, Jorgensen JA, Schaart G, Zhang D, Meijer K, Hopman M, Hesselink MKC, Ouwens DM, Shulman GI, Schrauwen-Hinderling VB, Schrauwen P. One-leg inactivity induces a reduction in mitochondrial oxidative capacity, intramyocellular lipid accumulation and reduced insulin signalling upon lipid infusion: a human study with unilateral limb suspension. Diabetologia 2020, 63: 1211-1222. PMID: 32185462, PMCID: PMC7228997, DOI: 10.1007/s00125-020-05128-1.Peer-Reviewed Original ResearchConceptsMitochondrial oxidative capacityLow mitochondrial oxidative capacityLipid infusionInsulin resistancePhysical inactivityOxidative capacityLipid-induced insulin resistanceUnilateral lower limb suspensionConclusions/interpretationTogetherIntramyocellular lipid depositionMusculus tibialis anteriorChronic metabolic disorderIntramyocellular lipid accumulationType 2 diabetesReduced insulin sensitivityMuscle fat accumulationMusculus vastus lateralisMitochondrial functionUnilateral limb suspensionIMCL contentContralateral legInsulin sensitivityResultsIn vivoTibialis anteriorFat accumulation
2019
Anti‐inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid‐induced insulin resistance
Camporez JP, Lyu K, Goldberg EL, Zhang D, Cline GW, Jurczak MJ, Dixit VD, Petersen KF, Shulman GI. Anti‐inflammatory effects of oestrogen mediate the sexual dimorphic response to lipid‐induced insulin resistance. The Journal Of Physiology 2019, 597: 3885-3903. PMID: 31206703, PMCID: PMC6876753, DOI: 10.1113/jp277270.Peer-Reviewed Original ResearchConceptsObesity-induced insulin resistanceHigh-fat dietEctopic lipid contentWhite adipose tissue lipolysisInsulin resistanceAdipose tissue lipolysisMale miceInsulin sensitivityFemale miceInsulin-stimulated suppressionWAT inflammationTissue lipolysisRodent studiesTumor necrosis factor αWhole-body insulin sensitivityLipid-induced insulin resistanceMetabolic homeostasisAge-matched menInterleukin-6 concentrationsSkeletal muscleAnti-inflammatory effectsType 2 diabetesInsulin-mediated suppressionSexual dimorphic responseNecrosis factor α
2016
Mitochondrial Protonophores For Treatment of NAFLD/NASH and Type 2 Diabetes
Shulman G. Mitochondrial Protonophores For Treatment of NAFLD/NASH and Type 2 Diabetes. The FASEB Journal 2016, 30 DOI: 10.1096/fasebj.30.1_supplement.257.2.Peer-Reviewed Original ResearchType 2 diabetesInsulin resistanceLipid-induced insulin resistanceNAFLD/NASHSkeletal muscleAdipose tissue inflammationEctopic lipid depositionNon-alcoholic steatohepatitisAmerican Diabetes AssociationEctopic lipid depositsAlcoholic steatohepatitisDiabetes AssociationTissue inflammationRecent studiesLipid depositionType 2Lipid depositsHepatic gluconeogenesisCellular mechanismsMitochondrial protonophoreDiabetesMitochondrial inefficiencyLiverMuscleMolecular triggers