2024
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
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
FRI032 Cellular Insights Into Metabolically Healthy And Unhealthy Obesity
Petersen M, Smith G, Yu J, Barve R, Yoshino J, Shulman G, Klein S. FRI032 Cellular Insights Into Metabolically Healthy And Unhealthy Obesity. Journal Of The Endocrine Society 2023, 7: bvad114.043. PMCID: PMC10555440, DOI: 10.1210/jendso/bvad114.043.Peer-Reviewed Original ResearchAbdominal subcutaneous adipose tissueWhole-body insulin sensitivityInsulin sensitivityMUO groupMuscle ceramide contentCeramide contentAdipose tissueGreater whole-body insulin sensitivityPlasma C-peptide concentrationC-peptide concentrationsAdverse metabolic effectsSubcutaneous adipose tissueExpression of genesSkeletal muscle expressionMitochondrial content/functionHealthy obesityMitochondrial structure/functionSkeletal muscle diacylglycerolUnhealthy obesityExtracellular matrix remodelingExcess adiposityMHL groupMetabolic effectsMuscle diacylglycerolInsulin action191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice
EL-AGROUDY N, SCHUMANN T, KURZBACH A, SANCAR G, SANDFORTH L, HERRMANN C, SHULMAN G, BIRKENFELD A. 191-OR: Deletion of the Type 2 Diabetes Candidate Gene SLC16A11 Reduces Peripheral Insulin Sensitivity in Mice. Diabetes 2023, 72 DOI: 10.2337/db23-191-or.Peer-Reviewed Original ResearchDb/db miceOb/obInsulin sensitivityDb miceMRNA expressionWhole-body insulin sensitivitySkeletal muscle insulin sensitivitySkeletal muscle insulin resistanceSkeletal musclePeripheral insulin sensitivityTreatment of T2D.Hyperinsulinemic-euglycemic clampLiver fat contentGlucose infusion rateMuscle insulin sensitivityMuscle insulin resistanceHepatic glucose productionHepatic mitochondrial functionWT littermate mice849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats
VIJAYAKUMAR A, MURAKAMI E, HUSS R, SRODA N, SHIMAZAKI A, KASHIWAGI Y, MYERS R, SUBRAMANIAN M, SHULMAN G. 849-P: Antidiabetic Effects of TLC-3595, a Selective ACC2 Inhibitor, in ZDF Rats. Diabetes 2023, 72 DOI: 10.2337/db23-849-p.Peer-Reviewed Original ResearchZucker diabetic fattyZDF ratsInsulin sensitivityAcetyl-CoA carboxylase 2T2D progressionAntidiabetic effectsClamp glucose infusion rateIntramyocellular lipid contentImproved insulin sensitivityHyperinsulinemic-euglycemic clampType 2 diabetesGlucose infusion rateNovel therapeutic approachesΒ-cell failureFatty acid oxidationFortress BiotechCardiac lipidsInsulin resistanceInfusion rateTherapeutic approachesStrong rationaleRatsGilead SciencesJanssen ResearchIMCL
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 concentrationsEthnic and gender differences in hepatic lipid content and related cardiometabolic parameters in lean individuals
Petersen KF, Dufour S, Li F, Rothman DL, Shulman GI. Ethnic and gender differences in hepatic lipid content and related cardiometabolic parameters in lean individuals. JCI Insight 2022, 7 PMID: 35167495, PMCID: PMC9057590, DOI: 10.1172/jci.insight.157906.Peer-Reviewed Original ResearchConceptsCardiometabolic risk factorsInsulin resistanceRisk factorsHDL cholesterolLDL cholesterolTotal cholesterolLean individualsMatsuda insulin sensitivity indexAI menCardiovascular risk factorsHomeostatic model assessmentHepatic triglyceride contentInsulin sensitivity indexType 2 diabetesHepatic lipid contentNovo Nordisk FoundationUric acid concentrationCardiometabolic parametersCardiovascular riskPremenopausal womenFatty liverPlasma insulinInsulin sensitivityPlasma concentrationsModel assessment
2021
Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z, Zhao M, Voilquin L, Jung Y, Aikio MA, Sahai T, Dou FY, Roche AM, Carcamo-Orive I, Knowles JW, Wabitsch M, Appel EA, Maikawa CL, Camporez JP, Shulman GI, Tsai L, Rosen ED, Gardner CD, Spiegelman BM, Svensson KJ. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell Metabolism 2021, 33: 1836-1852.e11. PMID: 34348115, PMCID: PMC8429235, DOI: 10.1016/j.cmet.2021.07.010.Peer-Reviewed Original ResearchConceptsFatty liver diseaseAdipose glucose uptakeGlucose toleranceLiver diseaseHepatic steatosisGlucose uptakeDiet-induced obese miceImpaired glucose toleranceInsulin-like growth factor receptorType 2 diabetesHepatic lipid synthesisIsthmin 1Growth factor receptorObese miceInsulin sensitivityTherapeutic dosingMouse modelGlucoregulatory functionGlucose regulationUnmet needTherapeutic potentialDiabetesLipid accumulationPI3K-AktFactor receptor281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism
GOEDEKE L, SON N, LAMOIA T, NASIRI A, KAHN M, ZHANG X, CLINE G, GOLDBERG I, SHULMAN G. 281-OR: Endothelial Cell Cd36 Regulates Systemic Glucose and Lipid Metabolism. Diabetes 2021, 70 DOI: 10.2337/db21-281-or.Peer-Reviewed Original ResearchFatty acid uptakeLong-chain fatty acid uptakeAcid uptakeEndothelial cell CD36EC-specific deletionDifferent cell typesInsulin-stimulated glucose uptakeLipid metabolismWhole-body glucose toleranceTransmembrane proteinTissue fatty acid uptakeWhole-body insulin sensitivityEndothelial cellsHepatic glucose productionCell typesInsulin sensitivityGlucose transportSystemic glucoseSkeletal muscleCD36Glucose uptakeWhole-body fat utilizationGlucose productionSynthase fluxNon-esterified fatty acid levels501-P: Lower Plasma Membrane Sn-1,2-Diacylglycerol Content and PKCepsilon/theta Activity Explain the Athlete’s Paradox
GASPAR R, LYU K, HUBBARD B, LEITNER B, LUUKKONEN P, HIRABARA S, SAKUMA I, NASIRI A, ZHANG D, KAHN M, CLINE G, PAULI J, PERRY R, PETERSEN K, SHULMAN G. 501-P: Lower Plasma Membrane Sn-1,2-Diacylglycerol Content and PKCepsilon/theta Activity Explain the Athlete’s Paradox. Diabetes 2021, 70 DOI: 10.2337/db21-501-p.Peer-Reviewed Original ResearchHigh-fat diet feedingMuscle insulin sensitivityEX miceInsulin sensitivitySpouse/partnerGlucose toleranceIntramyocellular lipidsAthlete's paradoxRC micePKCθ translocationHyperinsulinemic-euglycemic clamp studiesGilead SciencesJanssen ResearchMuscle TAG contentMuscle triglyceride contentMale C57BL/6J miceImproved glucose toleranceNovo NordiskMuscle insulin resistanceNovo Nordisk FoundationBoehringer Ingelheim PharmaceuticalsChow feedingHFD groupHFD miceInsulin resistanceShort-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
Effect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight Adults
Kahleova H, Petersen KF, Shulman GI, Alwarith J, Rembert E, Tura A, Hill M, Holubkov R, Barnard ND. Effect of a Low-Fat Vegan Diet on Body Weight, Insulin Sensitivity, Postprandial Metabolism, and Intramyocellular and Hepatocellular Lipid Levels in Overweight Adults. JAMA Network Open 2020, 3: e2025454. PMID: 33252690, PMCID: PMC7705596, DOI: 10.1001/jamanetworkopen.2020.25454.Peer-Reviewed Original ResearchMeSH KeywordsAbsorptiometry, PhotonAdultAgedBlood GlucoseBody CompositionBody WeightCholesterolCholesterol, HDLCholesterol, LDLC-PeptideDiet, Fat-RestrictedDiet, VeganEnergy IntakeEnergy MetabolismFemaleGlycated HemoglobinHepatocytesHumansInsulinInsulin ResistanceIntra-Abdominal FatLipid MetabolismLiverMaleMiddle AgedMuscle Fibers, SkeletalMuscle, SkeletalObesityOverweightPostprandial PeriodProton Magnetic Resonance SpectroscopyTriglyceridesConceptsLow-fat vegan dietHomeostasis model assessment indexIntramyocellular lipid levelsModel assessment indexIntervention groupLipid levelsBody weightInsulin resistancePostprandial metabolismVegan dietOverweight adultsDietary interventionInsulin sensitivityThermic effectControl groupPlant-based dietary interventionDual X-ray absorptiometryInsulin resistance leadExcess body weightInsulin sensitivity indexType 2 diabetesMajor health problemProton magnetic resonance spectroscopyX-ray absorptiometrySubset of participantsObesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3
Hall JA, Ramachandran D, Roh HC, DiSpirito JR, Belchior T, Zushin PH, Palmer C, Hong S, Mina AI, Liu B, Deng Z, Aryal P, Jacobs C, Tenen D, Brown CW, Charles JF, Shulman GI, Kahn BB, Tsai LTY, Rosen ED, Spiegelman BM, Banks AS. Obesity-Linked PPARγ S273 Phosphorylation Promotes Insulin Resistance through Growth Differentiation Factor 3. Cell Metabolism 2020, 32: 665-675.e6. PMID: 32941798, PMCID: PMC7543662, DOI: 10.1016/j.cmet.2020.08.016.Peer-Reviewed Original ResearchConceptsInsulin resistanceInsulin sensitivitySide effectsObesity-linked phosphorylationSignificant side effectsLigands of PPARγHyperinsulinemic-euglycemic clamp experimentsPromotes Insulin ResistanceDiabetogenic roleReceptor agonismGrowth differentiation factor 3Healthy miceBody weightMice revealsThiazolidinedionesClamp experimentsPPARγMiceInhibits BMPFamily membersFactor 3Putative targetsSerine 273Ectopic expressionBMP family membersMembrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotyping459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome
GOEDEKE L, ROTLLAN N, TOUSSAINT K, NASIRI A, ZHANG X, LEE J, ZHANG X, FERNÁNDEZ-HERNANDO C, SHULMAN G. 459-P: Liver-Targeted Mitochondrial Uncoupling by CRMP Improves Whole-Body Insulin Sensitivity and Attenuates Atherosclerosis in A LDLR-/- Mouse Model of Metabolic Syndrome. Diabetes 2020, 69 DOI: 10.2337/db20-459-p.Peer-Reviewed Original ResearchWhole-body insulin sensitivitySpouse/partnerInsulin sensitivityCardiovascular diseaseMetabolic syndromeAortic root plaque areaHigh fat-cholesterol dietLdlr-/- mouse modelTreatment of CVDEctopic lipid contentLDLR-/- micePeripheral insulin sensitivityNecrotic core areaType 2 diabetesAnti-atherogenic roleFibrous cap areaAdvisory PanelCRMP treatmentAttenuates AtherosclerosisCardiometabolic disordersFatty liverCholesterol dietInsulin resistanceNondiabetic individualsHepatic triglyceridesThe omentum of obese girls harbors small adipocytes and browning transcripts
Tarabra E, Nouws J, Vash-Margita A, Nadzam GS, Goldberg-Gell R, Van Name M, Pierpont B, Knight J, Shulman GI, Caprio S. The omentum of obese girls harbors small adipocytes and browning transcripts. JCI Insight 2020, 5 PMID: 32125283, PMCID: PMC7213797, DOI: 10.1172/jci.insight.135448.Peer-Reviewed Original ResearchConceptsSubcutaneous adipose tissueSAT depotsSleeve gastrectomySevere obesityInsulin resistanceInsulin sensitivitySmall adipocytesAdipose tissueAbdominal subcutaneous adipose tissueWeight lossType 2 diabetesOmental adipose tissueSubgroup of subjectsTranscriptomic profilesSAT biopsiesAdipocyte sizeObese girlsCardiovascular diseaseOne-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
Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis
Edmunds LR, Huckestein BR, Kahn M, Zhang D, Chu Y, Zhang Y, Wendell SG, Shulman GI, Jurczak MJ. Hepatic insulin sensitivity is improved in high‐fat diet‐fed Park2 knockout mice in association with increased hepatic AMPK activation and reduced steatosis. Physiological Reports 2019, 7: e14281. PMID: 31724300, PMCID: PMC6854109, DOI: 10.14814/phy2.14281.Peer-Reviewed Original ResearchConceptsPark2 KO miceHepatic insulin sensitivityKO miceInsulin sensitivityInsulin resistanceShort-term HFD feedingDiet-induced hepatic insulin resistanceWhole-body insulin sensitivityPark2 knockout miceImproved hepatic insulin sensitivityDiet-induced obesityHigh-fat dietBioactive lipid speciesTumor necrosis factorHepatic insulin resistanceHepatic AMPK activationNegative energy balanceEndoplasmic reticulum stress responseRegular chowCytokine levelsHFD feedingReduced steatosisChronic HFDInterleukin-6Necrosis factorAnti‐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
2018
Metabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats
SONG J, PERRY R, MUNK A, ZHANG Y, ZHANG D, SHULMAN G. Metabolic Inflexibility Revisited—Muscle Substrate Oxidation Is Mechanistically Dissociated from Muscle Insulin Resistance in Rats. Diabetes 2018, 67 DOI: 10.2337/db18-240-lb.Peer-Reviewed Original ResearchInsulin-resistant ratsMuscle insulin resistanceHigh-fat dietResistant ratsInsulin resistanceNormal ratsSoleus muscleLipid-induced muscle insulin resistanceSkeletal muscle insulin resistancePeripheral glucose metabolismHyperinsulinemic-euglycemic clampPathogenesis of obesityMuscle insulin sensitivityGlucose oxidationMuscle glucose transportAcute infusionPyruvate dehydrogenase fluxSubstrate oxidationFat dietMuscle glucoseInsulin sensitivityAcute modulationGlucose metabolismFat oxidationTissue-specific indicesMembrane 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 Sciences