2024
O-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice
Ohgaku S, Ida S, Ohashi N, Morino K, Ishikado A, Yanagimachi T, Murata K, Sato D, Ugi S, Nasiri A, Shulman G, Maegawa H, Kume S, Fujita Y. O-GlcNAc modification in endothelial cells modulates adiposity via fat absorption from the intestine in mice. Heliyon 2024, 10: e34490. PMID: 39130439, PMCID: PMC11315187, DOI: 10.1016/j.heliyon.2024.e34490.Peer-Reviewed Original ResearchEndothelial cellsHigh-fat dietControl miceLipid absorptionExpression of VEGFR3Body weightNitric oxide donorReduced body weightKnockout miceTherapeutic strategiesOxide donorDecreased expressionIntercellular junctionsMiceHigh-fatNutrient-sensing mechanismsFat absorptionO-GlcNAcylationGlucose metabolismVE-cadherinMorphological alterationsMetabolic regulatory mechanismsJunction morphologyLipid metabolismO-GlcNAc transferase899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice
VIJAYAKUMAR A, SRODA N, MURAKAMI E, WENG S, MYERS R, SUBRAMANIAN M, SHULMAN G. 899-P: Combinations of the Mitochondrial Protonophore TLC-6740 and/or the ACC2 Inhibitor TLC-3595 Provide Additive Glycemic Benefits to Semaglutide (SEMA) in db/db Mice. Diabetes 2024, 73 DOI: 10.2337/db24-899-p.Peer-Reviewed Original ResearchOral glucose tolerance testGLP-1R agonistsDb/db miceIncremental AUCGlucose tolerance testMale db/db miceImproved glucose toleranceSemaglutide groupGlycemic parametersSemaglutideTolerance testFood intakeGlucose toleranceGLP-1RLiver-targeted mitochondrial uncouplerDb/dbMiceGlucose bolusVEHAgonistsEvaluation of combinationsHbA1cDiabetesMitochondrial uncouplingAssess effects1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study
GANE E, HUSS R, SUR J, MURAKAMI E, WENG S, KIRBY B, SHAH A, SHULMAN G, SUBRAMANIAN M, VIJAYAKUMAR A, MYERS R. 1886-LB: Safety, PK, and Preliminary Efficacy of the Liver-Targeted Mitochondrial Protonophore TLC-6740—A Phase 1 Study. Diabetes 2024, 73 DOI: 10.2337/db24-1886-lb.Peer-Reviewed Original ResearchTreatment of obesityAdverse eventsSteady-state half-lifeEvaluate food effectsPhase 1 studyDose-dependent improvementDose-dependent reductionProportion of subjectsUnrelated to treatmentDose-dependent mannerMAD cohortsLab abnormalitiesSerum totalLDL-CFood effectHealthy subjectsClinical useWeight lossImpact of foodBody weightPreliminary efficacyObesityHalf-lifeTreatmentMitochondrial uncoupling1637-P: TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice
SRODA N, VIJAYAKUMAR A, MURAKAMI E, WENG S, SHULMAN G, MYERS R, SUBRAMANIAN M. 1637-P: TLC-6740, a Liver-Targeted Mitochondrial Protonophore, Increases Energy Expenditure and Lipid Utilization in Obese Mice. Diabetes 2024, 73 DOI: 10.2337/db24-1637-p.Peer-Reviewed Original ResearchEnergy intakeWeight lossEnergy expenditureRespiratory exchange ratioMitochondrial protonophoreObese miceDose-dependent weight lossReduced oral intakeData support evaluationDays of dosingC57 BL/6 miceDiet-induced obese miceNegative energy balanceMale C57 BL/6 miceIncreased energy expenditureWhole-body lipid utilizationCompared to pre-treatmentHigh-fat dietOral intakePO BIDBL/6 miceIndirect calorimetryMetabolic benefitsLipid utilizationVEH1571-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 diseaseTranslocationCardiometabolic characteristics of people with metabolically healthy and unhealthy obesity
Petersen M, Smith G, Palacios H, Farabi S, Yoshino M, Yoshino J, Cho K, Davila-Roman V, Shankaran M, Barve R, Yu J, Stern J, Patterson B, Hellerstein M, Shulman G, Patti G, Klein S. Cardiometabolic characteristics of people with metabolically healthy and unhealthy obesity. Cell Metabolism 2024, 36: 745-761.e5. PMID: 38569471, PMCID: PMC11025492, DOI: 10.1016/j.cmet.2024.03.002.Peer-Reviewed Original ResearchConceptsUnhealthy obesityPlasma PAI-1 concentrationAbnormalities associated with obesityMetabolically healthy obesityMetabolically unhealthy obesityPAI-1 concentrationsMetabolic heterogeneity of obesityHeterogeneity of obesityMetabolically healthy leanSystemic metabolic functionCharacteristics of peopleDecreased oxidative stressHealthy obesityCardiometabolic characteristicsAdipose tissue biologyHealthy leanSkeletal muscle biologyPlasma adiponectinPlasma glucoseObesityMetabolic heterogeneityOxidative stressPotential mechanismsTissue biologyMuscle biologyInsulin Resistance in Type 2 Diabetes
Roden M, Petersen K, Shulman G. Insulin Resistance in Type 2 Diabetes. 2024, 238-249. DOI: 10.1002/9781119697473.ch17.Peer-Reviewed Original Research
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 ResearchThe PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Luukkonen P, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang X, Lehtimäki T, Seppänen W, Orho-Melander M, Hodson L, Petersen K, Shulman G, Yki-Järvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metabolism 2023, 35: 1887-1896.e5. PMID: 37909034, DOI: 10.1016/j.cmet.2023.10.008.Peer-Reviewed Original ResearchConceptsDe novo lipogenesisHepatic de novo lipogenesisPlasma β-hydroxybutyrate concentrationsΒ-hydroxybutyrate concentrationsLiver diseaseNovo lipogenesisPNPLA3 I148M variantHepatic mitochondrial redox stateMajor genetic risk factorI148M variantFatty liver diseaseGenetic risk factorsHepatic mitochondrial dysfunctionKetogenic dietMixed mealRisk factorsHepatic metabolismHomozygous carriersM carriersMitochondrial dysfunctionCitrate synthase fluxM variantKetogenesisMitochondrial redox stateMitochondrial functionFRI032 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 actionHepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Mooring M, Yeung G, Luukkonen P, Liu S, Akbar M, Zhang G, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky M, Booth C, Konnikova L, Shulman G, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science Translational Medicine 2023, 15: eade3157. PMID: 37756381, PMCID: PMC10874639, DOI: 10.1126/scitranslmed.ade3157.Peer-Reviewed Original ResearchConceptsNonalcoholic steatohepatitisLiver inflammationNonalcoholic fatty liver diseaseProgression of NASHCysteine-rich angiogenic inducer 61Fatty liver diseaseLiver-specific knockout miceImproved glucose toleranceType 2 diabetesGlucose toleranceLiver diseaseNASH progressionProfibrotic macrophagesProinflammatory propertiesReduced fibrosisCardiovascular diseaseProfibrotic phenotypeFibrotic developmentKnockout miceNF-κBMetabolic diseasesNASH dietPDGFB expressionFibrosisProfibrotic programMAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis.
Park J, Hall C, Hubbard B, LaMoia T, Gaspar R, Nasiri A, Li F, Zhang H, Kim J, Haeusler R, Accili D, Shulman G, Yu H, Choi E. MAD2-Dependent Insulin Receptor Endocytosis Regulates Metabolic Homeostasis. Diabetes 2023, 72: 1781-1794. PMID: 37725942, PMCID: PMC10658066, DOI: 10.2337/db23-0314.Peer-Reviewed Original ResearchConceptsIR endocytosisInsulin receptor endocytosisCell division regulatorsInsulin receptorProlongs insulin actionReceptor endocytosisTranscriptomic profilesInsulin stimulationEndocytosisMetabolic homeostasisCell surfaceGenetic ablationMetabolic functionsInsulin actionP31cometMad2BubR1DisruptionSignalingRegulatorHomeostasisAdipose tissueInteractionHepatic fat accumulationMetabolism1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo
HUBBARD B, GASPAR R, ZHANG D, KAHN M, NASIRI A, SHULMAN G. 1510-P: Lipid-Induced Renal Cortical Insulin Resistance Perturbs Gluconeogenic and Oxidative Metabolism via an sn-1,2-diacylglycerol-PKCe-Insulin Receptor Kinase Axis In Vivo. Diabetes 2023, 72 DOI: 10.2337/db23-1510-p.Peer-Reviewed Original ResearchInsulin receptor kinasePyruvate carboxylaseHyperinsulinemic-euglycemic clampMitochondrial pyruvate oxidationInsulin resistanceOxidative metabolismMitochondrial pyruvate carboxylaseReceptor kinaseInhibitory phosphorylationAktS473 phosphorylationKinase axisChow fed miceImpairs insulinPyruvate oxidationKnockin micePhosphorylationKey targetFortress BiotechFed micePKCεDiacylglycerolRenal cortexHFDMetabolismBasal conditions1558-P: The Mitochondrial Calcium Uniporter Regulates Hepatic Mitochondrial Oxidation and Intracellular Redox In Vivo
LAMOIA T, HUBBARD B, GUERRA M, GOODMAN R, NATHANSON M, SHULMAN G. 1558-P: The Mitochondrial Calcium Uniporter Regulates Hepatic Mitochondrial Oxidation and Intracellular Redox In Vivo. Diabetes 2023, 72 DOI: 10.2337/db23-1558-p.Peer-Reviewed Original ResearchNonalcoholic fatty liver diseaseHepatic mitochondrial oxidationMitochondrial calcium uniporterHepatocellular redox stateFatty liver diseaseEctopic lipid accumulationType 2 diabetesHepatic lipid contentNovel therapeutic targetMitochondrial oxidationHepatic triacylglycerol contentMitochondrial calcium influxMitochondrial redox ratioMitochondrial calciumKnockout mouse modelFortress BiotechMitochondrial fat oxidationNonalcoholic steatohepatitisLiver diseaseWT miceKO miceMetabolic dysfunctionCalcium uniporterCalcium influxMouse model192-OR: Lipid-Induced Insulin Resistance in Brown Adipose Tissue Is Mediated by the sn-1,2 DAG-PKCe-IRKT1150 Phosphorylation Pathway
GASPAR R, HUBBARD B, SAKUMA I, LAMOIA T, ZHANG D, SHULMAN G. 192-OR: Lipid-Induced Insulin Resistance in Brown Adipose Tissue Is Mediated by the sn-1,2 DAG-PKCe-IRKT1150 Phosphorylation Pathway. Diabetes 2023, 72 DOI: 10.2337/db23-192-or.Peer-Reviewed Original Research191-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