2024
1571-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 7FibrosisInsulin 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
Hepatocyte 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 program1558-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 model849-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 ResearchIMCL222-OR: Metformin Reduces Fasting Glycemia in Well-Controlled Type 2 Diabetes by Promoting Aerobic Glycolysis Independent of Decreasing Endogenous Glucose Production
SARABHAI T, LAMOIA T, FRIESL S, JONUSCHEIT M, PETERSEN K, SHULMAN G, RODEN M. 222-OR: Metformin Reduces Fasting Glycemia in Well-Controlled Type 2 Diabetes by Promoting Aerobic Glycolysis Independent of Decreasing Endogenous Glucose Production. Diabetes 2023, 72 DOI: 10.2337/db23-222-or.Peer-Reviewed Original ResearchEndogenous glucose productionRates of EGPType 2 diabetesHepatic ATP contentMetformin treatmentGlucose clearanceNovo NordiskGlucose productionGlycogen contentGlucose-lowering effectHepatic TAG contentLactate productionBlood glucose levelsPlasma glucose concentrationPeripheral glucose clearanceHepatic glycogen contentATP contentAdvisory PanelFortress BiotechMetformin-induced inhibitionGlycemic controlDohme Corp.Hepatic triglyceridesMitochondrial electron transport chain activityGlucose levels
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 receptor323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart
GOEDEKE L, LEE J, MA Y, HU X, ZHANG J, DONG J, GALSGAARD K, GUERRERA N, HAEDERSDAL S, ZHANG X, PERRY R, CLINE G, YOUNG L, SHULMAN G. 323-OR: SGLT2 Inhibition Promotes Myocardial Ketone Utilization in the Normal and Failing Heart. Diabetes 2021, 70 DOI: 10.2337/db21-323-or.Peer-Reviewed Original ResearchPlasma glucose concentrationDAPA treatmentHeart failureAwake male Sprague-Dawley ratsMajor adverse cardiovascular eventsMale Sprague-Dawley ratsRecent clinical outcome studiesAdverse cardiovascular eventsHeart failure ratsType 2 diabetesClinical outcome studiesSprague-Dawley ratsGlucose concentrationΒOHB levelsCardiovascular eventsCardiovascular benefitsVehicle treatmentPermanent ligationSGLT2 inhibitorsCoronary arteryControl ratsKetone utilizationDawley ratsAcute effectsFailing HeartTherapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH
Goedeke L, Shulman GI. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH. Molecular Metabolism 2021, 46: 101178. PMID: 33545391, PMCID: PMC8085597, DOI: 10.1016/j.molmet.2021.101178.Peer-Reviewed Original ResearchConceptsFatty liver diseaseLiver diseaseSmall molecule mitochondrial uncouplersTherapeutic potentialMitochondrial uncouplerNon-human primate studiesType 2 diabetesWide therapeutic indexSystemic toxicity concernsTreatment of MetabolicCell-specific effectsInsulin resistanceTherapeutic indexMetabolic diseasesNonalcoholic hepatosteatosisSustained increaseToxicity concernsPrimate studiesDiseaseTherapeutic developmentMitochondrial inefficiencyNutrient oxidationATP productionTreatmentTissue
2020
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.
Ter Horst KW, Vatner DF, Zhang D, Cline GW, Ackermans MT, Nederveen AJ, Verheij J, Demirkiran A, van Wagensveld BA, Dallinga-Thie GM, Nieuwdorp M, Romijn JA, Shulman GI, Serlie MJ. Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease. Diabetes Care 2020, 44: 489-498. PMID: 33293347, PMCID: PMC7818337, DOI: 10.2337/dc20-1644.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisFatty liver diseaseBariatric surgeryLiver diseaseImpaired insulin-mediated suppressionGlucose productionHepatic de novo lipogenesisPeripheral glucose metabolismHyperinsulinemic-euglycemic clampType 2 diabetesInsulin-mediated suppressionInsulin-resistant subjectsHepatic insulin resistanceLiver biopsy samplesSuppress glucose productionLipogenic transcription factorsInsulin-mediated regulationObese subjectsInsulin resistanceAcute increaseNovo lipogenesisGlucose metabolismBiopsy samplesParadoxical increaseEffect 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 participantsCellular and Molecular Mechanisms of Metformin Action
LaMoia TE, Shulman GI. Cellular and Molecular Mechanisms of Metformin Action. Endocrine Reviews 2020, 42: 77-96. PMID: 32897388, PMCID: PMC7846086, DOI: 10.1210/endrev/bnaa023.Peer-Reviewed Original ResearchConceptsGlucose-lowering effectType 2 diabetesMetformin actionHepatic gluconeogenesisFirst-line therapyDosage of metforminRedox-dependent mechanismMechanism of actionMolecular mechanismsSafety profileMetformin inhibitsComplex I inhibitionMetformin concentrationsGlucose metabolismMetforminClinical settingPleotropic effectsDiscrepant effectsDiabetesAMPK activationCurrent literatureRelevant concentrationsI inhibitionRecent studiesRedox balanceSodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks
Perry RJ, Shulman GI. Sodium-glucose cotransporter-2 inhibitors: Understanding the mechanisms for therapeutic promise and persisting risks. Journal Of Biological Chemistry 2020, 295: 14379-14390. PMID: 32796035, PMCID: PMC7573269, DOI: 10.1074/jbc.rev120.008387.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsSodium-glucose cotransporter 2SGLT2 inhibitorsEuglycemic ketoacidosisGlucose reabsorptionTherapeutic promiseSGLT2 inhibitor therapyLower plasma glucose concentrationsModest weight lossGlucose-lowering agentsRenal glucose reabsorptionType 2 diabetesType 1 diabetesPlasma glucose concentrationGlucose concentrationBlood glucose concentrationHeart failureInhibitor therapyAtrial fibrillationCardiovascular diseaseCotransporter 2Preclinical studiesHealthy personsClinical utilityDiabetes managementProximal tubules459-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 triglyceridesMON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver
Sakuma I, Yokoyama M, Yamagata K, Hashimoto N, Nakayama A, Shulman G, Tanaka T. MON-635 FDXR Regulates Iron Metabolism and Glucose Metabolism in Liver. Journal Of The Endocrine Society 2020, 4: mon-635. PMCID: PMC7207756, DOI: 10.1210/jendso/bvaa046.1557.Peer-Reviewed Original ResearchNon-alcoholic fatty liver diseaseForkhead box protein O1Iron metabolismFoxO1 nuclear exclusionOxidative stressFatty liver diseaseSerum ferritin levelsMouse liverHigh-fat dietType 2 diabetesPathogenesis of diabetesNovel therapeutic targetIron regulatory genesHepatic iron contentTreatment of diabetesHepG2 cellsBox protein O1Glucose intoleranceMost patientsFerritin levelsLiver diseaseClinical studiesGluconeogenesis activationFDXR expressionGlucose metabolismThe 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