2025
ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Slusher A, Santoro N, Vash-Margita A, Galderisi A, Hu P, Tokoglu F, Li Z, Tarabra E, Strober J, Vatner D, Shulman G, Caprio S. ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis. Journal Of Clinical Investigation 2025, 135: e184740. PMID: 40091831, PMCID: PMC11910223, DOI: 10.1172/jci184740.Peer-Reviewed Original ResearchMeSH KeywordsAcyltransferasesAdolescentChildFatty LiverFemaleGlucose Clamp TechniqueHumansInsulinInsulin ResistanceLipaseLipolysisMalePediatric ObesityConceptsHyperinsulinemic-euglycemic clampSubcutaneous adipose tissueInsulin resistanceAdipose triglyceride lipaseInsulin infusionOral glucose tolerance testAbdominal fat distributionGlucose tolerance testMeasuring abdominal fat distributionLower liver fatActivating adipose triglyceride lipaseMetabolic disease riskLiver fat contentEctopic lipid storageFUNDINGThis workAdipose tissue lipolysisInhibition of adipose tissue lipolysisSubcutaneous adipose tissue samplesFat distributionTolerance testInsulin exposureLiver fatInfusionGlycerol turnoverAdipose tissue
2021
Minimal Model–Derived Insulin Sensitivity Index Underestimates Insulin Sensitivity in Black Americans
Fosam A, Yuditskaya S, Sarcone C, Grewal S, Fan H, Muniyappa R. Minimal Model–Derived Insulin Sensitivity Index Underestimates Insulin Sensitivity in Black Americans. Diabetes Care 2021, 44: 2586-2588. PMID: 34521638, PMCID: PMC8546281, DOI: 10.2337/dc21-0490.Peer-Reviewed Original Research
2020
Increased β-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults
Armiyaw L, Sarcone C, Fosam A, Muniyappa R. Increased β-Cell Responsivity Independent of Insulin Sensitivity in Healthy African American Adults. The Journal Of Clinical Endocrinology & Metabolism 2020, 105: dgaa234. PMID: 32382759, PMCID: PMC7266075, DOI: 10.1210/clinem/dgaa234.Peer-Reviewed Original ResearchConceptsNon-Hispanic whitesTotal β-cell responsivityΒ-cell responsivityPrimary insulin hypersecretionGlucose disposal rateInsulin sensitivityInsulin hypersecretionAfrican AmericansBasal insulin secretion rateGlucose responsivityIntravenous glucose tolerance testGlucose tolerance testHyperinsulinemic euglycemic glucose clamp techniqueC-peptide secretionGlucose clamp techniqueInsulin secretion rateNondiabetic African AmericansΒ-cell functionAfrican American adultsInsulin resistanceTolerance testNHW subjectsC-peptideInsulin secretionSignificant ethnic differences
2019
Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time
Galderisi A, Polidori D, Weiss R, Giannini C, Pierpont B, Tricò D, Caprio S. Lower Insulin Clearance Parallels a Reduced Insulin Sensitivity in Obese Youths and Is Associated With a Decline in β-Cell Function Over Time. Diabetes 2019, 68: 2074-2084. PMID: 31399433, PMCID: PMC6804624, DOI: 10.2337/db19-0120.Peer-Reviewed Original Research
2018
H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK
Geng T, Liu Y, Xu Y, Jiang Y, Zhang N, Wang Z, Carmichael GG, Taylor HS, Li D, Huang Y. H19 lncRNA Promotes Skeletal Muscle Insulin Sensitivity in Part by Targeting AMPK. Diabetes 2018, 67: db180370. PMID: 30201684, PMCID: PMC6198334, DOI: 10.2337/db18-0370.Peer-Reviewed Original ResearchConceptsMuscle insulin sensitivityEnergy sensor AMPKUnknown physiological functionImportant downstream effectorWhole-body energy metabolismCellular energy sensor AMPKEpigenetic mechanismsMuscle insulin resistanceDownstream effectorsAMPK activationMitochondrial biogenesisSystemic glucose homeostasisSkeletal muscle insulin sensitivityPhysiological functionsImportant regulatorAMPKInsulin-resistant human subjectsDUSP27Energy metabolismH19H19 expressionMuscle cellsSkeletal muscleGlucose uptakePivotal role
2017
A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease
Goffredo M, Santoro N, Tricò D, Giannini C, D’Adamo E, Zhao H, Peng G, Yu X, Lam TT, Pierpont B, Caprio S, Herzog RI. A Branched-Chain Amino Acid-Related Metabolic Signature Characterizes Obese Adolescents with Non-Alcoholic Fatty Liver Disease. Nutrients 2017, 9: 642. PMID: 28640216, PMCID: PMC5537762, DOI: 10.3390/nu9070642.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAmino Acids, Branched-ChainBiomarkersChildFemaleGlucose Clamp TechniqueHumansMaleNon-alcoholic Fatty Liver DiseaseObesityConceptsNon-alcoholic fatty liver diseaseMagnetic resonance imagingBranched-chain amino acidsFatty liver diseaseHepatic fat contentObese adolescentsInsulin resistanceLiver diseaseTwo-step hyperinsulinemic-euglycemic clampOral glucose tolerance testSecond magnetic resonance imagingSubset of patientsGlucose tolerance testHyperinsulinemic-euglycemic clampHigher plasma levelsHepatic insulin sensitivityChain amino acidsPlasma levelsTolerance testInsulin sensitivityMetabolomic signaturePlasma metabolitesResonance imagingValine levelsLipid metabolismMitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation
Lee HY, Lee JS, Alves T, Ladiges W, Rabinovitch PS, Jurczak MJ, Choi CS, Shulman GI, Samuel VT. Mitochondrial Targeted Catalase Protects Against High-Fat Diet-Induced Muscle Insulin Resistance by Decreasing Intramuscular Lipid Accumulation. Diabetes 2017, 66: db161334. PMID: 28476930, PMCID: PMC5521865, DOI: 10.2337/db16-1334.Peer-Reviewed Original ResearchConceptsHigh-fat dietMuscle insulin resistanceAcute lipid infusionInsulin resistanceRegular chowLipid infusionMCAT miceInsulin actionLipid-induced insulin resistanceDiet-induced insulin resistanceReactive oxygen speciesHyperinsulinemic-euglycemic clampWild-type miceMuscle fat oxidationIntramuscular lipid accumulationROS productionAcute infusionHFD-fedWT miceImpaired insulinPKCθ activationFat oxidationLipid emulsionMuscle insulinMiceThe human brain produces fructose from glucose
Hwang JJ, Jiang L, Hamza M, Dai F, Belfort-DeAguiar R, Cline G, Rothman DL, Mason G, Sherwin RS. The human brain produces fructose from glucose. JCI Insight 2017, 2: e90508. PMID: 28239653, PMCID: PMC5313070, DOI: 10.1172/jci.insight.90508.Peer-Reviewed Original ResearchMeSH KeywordsAdultBrainFemaleFructoseGlucoseGlucose Clamp TechniqueHealthy VolunteersHumansMaleProton Magnetic Resonance SpectroscopyRegression AnalysisSorbitolYoung AdultConceptsPolyol pathwayFructose levelsIntracerebral glucoseBlood-brain barrierPathogenesis of obesityType 2 diabetesEffects of fructoseHuman brainRegression model analysisCNS deliveryCNS effectsHyperglycemic clampHealthy subjectsDietary consumptionGlucoseBaselineBrainMixed-effects regression model analysisFeeding behaviorMinutesCN productionObesityDiabetesLevelsPathogenesis
2016
The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women
Horst K, Versteeg RI, Gilijamse PW, Ackermans MT, Heijboer AC, Romijn JA, la Fleur SE, Trinko R, DiLeone RJ, Serlie MJ. The vitamin D metabolites 25(OH)D and 1,25(OH)2D are not related to either glucose metabolism or insulin action in obese women. Diabetes & Metabolism 2016, 42: 416-423. PMID: 27262368, DOI: 10.1016/j.diabet.2016.04.011.Peer-Reviewed Original ResearchMeSH KeywordsAdultBlood GlucoseCalcifediolCalcitriolCohort StudiesFemaleGlucose Clamp TechniqueHumansMiddle AgedObesity, MorbidVitamin D DeficiencyConceptsVitamin D deficiencyObese womenInsulin actionD deficiencyVitamin DInsulin resistanceInsulin sensitivityGlucose metabolismEuglycaemic–hyperinsulinaemic clamp studiesActive vitamin D metaboliteBasal endogenous glucose productionObesity-related insulin resistanceTissue-specific insulin actionObesity-induced metabolic diseasesTissue-specific insulin sensitivitySkeletal muscle insulin sensitivityBody mass indexVitamin D metabolitesTotal body fatMuscle insulin sensitivityEndogenous glucose productionBaseline characteristicsSerum levelsMass indexD levels
2015
Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial
Ramirez CE, Nian H, Yu C, Gamboa JL, Luther JM, Brown NJ, Shibao CA. Treatment with Sildenafil Improves Insulin Sensitivity in Prediabetes: A Randomized, Controlled Trial. The Journal Of Clinical Endocrinology & Metabolism 2015, 100: 4533-4540. PMID: 26580240, PMCID: PMC4667163, DOI: 10.1210/jc.2015-3415.Peer-Reviewed Original ResearchMeSH KeywordsAdultAlbuminuriaDouble-Blind MethodEndothelium, VascularFemaleFibrinolysisGlucoseGlucose Clamp TechniqueGlucose Tolerance TestHemodynamicsHumansInsulinInsulin ResistanceMaleMiddle AgedOverweightPhosphodiesterase 5 InhibitorsPlasminogen Activator Inhibitor 1Prediabetic StateSildenafil CitrateConceptsPhosphodiesterase-5 inhibitionGlucose-stimulated insulin secretionInsulin sensitivity indexInsulin sensitivityInsulin secretionBaseline insulin sensitivity indexPlacebo-controlled studyClinical Research CenterBody mass indexEnd of treatmentPlasminogen activator inhibitor-1Tissue plasminogen activatorActivator inhibitor-1Placebo groupUrine albuminSildenafil groupCreatinine ratioEndothelial functionPrimary outcomeMass indexTreatment armsFibrinolytic balanceDisposition indexHyperglycemic clampOverweight individuals
2014
Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans
Ramirez CE, Shuey MM, Milne GL, Gilbert K, Hui N, Yu C, Luther JM, Brown NJ. Arg287Gln variant of EPHX2 and epoxyeicosatrienoic acids are associated with insulin sensitivity in humans. Prostaglandins And Other Lipid Mediators 2014, 113: 38-44. PMID: 25173047, PMCID: PMC4253976, DOI: 10.1016/j.prostaglandins.2014.08.001.Peer-Reviewed Original ResearchConceptsInsulin sensitivity indexEpoxyeicosatrienoic acidsInsulin sensitivityHigher insulin sensitivity indexPlasma epoxyeicosatrienoic acidsGlucose-stimulated insulin secretionBody mass indexArg/ArgSoluble epoxide hydrolase activitySoluble epoxide hydrolaseMetabolic syndromeMass indexDisposition indexInsulin resistanceHyperglycemic clampInsulin secretionSensitivity indexEpoxide hydrolase activityEPHX2Hydrolase activitySecretionPhenotyping studiesMetabolic phenotyping studiesEpoxide hydrolaseGenetic variantsHypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice
Kim JD, Toda C, D’Agostino G, Zeiss CJ, DiLeone RJ, Elsworth JD, Kibbey RG, Chan O, Harvey BK, Richie CT, Savolainen M, Myöhänen T, Jeong JK, Diano S. Hypothalamic prolyl endopeptidase (PREP) regulates pancreatic insulin and glucagon secretion in mice. Proceedings Of The National Academy Of Sciences Of The United States Of America 2014, 111: 11876-11881. PMID: 25071172, PMCID: PMC4136568, DOI: 10.1073/pnas.1406000111.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBlood GlucoseGene ExpressionGene Knockdown TechniquesGlucagonGlucose Clamp TechniqueGlucose IntoleranceHypothalamusIndolesInsulinInsulin SecretionIon ChannelsMaleMiceMice, TransgenicMitochondrial ProteinsPancreasPhosphorylationProlyl OligopeptidasesReceptor, InsulinRecombinant ProteinsSerine EndopeptidasesSerine Proteinase InhibitorsThiazolidinesUncoupling Protein 1Ventromedial Hypothalamic NucleusConceptsWild-type miceGlucose intoleranceGlucagon secretionProlyl endopeptidaseHyperinsulinemic-euglycemic clamp studiesWild-type control miceGlucose-induced insulin releaseGlucose-induced insulin secretionEuglycemic clamp studiesAutonomic nervous systemVMH injectionsSympathetic outflowWild-type controlsNorepinephrine levelsGlucagon levelsGlucose toleranceControl miceInsulin levelsCentral infusionPancreatic functionVentromedial nucleusInsulin secretionNeuronal activationGlucose-intolerant phenotypeCentral regulationDietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans
Luther JM, Byrne LM, Yu C, Wang TJ, Brown NJ. Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans. The Journal Of Clinical Endocrinology & Metabolism 2014, 99: e1895-e1902. PMID: 25029426, PMCID: PMC4184066, DOI: 10.1210/jc.2014-2122.Peer-Reviewed Original ResearchConceptsHigh sodium dietHigh sodium intakeInsulin sensitivity indexSodium intakeInsulin secretionAldosterone systemAldosterone infusionInsulin sensitivityAcademic clinical research centerAcute insulin secretory responseLow dietary sodium intakeDecrease insulin secretionC-peptide responsePlasma renin activityDietary sodium intakeLow sodium dietSystolic blood pressureClinical Research CenterInsulin secretory responseAcute insulin responseHigh-risk individualsImpairs insulin secretionGlucose-stimulated insulinIncident diabetesNormotensive volunteers
2013
Faster In and Faster Out: Accelerating Insulin Absorption and Action by Insulin Infusion Site Warming
Cengiz E, Weinzimer SA, Sherr JL, Tichy EM, Carria L, Cappiello D, Steffen A, Tamborlane WV. Faster In and Faster Out: Accelerating Insulin Absorption and Action by Insulin Infusion Site Warming. Diabetes Technology & Therapeutics 2013, 16: 20-25. PMID: 24367934, PMCID: PMC3887414, DOI: 10.1089/dia.2013.0187.Peer-Reviewed Original ResearchValidation of surrogate indexes of insulin sensitivity in acute phase of myocardial infarction based on euglycemic-hyperinsulinemic clamp
Moura F, Carvalho L, Cintra R, Martins N, Figueiredo V, Quinaglia e Silva J, Almeida O, Coelho O, Sposito A. Validation of surrogate indexes of insulin sensitivity in acute phase of myocardial infarction based on euglycemic-hyperinsulinemic clamp. AJP Endocrinology And Metabolism 2013, 306: e399-e403. PMID: 24347056, DOI: 10.1152/ajpendo.00566.2013.Peer-Reviewed Original ResearchMeSH KeywordsAgedBlood GlucoseDiabetes Mellitus, Type 2FastingFemaleGlucose Clamp TechniqueHumansInsulinInsulin ResistanceMaleMiddle AgedMyocardial InfarctionConceptsQuantitative insulin sensitivity check indexEuglycemic-hyperinsulinemic clampHomeostatic model assessmentHOMA-IRInsulin sensitivityMyocardial infarctionSurrogate indexHomeostatic model assessment of insulin resistanceModel assessment of insulin resistanceConsecutive nondiabetic patientsHomeostatic model assessment of insulin sensitivityAssessment of insulin resistanceST-segment elevation MISurrogate indexes of insulin sensitivityInsulin sensitivity check indexIndices of insulin sensitivityAcute phase of myocardial infarctionReceiver operating characteristic curveAcute MI patientsAssessment of insulin sensitivityPhase of myocardial infarctionGold standard reference methodBland-Altman plotsOperating characteristics curvePoor patient outcomesBlunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus
Arbelaez AM, Xing D, Cryer PE, Kollman C, Beck RW, Sherr J, Ruedy KJ, Tamborlane WV, Mauras N, Tsalikian E, Wilson DM, White NH, Group F. Blunted glucagon but not epinephrine responses to hypoglycemia occurs in youth with less than 1 yr duration of type 1 diabetes mellitus. Pediatric Diabetes 2013, 15: 127-134. PMID: 23992543, PMCID: PMC3858506, DOI: 10.1111/pedi.12070.Peer-Reviewed Original ResearchConceptsType 1 diabetes mellitusPeak epinephrineEpinephrine responseDiabetes mellitusT1DM subjectsRecent-onset type 1 diabetes mellitusHypoglycemia-associated autonomic failureBarrier of hypoglycemiaInsulin-induced hypoglycemiaAutonomic failureCounterregulatory hormonesSubsequent hypoglycemiaGlucagon responsePatients 9Recurrent hypoglycemiaGlycemic controlHypoglycemic clampEpinephrine levelsHypoglycemiaHormonal responsesT1DMGlucagonMellitusControl 19CR responseLactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia
Herzog RI, Jiang L, Herman P, Zhao C, Sanganahalli BG, Mason GF, Hyder F, Rothman DL, Sherwin RS, Behar KL. Lactate preserves neuronal metabolism and function following antecedent recurrent hypoglycemia. Journal Of Clinical Investigation 2013, 123: 1988-1998. PMID: 23543056, PMCID: PMC3638906, DOI: 10.1172/jci65105.Peer-Reviewed Original ResearchConceptsAntecedent recurrent hypoglycemiaRecurrent hypoglycemiaHypoglycemic conditionsIntensive insulin therapyTight glycemic controlType 2 diabetesInsulin therapyGlycemic controlBrain metabolismElevated lactateNeuronal metabolismRodent modelsNeuronal activityGlucose metabolismHypoglycemiaLactate uptakeNeuronal functionType 1Metabolic regulatorOxidative capacityModest incrementLactateMetabolismUnexpected findingBrain
2012
Acceleration of insulin pharmacodynamic profile by a novel insulin infusion site warming device
Cengiz E, Weinzimer SA, Sherr JL, Tichy E, Martin M, Carria L, Steffen A, Tamborlane WV. Acceleration of insulin pharmacodynamic profile by a novel insulin infusion site warming device. Pediatric Diabetes 2012, 14: 168-173. PMID: 23107353, PMCID: PMC3572265, DOI: 10.1111/pedi.12001.Peer-Reviewed Original ResearchConceptsPlasma insulin levelsInsulin actionInsulin levelsAspart insulinRapid-acting insulin analoguesPhysiologic insulin actionClosed-loop insulin deliveryPostprandial glucose excursionsEuglycemic clamp techniqueIp activationTime-action profileType 1 diabetesWarming devicesEuglycemic clamp procedureBolus doseGlucose excursionsPharmacodynamic profileClamp procedurePeak actionInfusion siteBlood flowInsulin analoguesClamp techniqueInsulin absorptionInsulin bolusHigh-density lipoprotein levels are strongly associated with the recovery rate of insulin sensitivity during the acute phase of myocardial infarction: A study by euglycemic hyperinsulinemic clamp
Carvalho L, Martins N, Moura F, Cintra R, Almeida O, Quinaglia e Silva J, Sposito A, Group B. High-density lipoprotein levels are strongly associated with the recovery rate of insulin sensitivity during the acute phase of myocardial infarction: A study by euglycemic hyperinsulinemic clamp. Journal Of Clinical Lipidology 2012, 7: 24-28. PMID: 23351579, DOI: 10.1016/j.jacl.2012.10.003.Peer-Reviewed Original ResearchMeSH KeywordsAcute DiseaseAge FactorsAgedBlood Chemical AnalysisFemaleGlucose Clamp TechniqueHospitalizationHumansHydroxymethylglutaryl-CoA Reductase InhibitorsInsulin ResistanceLipoproteins, HDLMagnetic Resonance ImagingMaleMiddle AgedMyocardial InfarctionSeverity of Illness IndexSex FactorsTreatment OutcomeTriglyceridesConceptsAcute phase of MIHigh HDL groupHDL groupHDL-CPhase of MIMyocardial infarctionEuglycemic hyperinsulinemic clampAcute phaseInsulin sensitivityIS indexAssociated with increased morbidityConsecutive nondiabetic patientsHyperinsulinemic clampLevels of HDL-CPlasma levels of HDL-CST-segment elevation MIHigh-density lipoprotein levelsLow HDL groupHigh-density lipoprotein (HDLHDL-C levelsPlasma HDL-CWaist circumferenceRate of ISDecrease of insulin sensitivityLipoprotein (HDLReversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes
Petersen KF, Dufour S, Morino K, Yoo PS, Cline GW, Shulman GI. Reversal of muscle insulin resistance by weight reduction in young, lean, insulin-resistant offspring of parents with type 2 diabetes. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 8236-8240. PMID: 22547801, PMCID: PMC3361376, DOI: 10.1073/pnas.1205675109.Peer-Reviewed Original ResearchConceptsMuscle insulin resistanceInsulin-resistant offspringType 2 diabetesBranched-chain amino acidsInsulin resistanceIR offspringInsulin-stimulated muscle glucose uptakeWeight lossPeripheral insulin responsivenessReduction of IMCLModest weight lossPeripheral glucose metabolismC-reactive proteinHyperinsulinemic-euglycemic clampIntramyocellular lipid accumulationMuscle glucose uptakeAverage weight lossWeight reductionTotal adiponectinHypocaloric dietIL-6IMCL contentPlasma concentrationsWeight stabilizationIMCL accumulation
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