2025
B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity
Puente-Ruiz S, Ide L, Schuller J, Ben-Kraiem A, Hoffmann A, Ghosh A, Noé F, Wolfrum C, Krause K, Gericke M, Klöting N, Brüning J, Wunderlich F, Blüher M, Jais A. B cell-derived nociceptin/orphanin FQ contributes to impaired glucose tolerance and insulin resistance in obesity. IScience 2025, 28: 112819. DOI: 10.1016/j.isci.2025.112819.Peer-Reviewed Original ResearchMacrophage recruitmentMetabolic inflammationGlucose toleranceEffects of nociceptin/orphanin FQInsulin resistanceN/OFQ-NOP systemAdverse metabolic effectsImpaired glucose toleranceImmune cell migrationDiet-induced obesityNociceptin/orphanin FQB cellsEnhanced insulin sensitivityKnockout miceOpioid peptidesImmune regulationGlucose intoleranceMetabolic effectsImmunomodulatory propertiesInflammatory processN/OFQInsulin sensitivityObesityTherapeutic targetAdipose tissue1647-P: Coenzyme A Synthase Knockdown Increases Hepatic Mitochondrial Fat Oxidation and Reduces Hepatic Steatosis and Hepatic Insulin Resistance
GASPAR R, SAKUMA I, HUBBARD B, LAMOIA T, ZHENG J, PARIKH S, KAHN M, SILVEIRA L, DUFOUR S, NASIRI A, PERELIS M, PETERSEN K, SAMUEL V, SHULMAN G. 1647-P: Coenzyme A Synthase Knockdown Increases Hepatic Mitochondrial Fat Oxidation and Reduces Hepatic Steatosis and Hepatic Insulin Resistance. Diabetes 2025, 74 DOI: 10.2337/db25-1647-p.Peer-Reviewed Original ResearchHFD-fed miceAcetyl-CoAHepatic insulin resistanceHFD-fedHepatic acetyl-CoA contentMalonyl-CoA levelsCoenzyme A synthaseFatty acid synthesisHepatic acetyl-CoAAcetyl-CoA contentSteatotic liver diseasePathogenesis of type 2 diabetesHigh-fat dietTCA cycleMitochondrial fat oxidationWhole-body energy expenditureCoA biosynthesisHepatic steatosisAcid synthesisMetabolic pathwaysInsulin resistanceReduced hepatic steatosisDecreased hepatic steatosisCOASYTriacylglycerol content214-OR: Increases in TUG Abundance and Expression Are a Feature of Insulin-Resistant Human Adipose Tissue
STROBER J, TER HORST K, SLUSHER A, PAULO J, GASSAWAY B, SHUKEN S, CAPRIO S, SERLIE M, BOGAN J, VATNER D. 214-OR: Increases in TUG Abundance and Expression Are a Feature of Insulin-Resistant Human Adipose Tissue. Diabetes 2025, 74 DOI: 10.2337/db25-214-or.Peer-Reviewed Original ResearchWhite adipose tissueHuman white adipose tissueInsulin signalingInsulin resistanceInsulin-stimulated Akt phosphorylationInsulin-responsive GLUT4Pathogenesis of metabolic diseasesTUG cleavageFructose-sweetened beveragesBariatric surgery cohortMetabolic diseasesCohort of patientsAdipose tissueProteomic analysisHuman IRGene expressionMolecular regulationPathway proteinsHyperinsulinemic euglycemic clampAkt phosphorylationSurgery cohortBariatric surgeryHuman adipose tissueNational Institutes of HealthTC101727-P: Reduced Aromatic Amino Acid Suppression during Acute Hyperglycemia in Young Adults with Obesity
MATSON B, GUNAWAN F, ROTHMAN D, MASON G, NEWGARD C, HWANG J. 1727-P: Reduced Aromatic Amino Acid Suppression during Acute Hyperglycemia in Young Adults with Obesity. Diabetes 2025, 74 DOI: 10.2337/db25-1727-p.Peer-Reviewed Original ResearchCentral nervous systemAcute hyperglycemiaLean controlsBrain glucose levelsMass spectrometry-based metabolomic profilingMeasured plasma amino acidsInsulin resistanceGlucose levelsBranched chain amino acidsPlasma amino acidsDevelopment of insulin resistanceAromatic amino acid levelsChain amino acidsAcid suppressionResponse to hyperglycemiaMetabolomic profilesImpaired suppressionHyperglycemic clampObesityInsulin sensitivityHyperglycemiaNervous systemAmino acid changesBrain glucoseHealthy adults358-OR: Acute Fatty Acid Elevation Does Not Alter Brain Glucose Uptake in Humans
MATSON B, CHANG W, PALMIOTTO J, ROTHMAN D, BELFORT DE AGUIAR R, MASON G, HWANG J. 358-OR: Acute Fatty Acid Elevation Does Not Alter Brain Glucose Uptake in Humans. Diabetes 2025, 74 DOI: 10.2337/db25-358-or.Peer-Reviewed Original ResearchElevation of non-esterified fatty acidsNon-esterified fatty acid levelsHyperglycemic clampBrain glucose uptakeCirculating non-esterified fatty acidsBrain glucoseAcute elevationIntralipid infusionInsulin resistanceIntravenous infusion of salineAbsence of insulin resistanceNon-esterified fatty acidsInduce peripheral insulin resistanceHealthy adultsInfusion of salinePresence of hyperglycemiaGlucose uptakeMeasures of insulin sensitivityPeripheral insulin resistanceHigh-fat dietGlucose infusion rateIntravenous infusionPlasma glucoseLean individualsMRS scans286-OR: Spatial Regulation of Glucose and Lipid Metabolism by Hepatic Insulin Signaling
HE B, COPPS K, WHITE M, TAO R. 286-OR: Spatial Regulation of Glucose and Lipid Metabolism by Hepatic Insulin Signaling. Diabetes 2025, 74 DOI: 10.2337/db25-286-or.Peer-Reviewed Original ResearchInsulin signalingHepatic insulin signalingDisrupted insulin signalingRegulation of glucoseSpatial regulationLipid homeostasisMetabolic enzymesFunctional significanceGlycolytic metabolismSystemic glucoseLipid metabolismGlucose homeostasisHepatic insulin sensitivityExcessive lipogenesisLipogenesisHomeostasisElevated blood glucoseType 2 diabetesMetabolismMetabolic dysregulationGlucoseHepatosteatosisLiver-to-muscleInsulin resistanceLipid215-OR: Increased White Adipose Tissue Oxidative Capacity and Insulin Resistance Are Early Changes upon High-Fat Diet in Healthy Humans
XOURAFA G, GRANATA C, TRENKAMP S, KORZEKWA B, SCHRAUWEN-HINDERLING V, PETERSEN K, SHULMAN G, KAHL S, RODEN M. 215-OR: Increased White Adipose Tissue Oxidative Capacity and Insulin Resistance Are Early Changes upon High-Fat Diet in Healthy Humans. Diabetes 2025, 74 DOI: 10.2337/db25-215-or.Peer-Reviewed Original ResearchWhite adipose tissueFat mass indexInsulin resistanceHigh-fat dietLipid contentEuropean Association for the StudyNon-esterified fatty acidsInsulin sensitivityLiver lipid contentParallel-group studyEuropean Association for the Study of DiabetesNon-obese individualsAdipose tissue insulin resistanceWhole-body insulin sensitivityPromote insulin resistanceTissue insulin resistanceHepatic ATP levelsHigh-resolution respirometryHyperinsulinemic-euglycemic clampMitochondrial respirationStudy of DiabetesWhole-body insulin resistanceInsulin stimulationHepatic lipid contentHypercaloric high-fat dietGlucagon-like Peptide-1 receptor agonists for the prevention and treatment of Parkinson’s disease
Lee S, Yin L, Xiao N, Rhee T, Lo H, Wong S, Fox S, Teopiz K, Lam B, Zheng Y, Le G, Mansur R, Rosenblat J, McIntyre R. Glucagon-like Peptide-1 receptor agonists for the prevention and treatment of Parkinson’s disease. CNS Spectrums 2025, 30: e44. PMID: 40485141, DOI: 10.1017/s109285292510031x.Peer-Reviewed Original ResearchConceptsGlucagon-like peptide-1 receptor agonistsPeptide-1 receptor agonistsGLP-1RAsCentral nervous systemReceptor agonistsEvidence of clinically meaningful benefitFood and Drug Administration (FDA)-approved treatmentsTreatment-emergent adverse eventsParkinson's diseaseEffects of GLP-1RAsEmergent adverse eventsClinically meaningful benefitFDA-approved treatmentClinical trial evidenceNo current therapyTreatment of Parkinson's diseasePreclinical evidenceAdverse eventsCurrent therapiesMeaningful benefitClinical evidenceFeatures of PDTherapeutic benefitTrial evidenceInsulin resistanceTranscriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice
González J, Scharfman O, Zhu W, Kasamoto J, Gould V, Perry R, Higgins-Chen A. Transcriptomic and epigenomic signatures of liver metabolism and insulin sensitivity in aging mice. Mechanisms Of Ageing And Development 2025, 225: 112068. PMID: 40324540, PMCID: PMC12151592, DOI: 10.1016/j.mad.2025.112068.Peer-Reviewed Original ResearchConceptsDNA methylation modulesHepatic insulin resistanceRNA modulesProtein-protein interaction network analysisMetabolic pathwaysMethylation modulatorsPyruvate carboxylase fluxInteraction network analysisCitrate synthase fluxDNA methylation analysisCanonical metabolic pathwaysLipid metabolic pathwaysDecreased fatty acid oxidationComprehensive phenotypic characterizationMZF-1Fatty acid oxidationEpigenomic signaturesInsulin-stimulated conditionsModule genesNetwork analysisPhenotypic characterizationMitochondrial metabolic defectsInsulin resistanceLiver insulin resistanceMethylation analysisSpatial regulation of glucose and lipid metabolism by hepatic insulin signaling
He B, Copps K, Stöhr O, Liu B, Hu S, Joshi S, Haigis M, White M, Zhu H, Tao R. Spatial regulation of glucose and lipid metabolism by hepatic insulin signaling. Cell Metabolism 2025, 37: 1568-1583.e7. PMID: 40245868, DOI: 10.1016/j.cmet.2025.03.015.Peer-Reviewed Original ResearchInsulin signalingHepatic insulin signalingDisrupted insulin signalingRegulation of glucoseSpatial regulationLipid homeostasisElevated gluconeogenesisMetabolic enzymesFunctional significanceGlycolytic metabolismSystemic glucoseLipid metabolismGlucose homeostasisHepatic insulin sensitivityExcessive lipogenesisLipogenesisHomeostasisMetabolismMetabolic dysregulationHepatosteatosisHepatocytesGlucoseInsulin resistanceLipidType 2 diabetesImpact of body weight on IVF: pathophysiology, outcomes, and clinical considerations
Sekula N, Basar M, Pal L. Impact of body weight on IVF: pathophysiology, outcomes, and clinical considerations. Current Opinion In Obstetrics & Gynecology 2025, 37: 130-140. PMID: 40172001, DOI: 10.1097/gco.0000000000001023.Peer-Reviewed Original ResearchConceptsIVF outcomesExcess weightIVF cycle outcomesIVF treatment cyclesLive birth rateCycle outcomesImpact of excess weightAssociation of excess weightImpact of body weightClinical pregnancyExcess body weightBirth rateBody weightIVFAdverse implicationsUterine receptivityDetrimental implicationsWeight excessTreatment cyclesInflammatory processInsulin resistancePathogenic mechanismsClinical considerationsOutcomesDNA repairATGL 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 ResearchConceptsHyperinsulinemic-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 tissueThe Molecular Basis of Polycystic Ovary Syndrome and Its Cardiometabolic Correlates: Exploring the Intersection and Its Clinical Implications—A Narrative Review
Mahabamunuge J, Sekula N, Lepore C, Kudrimoti M, Upadhyay A, Alshowaikh K, Li H, Seifer D, AlAshqar A. The Molecular Basis of Polycystic Ovary Syndrome and Its Cardiometabolic Correlates: Exploring the Intersection and Its Clinical Implications—A Narrative Review. Biomedicines 2025, 13: 709. PMID: 40149685, PMCID: PMC11940587, DOI: 10.3390/biomedicines13030709.Peer-Reviewed Original ResearchPolycystic ovary syndromeType 2 diabetes mellitusCardiometabolic morbidityIncreased cardiovascular riskDevelopment of hypertensionCardiovascular risk factorsNarrative reviewPotential clinical implicationsAndrogen excessEndothelial dysfunctionCardiovascular riskClinical conditionsPredisposed individualsTherapeutic strategiesAdipokine secretionRisk factorsInsulin resistanceCardiometabolic diseasesCardiovascular diseaseClinical implicationsMorbidityMellitusSyndromeMolecular mechanismsDiseaseDeterminants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals
Pesta D, Anadol-Schmitz E, Sarabhai T, Kamp Y, Gancheva S, Trinks N, Zaharia O, Mastrototaro L, Lyu K, Habets I, Kamp-Bruls Y, Dewidar B, Weiss J, Schrauwen-Hinderling V, Zhang D, Gaspar R, Strassburger K, Kupriyanova Y, Al-Hasani H, Szendroedi J, Schrauwen P, Phielix E, Shulman G, Roden M. Determinants of increased muscle insulin sensitivity of exercise-trained versus sedentary normal weight and overweight individuals. Science Advances 2025, 11: eadr8849. PMID: 39742483, PMCID: PMC11691647, DOI: 10.1126/sciadv.adr8849.Peer-Reviewed Original ResearchConceptsOverweight-to-obeseNormal weightEndurance-trained humansMuscle mitochondrial contentAthlete's paradoxTrained athletesExercise-trainedOverweight individualsAthletesObesity subtypesObservational studyIntramyocellular triglyceride accumulationInsulin sensitivityHigher insulin sensitivityMitochondrial contentIncreased insulin sensitivityMuscleFemale individualsIndividualsInsulin resistanceObesityMitochondrial partitioningIncreased calpainNPKC activityProtein kinase C
2024
Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity
Galuppo B, Mannam P, Bonet J, Pierpont B, Trico’ D, Haskell-Luevano C, Ericson M, Freeman K, Philbrick W, Bale A, Caprio S, Santoro N. Rare variants in the melanocortin 4 receptor gene (MC4R) are associated with abdominal fat and insulin resistance in youth with obesity. International Journal Of Obesity 2024, 49: 819-826. PMID: 39738493, PMCID: PMC12095050, DOI: 10.1038/s41366-024-01706-0.Peer-Reviewed Original ResearchOral glucose tolerance testVisceral adipose tissueMelanocortin-4 receptor geneSubcutaneous adipose tissueVariant groupYale Pediatric Obesity ClinicInsulin resistanceEarly-onset obesityBMI z-scorePediatric obesity clinicRare variantsAdipose tissueAbdominal fat distributionDegree of obesityGlucose tolerance testTotal body fatIntrahepatic fat contentLower insulin sensitivityIntrahepatic fat accumulationAssociated with abdominal fatAbdominal MRIObesity clinicMetabolic sequelaePathogenic variantsFat distributionAssociation of gestational and childhood circulating C-peptide concentrations in the hyperglycemia and adverse pregnancy outcomes follow-up study
Rajamoorthi A, Zheng H, Skowronski A, Zork N, Reddy U, Tung P, Kupsco A, Gallagher D, Salem R, Leibel R, LeDuc C, Thaker V. Association of gestational and childhood circulating C-peptide concentrations in the hyperglycemia and adverse pregnancy outcomes follow-up study. Diabetes Research And Clinical Practice 2024, 220: 111967. PMID: 39716665, PMCID: PMC11840794, DOI: 10.1016/j.diabres.2024.111967.Peer-Reviewed Original ResearchConceptsOral glucose tolerance testC-peptide concentrationsC-peptideInsulin sensitivityCord bloodFollow-up studyInsulinogenic indexHOMA-IRCirculating C-peptide concentrationsCord blood C-peptideMaternal glucose concentrationsBlood C-peptideBMI z-scoreGlucose tolerance testPancreatic beta-cell developmentBeta-cell developmentGestational ageOGTT glucoseMaternal fastingAssociations of gestationalPubertal stageTolerance testInsulin resistanceZ-scoreMaternal covariatesDaily glucose variability is associated with intrahepatic fat content, β cell sensitivity, and biomarkers of glycolysis in youth with obesity
Barbieri E, Bonet J, Fox D, Nelson R, Nelson M, Nelson L, Fernandez C, Van Name M, Samuels S, Caprio S, Sabati M, Galderisi A, Sherr J, Man C, Santoro N. Daily glucose variability is associated with intrahepatic fat content, β cell sensitivity, and biomarkers of glycolysis in youth with obesity. Obesity 2024, 33: 116-124. PMID: 39658509, PMCID: PMC11666407, DOI: 10.1002/oby.24175.Peer-Reviewed Original ResearchConceptsIntrahepatic fat contentDaily glucose variabilityLiver proton density fat fractionProton density fat fractionGlucose variabilityInsulin sensitivityOral glucose tolerance testFat fractionInsulin secretionAssociated with insulin resistanceFirst-phase insulin secretionAssociated with 2-h glucoseGlucose tolerance testGlucose standard deviationMagnetic resonance imagingOral minimal modelCoefficient of variationBasal insulin secretionPediatric obesityPostprandial glucoseTolerance testCell sensitivityInsulin resistanceObesityResonance imagingUrban Environmental Threat Moderates the Relationship Between Depression and Insulin Resistance Among Latinxs With Type 2 Diabetes
Matlock K, Albright‐Pierce M, Bermúdez‐Millán A, Pérez‐Escamilla R, Segura‐Pérez S, Wagner J. Urban Environmental Threat Moderates the Relationship Between Depression and Insulin Resistance Among Latinxs With Type 2 Diabetes. Stress And Health 2024, 40: e3504. PMID: 39579357, PMCID: PMC11636443, DOI: 10.1002/smi.3504.Peer-Reviewed Original ResearchDepressive symptomsType 2 diabetesParticipants self-reported depressive symptomsSelf-reported depressive symptomsImpact of depressionMinoritised ethnic groupsHealth-related factorsPatient Health QuestionnaireCommunity sampleFasting blood drawUrban Hassles IndexHealth QuestionnaireLatinx adultsDepressionGreater insulin resistanceInsulin resistanceHOMA-IR formulaUrban living conditionsCalculate insulin resistanceLatinxBlood drawSymptomsSevere symptomsEthnic groupsRegression analysisAdipose tissue insulin resistance in children and adolescents: linking glucose and free fatty acid metabolism to hepatic injury markers
Bonet J, Weiss R, Galderisi A, Man C, Caprio S, Santoro N. Adipose tissue insulin resistance in children and adolescents: linking glucose and free fatty acid metabolism to hepatic injury markers. AJP Endocrinology And Metabolism 2024, 327: e723-e728. PMID: 39503461, PMCID: PMC11684862, DOI: 10.1152/ajpendo.00270.2024.Peer-Reviewed Original ResearchImpaired glucose toleranceInsulin sensitivity indexAlanine transaminaseInsulin resistanceFree fatty acid metabolismInsulin sensitivityP<10<sup>-6</sup>Years of follow-upMeasurement of liver function testsLiver function testsFree fatty acidsAdipose tissue insulin resistanceAdipose tissue insulin sensitivityHepatic injury markersPlasma alanine transaminaseEstimated insulin sensitivity indexTissue insulin sensitivityMann-Whitney testTissue insulin resistanceType 2 diabetesDevelopment of insulin resistanceProgression of insulin resistanceOral minimal modelCardiometabolic complicationsInsulin-resistant statesFunctional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity
Mohammed I, Selvaraj S, Ahmed W, Al-Barazenji T, Dauleh H, Love D, Saraiva L, Hussain K. Functional Evaluation of a Novel Homozygous ADCY3 Variant Causing Childhood Obesity. International Journal Of Molecular Sciences 2024, 25: 11815. PMID: 39519366, PMCID: PMC11547096, DOI: 10.3390/ijms252111815.Peer-Reviewed Original ResearchAdenylate cyclase 3Early-onset obesityRegulating various downstream signaling pathwaysIn silico functional characterizationHomozygous nonsense variant c.Homozygous loss-of-function variantsIn silico functional analysisLoss-of-function variantsReceptor loss of functionNonsense variant c.Impaired enzymatic activityGene panel sequencingATP to cAMPIn silico validationDownstream signaling pathwaysGain-of-function variantsPrimary cilia of neuronsIn vitroInsulin resistanceLoss of functionTransmembrane proteinsFunctional characterizationPrimary ciliaNovel p.Variant c.
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