2025
1687-P: Sequential Combination of the Mitochondrial Protonophore (MP) TLC-6740 with Semaglutide Normalizes Body Weight and Preserves Lean Mass in DIO Mice
SRODA N, SHARMA M, MURAKAMI E, LOGAN C, WENG S, KIRBY B, MYERS R, SUBRAMANIAN M, SHULMAN G, VIJAYAKUMAR A. 1687-P: Sequential Combination of the Mitochondrial Protonophore (MP) TLC-6740 with Semaglutide Normalizes Body Weight and Preserves Lean Mass in DIO Mice. Diabetes 2025, 74 DOI: 10.2337/db25-1687-p.Peer-Reviewed Original ResearchLean massDIO miceFM lossBody weightMitochondrial protonophoreData support evaluationNormal body weightReduced food intakeRegulate body weightOral glucose toleranceEvaluate weight lossIncreased energy expenditureMale DIO miceSequential combinationDiet-inducedFood intakeGlucose toleranceMetabolic disordersSemaglutideMiceWeight lossEnergy expenditureOGTTOGTT AUCIncretin18-OR: Lower Incretin Effect and Reduced GIP Characterize the Metabolic Phenotype of People with Multiple Islet Autoantibodies and Normal Glucose Tolerance
GALDERISI A, MARCHIORI H, ALGUARD M, DESOUSA M, TICHY E, FLYNN A, GAGLIA J, DALLA MAN C, SHERR J. 18-OR: Lower Incretin Effect and Reduced GIP Characterize the Metabolic Phenotype of People with Multiple Islet Autoantibodies and Normal Glucose Tolerance. Diabetes 2025, 74 DOI: 10.2337/db25-18-or.Peer-Reviewed Original ResearchOral glucose tolerance testNormal glucose toleranceInsulin secretion rateGlucose tolerance testIncretin effectStage 0GLP-1Islet autoantibodiesTolerance testGlucose tolerancePreclinical type 1 diabetesStage 1Reduced incretin effectHormone GLP-1Iv glucose tolerance testType 1 diabetesMultiple islet autoantibodiesPhenotype of peopleOral minimal modelC-peptideMetabolic phenotypeGlucose profilesIncretinMeasurement of glucoseInsulin secretionB 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. PMID: 40662198, PMCID: PMC12256348, 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 tissueWS16.05Impact of elexacaftor/tezacaftor/ivacaftor on glucose tolerance in adolescents with cystic fibrosis. Data from the MODUL-CF study
Bonnel A, Galderisi A, Weiss L, Sermet-Gaudelus I, Besancon A, Letierce A, Sahki D, Group M. WS16.05Impact of elexacaftor/tezacaftor/ivacaftor on glucose tolerance in adolescents with cystic fibrosis. Data from the MODUL-CF study. Journal Of Cystic Fibrosis 2025, 24: s33. DOI: 10.1016/j.jcf.2025.03.586.Peer-Reviewed Original ResearchOral glucose tolerance testAbnormal glucose toleranceNormal glucose toleranceCF-related diabetesBaseline oral glucose tolerance testAbnormal glucose tolerance groupCystic fibrosisGlucose toleranceNormal glucose tolerance groupEffective CFTR modulatorsOGTT glucoseBMI z-scoreYear of treatmentImpaired fasting glucoseImpaired glucose toleranceGlucose tolerance testForced expiratory volumeCFTR modulatorsPulmonary infectionDecrease recurrenceBaseline characteristicsRelated diabetesFasting GlucoseTolerance testInsulin treatmentEffect of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Adolescents With Cystic Fibrosis
Galderisi A, Weiss L, Besançon A, Stremler N, Reix P, Wizla N, Lustre A, Rames C, Tatopoulos A, Perisson C, Dalphin M, Troussier F, Houdouin V, Bessaci K, Cosson L, Gabsi A, Corvol H, Deneuville E, Storni V, Ramel S, Bui S, Heraud M, Remus N, Huet F, Scalbert M, Mely L, Gachelin E, Giannantonio M, Letierce A, Sahki D, Marguet C, Bonnel A, Sermet-Gaudelus I. Effect of Elexacaftor/Tezacaftor/Ivacaftor on Glucose Tolerance in Adolescents With Cystic Fibrosis. The Journal Of Clinical Endocrinology & Metabolism 2025, dgaf099. PMID: 39977216, DOI: 10.1210/clinem/dgaf099.Peer-Reviewed Original ResearchOral glucose tolerance testBaseline oral glucose tolerance testAbnormal glucose toleranceNormal glucose toleranceAbnormal glucose tolerance groupCystic fibrosisGlucose toleranceNormal glucose tolerance groupEffective CFTR modulatorsCF-related diabetesInsulin secretionImpaired fasting glucoseGlucose tolerance testImpaired glucose toleranceForced expiratory volumeBMIz-scoreCFTR modulatorsBaseline characteristicsRelated diabetesFasting GlucoseTolerance testTherapeutic strategiesInsulin treatmentExpiratory volumeGlucose levelsA Glucose Fraction Independent of Insulin Secretion: Implications for Type 1 Diabetes Progression in Autoantibody-Positive Cohorts
Sosenko J, Cuthbertson D, Jacobsen L, Redondo M, Sims E, Ismail H, Herold K, Skyler J, Nathan B, Groups D. A Glucose Fraction Independent of Insulin Secretion: Implications for Type 1 Diabetes Progression in Autoantibody-Positive Cohorts. Diabetes Technology & Therapeutics 2025, 27: 179-186. PMID: 39757867, PMCID: PMC12084817, DOI: 10.1089/dia.2024.0422.Peer-Reviewed Original ResearchConceptsIndependent of insulin secretionArea under the curveAUC C-peptideAutoantibody-positive individualsC-peptideInsulin secretionAUC glucoseGlucose toleranceFirst-phase insulin responseDiabetes Prevention Trial-Type 1Type 1 diabetes progressionOral glucose tolerance test dataGlucose tolerance test dataPrediction of T1DImpaired glucose toleranceOral glucose toleranceType 1 diabetesDPT-1TrialNet PathwayIncreased glycemiaInsulin responseInverse correlationSecretionT1DLack of correlationEarly‐Life Exposure to Bisphenol A Damaged Pancreas That May Increase Offspring Sensitivity to High‐Fat Diets
Chen F, Zhang H, Huang H, Liu J, Zhu W, Lu L, Xie Y, Li H, Pi S, Zhong J, Ding S, Zhang K, Wu F, Zhang B, He Y. Early‐Life Exposure to Bisphenol A Damaged Pancreas That May Increase Offspring Sensitivity to High‐Fat Diets. Journal Of Toxicology 2025, 2025: 6189790. PMID: 40842956, PMCID: PMC12367390, DOI: 10.1155/jt/6189790.Peer-Reviewed Original ResearchEarly-life BPA exposureHigh-fat dietBPA exposureOffspring miceLipid profileMetabolic diseases in adulthoodRisk of metabolic diseases in adulthoodLipidomic analysisSensitivity to high-fat dietSusceptibility of miceDisease in adulthoodDevelopment of metabolic diseasesPancreatic MDA contentB-cell massPDX1</i>Gene mRNA expressionB cellsMale miceGlucose toleranceGestation to weaningMRNA expressionInsulin toleranceMouse pancreasMiceMetabolic diseases
2024
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
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 effectsActivation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor
Engström Ruud L, Font-Gironès F, Zajdel J, Kern L, Teixidor-Deulofeu J, Mannerås-Holm L, Carreras A, Becattini B, Björefeldt A, Hanse E, Fenselau H, Solinas G, Brüning J, Wunderlich T, Bäckhed F, Ruud J. Activation of GFRAL+ neurons induces hypothermia and glucoregulatory responses associated with nausea and torpor. Cell Reports 2024, 43: 113960. PMID: 38507407, DOI: 10.1016/j.celrep.2024.113960.Peer-Reviewed Original ResearchGlucose to lipid oxidationMetabolomics analysis of bloodImpaired insulin sensitivityRelease of stress hormonesAdipose tissue differentiationAnalysis of bloodGlucose uptakeVisceral fatChronic activationAcute activationGlucose toleranceMetabolomic analysisTranscriptome of muscleObesity treatmentTorpor-like stateNeuronal activityCell-specific activityInsulin sensitivityNauseaMetformin effectsHypothermiaWeight lossNeuronsEnergy homeostasisAugmented glucose uptakeTAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding
Dedic N, Wang L, Hajos-Korcsok E, Hecksher-Sørensen J, Roostalu U, Vickers S, Wu S, Anacker C, Synan C, Jones P, Milanovic S, Hopkins S, Bristow L, Koblan K. TAAR1 agonists improve glycemic control, reduce body weight and modulate neurocircuits governing energy balance and feeding. Molecular Metabolism 2024, 80: 101883. PMID: 38237896, PMCID: PMC10839149, DOI: 10.1016/j.molmet.2024.101883.Peer-Reviewed Original ResearchConceptsTrace amine-associated receptor 1Trace amine-associated receptor 1 agonistAntipsychotic drugsEffects of TAAR1 agonistsOlanzapine-induced weight gainDiet-induced obesityReduced body weightFood intakeHigh-fat dietSub-chronic administrationC-Fos protein expressionDiet-induced obese miceImprove glycemic controlRegulators of metabolic controlGlycemic controlGastric emptyingSchizophrenia patientsTAAR1 agonistsHedonic feedingLimbic structuresBody weightMetabolic parametersMouse modelGlucose toleranceWeight gain
2023
CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice
Hammerschmidt P, Steculorum S, Bandet C, Del Río-Martín A, Steuernagel L, Kohlhaas V, Feldmann M, Varela L, Majcher A, Quatorze Correia M, Klar R, Bauder C, Kaya E, Porniece M, Biglari N, Sieben A, Horvath T, Hornemann T, Brodesser S, Brüning J. CerS6-dependent ceramide synthesis in hypothalamic neurons promotes ER/mitochondrial stress and impairs glucose homeostasis in obese mice. Nature Communications 2023, 14: 7824. PMID: 38016943, PMCID: PMC10684560, DOI: 10.1038/s41467-023-42595-7.Peer-Reviewed Original ResearchConceptsMitochondrial stressSpecific ceramide speciesSteroidogenic factor 1Hypothalamic neuronsMitochondrial dynamicsMitochondrial morphologyCeramide synthaseObese miceGlucose homeostasisCeramide speciesCeramide synthesisConditional deletionHypothalamic lipotoxicityCultured hypothalamic neuronsAdverse metabolic effectsFactor 1High-fat dietImpairs glucose homeostasisDiet-induced alterationsCerS6DeletionHomeostasisGlucose toleranceCeramideInsulin sensitivityCheckpoint kinase 2 controls insulin secretion and glucose homeostasis
Chong A, Vandana J, Jeng G, Li G, Meng Z, Duan X, Zhang T, Qiu Y, Duran-Struuck R, Coker K, Wang W, Li Y, Min Z, Zuo X, de Silva N, Chen Z, Naji A, Hao M, Liu C, Chen S. Checkpoint kinase 2 controls insulin secretion and glucose homeostasis. Nature Chemical Biology 2023, 20: 566-576. PMID: 37945898, PMCID: PMC11062908, DOI: 10.1038/s41589-023-01466-4.Peer-Reviewed Original ResearchGlucose-stimulated insulin secretionInsulin secretionHuman β-cellsCynomolgus macaquesΒ-cellsImproved glucose clearanceType 2 diabetic human isletsDiabetic mouse modelDiabetic human isletsHuman β-cell lineDiscovery of insulinT2D conditionsΒ-cell lineGlucose toleranceGlucose clearanceMouse modelGlucose homeostasisMice showHuman isletsSecretionVivo studiesUntargeted metabolic profilingCell linesCheckpoint kinase 2IsletsAlterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity
Tricò D, Chiriacò M, Nouws J, Vash-Margita A, Kursawe R, Tarabra E, Galderisi A, Natali A, Giannini C, Hellerstein M, Ferrannini E, Caprio S. Alterations in Adipose Tissue Distribution, Cell Morphology, and Function Mark Primary Insulin Hypersecretion in Youth With Obesity. Diabetes 2023, 73: 941-952. PMID: 37870826, PMCID: PMC11109779, DOI: 10.2337/db23-0450.Peer-Reviewed Original ResearchPrimary insulin hypersecretionΒ-cell glucose sensitivityAdipose tissue distributionInsulin hypersecretionInsulin resistanceGlucose toleranceUnfavorable metabolic phenotypeWorse glucose toleranceLeptin serum levelsAbnormal glucose toleranceTissue distributionExcessive insulin secretionHigher leptin levelsVisceral fat depotsNon-diabetic adolescentsEuglycemic hyperinsulinemic clampWhole-body adiposityAbdominal subcutaneous adipocytesBody weight gainGlucose sensitivityPrimary hypersecretionGlucose intoleranceSerum levelsLeptin levelsChronic hyperinsulinemiaHepatocyte 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 programThe lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity
Umano G, Cirillo G, Sanchez G, Rondinelli G, Foderini M, Ferrara S, Di Sessa A, Marzuillo P, Papparella A, Santoro N, del Giudice E. The lncOb rs10487505 polymorphism impairs insulin sensitivity and glucose tolerance in children and adolescents with obesity. Obesity 2023, 31: 2359-2364. PMID: 37550829, DOI: 10.1002/oby.23835.Peer-Reviewed Original ResearchConceptsHomeostasis model assessmentInsulin resistanceDisposition indexLower whole-body insulin sensitivity indexModel assessmentWhole-body insulin sensitivity indexRisk of prediabetesHigher fasting insulinLower disposition indexPlasma leptin levelsInsulin sensitivity indexBMI z-scoreLeptin plasma levelsLeptin gene transcriptionFasting insulinGlucose toleranceLeptin levelsCC patientsRetrospective studyPlasma levelsAnthropometrical evaluationInsulin sensitivityHormone levelsHigh prevalenceHigh riskSerendipitous Discovery of T Cell–Produced KLK1b22 as a Regulator of Systemic Metabolism
Arwood M, Sun I, Patel C, Sun I, Oh M, Bettencourt I, Claiborne M, Chan-Li Y, Zhao L, Waickman A, Mavrothalassitis O, Wen J, Aja S, Powell J. Serendipitous Discovery of T Cell–Produced KLK1b22 as a Regulator of Systemic Metabolism. ImmunoHorizons 2023, 7: 493-507. PMID: 37358498, PMCID: PMC10580127, DOI: 10.4049/immunohorizons.2300016.Peer-Reviewed Original ResearchConceptsGlucose toleranceT cellsSystemic metabolismGenome ProjectWild-type T cellsMicroarray analysisCell differentiationNovel roleRhebMammalian targetInsulin receptorT cell differentiationReduced glucose toleranceMarked increaseStrains of miceBeige fatExpressionInsulin sensitivityOverexpressionSystemic overexpressionMetabolismCellsMiceToleranceFurther studiesInactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity
Lotfollahzadeh S, Xia C, Amraei R, Hua N, Kandror K, Farmer S, Wei W, Costello C, Chitalia V, Rahimi N. Inactivation of Minar2 in mice hyperactivates mTOR signaling and results in obesity. Molecular Metabolism 2023, 73: 101744. PMID: 37245847, PMCID: PMC10267597, DOI: 10.1016/j.molmet.2023.101744.Peer-Reviewed Original ResearchConceptsMTOR activationHigh-fat dietObesity-associated diseasesGlucose toleranceKO miceChronic diseasesPathophysiological roleBody fatMetabolic disordersHypertrophic adipocytesKnockout miceObesityAdipose tissuePhysiological negative regulatorType 2HEK-293 cellsImpaired expressionComplex disorderCell culture studiesAdipocytesDiseaseMiceDisordersMTORUnknown roleInnate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation
Goldberg E, Letian A, Dlugos T, Leveau C, Dixit V. Innate immune cell-intrinsic ketogenesis is dispensable for organismal metabolism and age-related inflammation. Journal Of Biological Chemistry 2023, 299: 103005. PMID: 36775129, PMCID: PMC10025153, DOI: 10.1016/j.jbc.2023.103005.Peer-Reviewed Original ResearchConceptsAge-related inflammationKetone bodiesOrganismal metabolismMyeloid cellsChronic low-grade inflammationKetogenic diet feedingLow-grade inflammationHigh-fat dietAbundant ketone bodyGlucose toleranceNLRP3 inflammasomeDiet feedingGlucose homeostasisMouse modelBody weightInflammationMetabolic checkpointOnly organConditional ablationTerminal enzymeΒ-hydroxybutyrateFunctional targetingMethylglutaryl-CoA lyaseKetogenesisModest effect
2022
Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents
Muñoz V, Gaspar R, Mancini M, de Lima R, Vieira R, Crisol B, Antunes G, Trombeta J, Bonfante I, Simabuco F, da Silva A, Cavaglieri C, Ropelle E, Cintra D, Pauli J. Short-term physical exercise controls age-related hyperinsulinemia and improves hepatic metabolism in aged rodents. Journal Of Endocrinological Investigation 2022, 46: 815-827. PMID: 36318449, DOI: 10.1007/s40618-022-01947-8.Peer-Reviewed Original ResearchConceptsInsulin sensitivityHepatic metabolismPhysical exerciseInsulin resistanceAerobic exerciseMetabolic healthAged rodentsShort-term aerobic exerciseAge-related insulin resistanceShort-term exercise trainingSignificant metabolic impairmentType 2 diabetesHepatic fat accumulationWhole-body glucoseDevelopment/progressionHepatic fat metabolismExercise trainingGlucose toleranceInsulin secretionFat accumulationHigh prevalenceHyperinsulinemic ratsMetabolic impairmentElderly populationGlucose homeostasisEffects of the Seed Oil of Carica papaya Linn on Food Consumption, Adiposity, Metabolic and Inflammatory Profile of Mice Using Hyperlipidic Diet
Santana L, do Espirito Santo B, Tatara M, Negrão F, Croda J, Alves F, de Oliveira Filiú W, Cavalheiro L, Nazário C, Asato M, de Faria B, do Nascimento V, de Cássia Avellaneda Guimarães R, de Cássia Freitas K, Hiane P. Effects of the Seed Oil of Carica papaya Linn on Food Consumption, Adiposity, Metabolic and Inflammatory Profile of Mice Using Hyperlipidic Diet. Molecules 2022, 27: 6705. PMID: 36235241, PMCID: PMC9570947, DOI: 10.3390/molecules27196705.Peer-Reviewed Original ResearchConceptsOral glucose toleranceHigh-fat dietArea of adipocytesInsulin sensitivity testAcute toxicity testInflammatory profileGlucose toleranceTotal cholesterolFatty acidsIL-6Insulin resistanceMCP-1Swiss miceHyperlipidic dietLower insulinCaloric intakeMonounsaturated fatty acidsProtective effectHypoglycemic effectAdipose tissueCytokine resistanceWeight gainAdiposityFood consumptionFatty acid composition
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