2025
A 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, 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 correlation
2024
Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes
Redondo M, Cuthbertson D, Steck A, Herold K, Oram R, Atkinson M, Brusko T, Parikh H, Krischer J, Onengut-Gumuscu S, Rich S, Sosenko J. Characteristics of autoantibody-positive individuals without high-risk HLA-DR4-DQ8 or HLA-DR3-DQ2 haplotypes. Diabetologia 2024, 68: 588-601. PMID: 39670998, PMCID: PMC11832693, DOI: 10.1007/s00125-024-06338-7.Peer-Reviewed Original ResearchHLA-DR4-DQ8HLA-DR3-DQ2High-risk HLA haplotypesType 1 diabetesAutoantibody-positive individualsHLA haplotypesHLA-DR3-DQ2 haplotypeClinical type 1 diabetesType 1 diabetes pathogenesisPrevalence of autoantibodiesPrevalence of overweight/obesityIslet autoantibody-positive individualsAutoantibody-positive relativesHLA-DRB1Metabolic markersC-peptideIA-2DR3/DR4Aetiological heterogeneityYounger ageNon-Hispanic participantsPhenotypic differencesAssociated with phenotypic differencesPrevalenceRelatives of individualsTrajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab
Galderisi A, Sims E, Evans-Molina C, Petrelli A, Cuthbertson D, Nathan B, Ismail H, Herold K, Moran A. Trajectory of beta cell function and insulin clearance in stage 2 type 1 diabetes: natural history and response to teplizumab. Diabetologia 2024, 68: 646-661. PMID: 39560746, PMCID: PMC11832608, DOI: 10.1007/s00125-024-06323-0.Peer-Reviewed Original ResearchProgrammed death-1AUC C-peptideSlow progressorsRapid progressorsInsulin secretionInsulin clearanceC-peptideDisease-free survival ratesT effector memory cellsCD8+ T effector memory cellsNatural historyImpact of immunotherapyPlacebo-treated individualsT memory cellsBaseline insulin secretionBeta cell functionInterpreting clinical trialsLoss of insulin secretionDeath-1Elevated insulin secretionPlacebo-treatedTreatment armsTeplizumabClinical trialsDisposition indexA phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes
Bender C, Wiedeman A, Hu A, Ylescupidez A, Sietsema W, Herold K, Griffin K, Gitelman S, Long S, Gottlieb P, Strock R, Chesshir L, Redondo M, Williams C, Clements M, Moore W, DiMeglio L, Legge M, Mullen M, Sanchez J, Spall M, Woerner S, Gaglia J, Resnick B, Bryant N, Krishfield S, Turley J, Koshy N, Mackey M, Guttmann-Bauman I, Fitch R, Bartholow L, Shelso J, Al Nofal A, Hanisch K, Casas L, Thurlow B, Gottschalk M, Hashiguchi M, Paglia L, Lam A, Sanda S, Torok C, Wesch R, Moore D, Russell W, Smith T, Brown A, Brendle F, Haller M, Cintron M, Baidal D, Matheson D, Blaschke C, Moran A, Pappensus E, Leschyshyn J, Street A. A phase 2 randomized trial with autologous polyclonal expanded regulatory T cells in children with new-onset type 1 diabetes. Science Translational Medicine 2024, 16: eadn2404. PMID: 38718135, DOI: 10.1126/scitranslmed.adn2404.Peer-Reviewed Original ResearchConceptsRegulatory T cellsType 1 diabetesT cellsC-peptideFoxp3<sup>+</sup> regulatory T cellsNew-onset type 1 diabetesResidual B-cell functionPhase 1 clinical trialAutoimmune type 1 diabetesC-peptide preservationHigh-dose cohortPhase 2 randomized trialYears compared to placeboNew-onset T1DBaseline C-peptidePeripheral blood samplesSuppression in vitroDetected 1 weekMatching placeboAdoptive transferDouble-blindHigh-dosePrevent autoimmunityLow-doseFold expansionEarly Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials.
Jacobsen L, Cuthbertson D, Bundy B, Atkinson M, Moore W, Haller M, Russell W, Gitelman S, Herold K, Redondo M, Sims E, Wherrett D, Moran A, Pugliese A, Gottlieb P, Sosenko J, Ismail H. Early Metabolic Endpoints Identify Persistent Treatment Efficacy in Recent-Onset Type 1 Diabetes Immunotherapy Trials. Diabetes Care 2024, 47: 1048-1055. PMID: 38621411, PMCID: PMC11294635, DOI: 10.2337/dc24-0171.Peer-Reviewed Original ResearchConceptsC-peptide area-under-the-curveArea under the curveC-peptideRecent-onset type 1 diabetesTreatment efficacyEarly-phase clinical trialsC-peptide preservationPrimary end pointB cell functionDetect treatment efficacyType 1 diabetesPost hoc analysisRandomized controlled trialsImmune therapyImmunotherapy trialsMonths posttherapyClinical trialsTreatment effectsEnd pointsMetabolic indicesHoc analysisControlled trialsType 1 diabetes trialsMetabolic endpointsIntervention trialsEvidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes.
Latres E, Greenbaum C, Oyaski M, Dayan C, Colhoun H, Lachin J, Skyler J, Rickels M, Ahmed S, Dutta S, Herold K, Marinac M. Evidence for C-Peptide as a Validated Surrogate to Predict Clinical Benefits in Trials of Disease-Modifying Therapies for Type 1 Diabetes. Diabetes 2024, 73: 823-833. PMID: 38349844, DOI: 10.2337/dbi23-0012.Peer-Reviewed Original ResearchBeta cell functionType 1 diabetesMeasures of beta cell functionDisease-modifying therapiesC-peptideTrials of disease-modifying therapiesClinical benefitCell functionDestruction of pancreatic beta cellsStimulated C-peptideC-peptide levelsEnd-organ complicationsProspective cohort studyAssociated with protectionEnd-organ complications of diabetesChronic autoimmune diseaseClinically meaningful outcomesClinical outcome measuresComplications of diabetesClinical trials of disease-modifying therapiesBeta cell preservationDemonstration of efficacyPancreatic beta cellsPeripheral bloodAutoimmune diseasesComparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals
Sims E, Cuthbertson D, Jacobsen L, Ismail H, Nathan B, Herold K, Redondo M, Sosenko J. Comparisons of Metabolic Measures to Predict T1D vs Detect a Preventive Treatment Effect in High-Risk Individuals. The Journal Of Clinical Endocrinology & Metabolism 2024, 109: 2116-2123. PMID: 38267821, PMCID: PMC11244203, DOI: 10.1210/clinem/dgae048.Peer-Reviewed Original ResearchSix-month changesPrevention trialsC-peptidePredicting diabetesMetabolic endpointsPreventive treatment effectsMetabolic measuresEffect of disease-modifying therapiesProportional hazards regressionTreatment effectsResponse to immunotherapyMeasurement of glucoseNatural history studiesPrevention StudyHazards regressionInclusion criteriaDisease-modifying therapiesT1D prevention trialsComparing placeboTreatment armsTeplizumabTrialNet PathwayHigh riskDetect treatment effectsCombined glucose
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