Sims, Emily K.Cuthbertson, DavidFelton, Jamie L.Ismail, Heba M.Nathan, Brandon M.Jacobsen, Laura M.Paprocki, EmilyPugliese, AlbertoPalmer, JerryAtkinson, MarkEvans-Molina, CarmellaSkyler, Jay S.Redondo, Maria J.Herold, Kevan C.Sosenko, Jay M.2024-05-022024-05-022022-12-01Sims, E. K., Cuthbertson, D., Felton, J. L., Ismail, H. M., Nathan, B. M., Jacobsen, L. M., Paprocki, E., Pugliese, A., Palmer, J., Atkinson, M., Evans-Molina, C., Skyler, J. S., Redondo, M. J., Herold, K. C., & Sosenko, J. M. (2022). Persistence of β-Cell Responsiveness for Over Two Years in Autoantibody-Positive Children With Marked Metabolic Impairment at Screening. Diabetes Care, 45(12), 2982–2990. https://doi.org/10.2337/dc22-1362https://hdl.handle.net/1805/40443OBJECTIVE We studied longitudinal differences between progressors and nonprogressors to type 1 diabetes with similar and substantial baseline risk. RESEARCH DESIGN AND METHODS Changes in 2-h oral glucose tolerance test indices were used to examine variability in diabetes progression in the Diabetes Prevention Trial–Type 1 (DPT-1) study (n = 246) and Type 1 Diabetes TrialNet Pathway to Prevention study (TNPTP) (n = 503) among autoantibody (Ab)+ children (aged <18.0 years) with similar baseline metabolic impairment (DPT-1 Risk Score [DPTRS] of 6.5–7.5), as well as in TNPTP Ab− children (n = 94). RESULTS Longitudinal analyses revealed annualized area under the curve (AUC) of C-peptide increases in nonprogressors versus decreases in progressors (P ≤ 0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a two-dimensional grid) also differed significantly (P < 0.001). Despite marked baseline metabolic impairment of nonprogressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide–to–AUC glucose ratio (AUC ratio), and Index60 did not differ from Ab− relatives during follow-up. Divergence between nonprogressors and progressors occurred by 6 months from baseline in both cohorts (AUC glucose, P ≤ 0.007; AUC ratio, P ≤ 0.034; Index60, P < 0.001; vector indices of change, P < 0.001). Differences in 6-month change were positively associated with greater diabetes risk (respectively, P < 0.001, P ≤ 0.019, P < 0.001, and P < 0.001) in DPT-1 and TNPTP, except AUC ratio, which was inversely associated with risk (P < 0.001). CONCLUSIONS Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than nonprogressors within 6 months and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between nonprogressors and Ab− relatives, suggesting persistent β-cell responsiveness in nonprogressors.en-USPublisher Policytype I diabetesbaseline riskprogressorsnonprogressorsArticle