Persistence of β-cell responsiveness for over two years in autoantibody-positive children with marked metabolic impairment at screening

Alberto Pugliese,Brandon M Nathan,Carmella Evans-Molina,David Cuthbertson,Emily K Sims,Emily Paprocki,Heba M Ismail,Jamie L Felton,Jay M Sosenko,Jay S Skyler,Jerry Palmer,Kevan C Herold,Laura M Jacobsen,Maria J Redondo,Mark Atkinson

doi:10.2337/figshare.21040171.v1

Abstract

Objective: We studied longitudinal differences between progressors and non-progressors to type 1 diabetes with similar and substantial baseline risk. Research Design and Methods: Changes in two-hour oral glucose tolerance test (OGTT) indices were used to examine variability in diabetes progression among autoantibody (Ab)+ children (<18.0 years) with similar baseline metabolic impairment [DPT-1 risk score (DPTRS) of 6.5-7.5] in the Diabetes Prevention Trial-Type 1 (DPT-1; n=246) and TrialNet Pathway to Prevention studies (TNPTP; n=503), as well as Ab- children in TNPTP (n=94). Results: Longitudinal analyses revealed annualized AUC C-peptide increases in non-progressors vs. decreases in progressors (p≤0.026 for DPT-1 and TNPTP). Vector indices for AUC glucose and AUC C-peptide changes (on a 2-dimensional grid) also differed significantly (p<0.001). Despite marked baseline metabolic impairment of non-progressors, changes in AUC C-peptide, AUC glucose, AUC C-peptide/AUC glucose, and Index60 did not differ from Ab- relatives during follow-up. Divergence between non-progressors 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 associated with greater diabetes risk (respectively, p<0.001, p≤0.019, p<0.001, p<0.001) in DPT-1 and TNPTP, except AUC ratio which was associated with less risk. Conclusions: Novel findings show that even with similarly abnormal baseline risk, progressors had appreciably more metabolic impairment than non-progressors within 6 months, and that the measures showing impairment were predictive of type 1 diabetes. Longitudinal metabolic patterns did not differ between non-progressors and Ab- relatives, suggesting persistent β-cell responsiveness in non-progressors.

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