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

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posted on 2022-11-03, 15:13 authored by Emily K. Sims, David Cuthbertson, Jamie L. Felton, Heba M. Ismail, Brandon M. Nathan, Laura M. Jacobsen, Emily Paprocki, Alberto Pugliese, Jerry Palmer, Mark Atkinson, Carmella Evans-Molina, Jay S. Skyler, Maria J. Redondo, Kevan C. Herold, Jay M. Sosenko

  

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.

Funding

Doris Duke Charitable Foundation 2021258

U.S. Department of Health and Human Services > National Institutes of Health > Eunice Kennedy Shriver National Institute of Child Health and Human Development R01 DK121843 R01 DK124395 R01DK121929 U01 DK061034 U01 DK061042 U01 DK061058 U01 DK085453 U01 DK085461 U01 DK085465 U01 DK085466 U01 DK085476 U01 DK085499 U01 DK085504 U01 DK085509 U01 DK103153 U01 DK103180 U01 DK103266 U01 DK103282 U01 DK106984 U01 DK106994 U01 DK107013 U01 DK107014 U01DK127382-012 UC4 DK097835 UC4 DK106993

JDRF

John Templeton Foundation 62288

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