1023-OR: Divergent Exocrine Pancreatic Trajectories in Children Progressing to Stage 1 vs. Stage 3 Type 1 Diabetes

Introduction and Objective: Exocrine pancreas dysfunction is evident in presymptomatic type 1 diabetes (T1D), yet its natural history remains unclear. We evaluated whether longitudinal decline in fecal elastase (FE-1) tracks more closely with islet autoimmunity or progression to dysglycemia and assessed its predictive utility. Methods: In a nested case-control study within The Environmental Determinants of Diabetes in the Young (TEDDY), longitudinal FE-1 was measured in two cohorts: Cohort A (n=122; 19 samples/subject) who progressed to Stage 3 T1D by age 4, and Cohort B (n=104; 23 samples/subject) who developed Stage 1 T1D by age 4 without dysglycemia by age 6, each with matched controls. FE-1 was compared cross-sectionally at baseline (median age 4 months), Stage 1, and Stage 3 using conditional logistic regression and paired Wilcoxon tests. Linear mixed models assessed log-transformed FE-1 trajectories over time, centered at Stage 1 onset (both cohorts) and Stage 3 onset (Cohort A), adjusting for age, sex, site, and HLA. ROC analyses evaluated absolute and rate of FE-1 decline at Stage 1 as predictors of Stage 3 progression. Results: Cohort A cases had lower FE-1 than controls at baseline (1241 vs 1586 μg/g, p=0.004), Stage 1 (944 vs 1238 μg/g, p=0.006), and Stage 3 (533 vs 1383 μg/g, p<0.001), while Cohort B showed no case-control differences. FE-1 declined prior to Stage 1 and 3 in Cohort A (β=-0.0006, p<0.001) and Stage 1 in Cohort B (β=-0.0003, p=0.001), with a steeper decline in Cohort A (p<0.001). GAD-first autoimmunity was associated with greater FE-1 decline than MIAA-first prior to Stage 1 in both cohorts and Stage 3 in Cohort A. FE-1 alone demonstrated poor-to-fair discrimination (AUC 0.57-0.62); however, combining FE-1 with first appearing autoantibody improved prediction of Stage 3 progression (AUC 0.71 vs 0.64 with first autoantibody alone). Conclusion: Early and progressive FE-1 decline identifies children at risk for early progression to clinical T1D and supports integration of exocrine biomarkers into prevention-stage risk stratification. Disclosure B.S. Bruggeman: Research Support; Current; GentiBio. K. Morneault-Gill: None. C. Wasserfall: None. H. Gao: None. M. Guyot: None. C.E. Forsmark: Consultant; Current; AbbVie Inc., Nestlé Health Science. D. Schatz: Research Support; Current; Immune Tolerance Network. Consultant; Current; Kriya Therapeutics. Research Support; Current; National Institute of Diabetes and Digestive and Kidney Diseases. Consultant; Current; Biomea, Amarna. Advisory Panel; Current; PoITREG. J. Krischer: None. M.L. Campbell-Thompson: None. M.J. Haller: Advisory Panel; Current; MannKind Corporation, Sanofi, SAB Biotherapeutics, Inc. Funding National Institutes of Health (R03DK129971, K23DK131363)