2382-P: Modelling β-Cell Decline across Preclinical Type 1 Diabetes (T1D)

Introduction and Objective: Quantifying β-cell function in preclinical T1D is essential for understanding progression and intervention design. The Oral Minimal Model (OMM) applied to OGTTs provides a mechanistic estimate of β-cell responsiveness (ɸtotal). We derive stage-specific ɸtotal trajectories, compared to AUC C-peptide, aligned to 4 years before Stage 1 (S1) and Stage 2 (S2) transition, to better characterise β-cell decline. Methods: ɸtotal and AUC C-peptide were derived from 2597 OGTTs in 867 TrialNet Pathway to Prevention/TEDDY participants with a transition event. Generalized Additive Mixed Models adjusted for sex, age, BMI, and participant level random effects modelled trajectories. 2 year progression probability was evaluated using all S1 observations (7152 OGTTs; N=2583). Results: ɸtotal was higher in S1 than S2 (-32.2%, p 0.001), with clearer stage contrast than AUC C-peptide (-2.9% p=0.03). Over the last 4 years of S1, ɸtotal had steady exponential decline (~4.8%/yr, p0.001), undetectable until the final year with AUC C-peptide (Fig 1). In S2, decline was more variable with both measures until the final year of accelerated deterioration. In S1, ɸtotal ≥ 3.8 had 89% negative predictive value for non-progression within 2 years. Conclusion: ɸtotal captures early functional deterioration in S1 T1D compared to AUC C-peptide and provides robust rule-out information for near-term progression, supporting greater sensitivity and statistical power for monitoring and trial design in early-stage T1D. Disclosure A. Carr: None. S. Perazzolo: None. J.A. Hedrick: None. P. Senior: Consultant; Ended; Abbott. Consultant; Current; Dexcom, Inc. Consultant; Ended; GlaxoSmithKline plc. Research Support; Current; Eli Lilly and Company. Consultant; Current; Novo Nordisk, Sana Biotechnology Inc., Sanofi, Vertex Pharmaceuticals Incorporated. Consultant; Ended; Ypsomed AG. H.M. Ismail: None. T. Moran: Other - Data Safety Monitoring Board Member; Ended; Novo Nordisk. Advisory Panel; Ended; Abbott Diabetes. Research Support; Current; Abbott Diabetes. C.M. Dayan: Consultant; Current; Sanofi, SAB Biotherapeutics, Inc., Immunocore, Ltd. Consultant; Ended; Vertex Pharmaceuticals Incorporated. Consultant; Current; Quell. Advisory Panel; Current; Amarna, ArgenX, Amgen Inc. A. Galderisi: Advisory Panel; Current; Sanofi. Advisory Panel; Ended; Novo Nordisk. Advisory Panel; Current; vTv Therapeutics. Funding Breakthrough T1D (3-SRA-2022-1186-S-B, 3-SRA-2023-1422-S-B, 3-SRA-2023-1422-S-B). The Type 1 Diabetes TrialNet Study Group is a clinical trials network currently funded by the National Institutes of Health (NIH) through the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), the National Institute of Allergy and Infectious Diseases (NIAID), and the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), through the cooperative agreements U01 DK060782, U01 DK060916, U01 DK060987, U01 DK061010, U01 DK061016, U01 DK061029, U01 DK061030, U01 DK061034, U01 DK061035, U01 DK061036, U01 DK061037, U01 DK061040, U01 DK061041, U01 DK061042, U01 DK061055, U01 DK061058, U01 DK084565, U01 DK085453, U01 DK085461, U01 DK085463, U01 DK085465, UC4 DK085466, U01 DK085476, U01 DK085499, U01 DK085504, U01 DK085505, U01 DK085509, U01 DK097835, U01 DK103153, U01 DK103180, U01 DK103266, U01 DK103282, U01 DK106984, U01 DK106993, U01 DK106994, U01 DK107013, U01 DK107014, and a contract HHSN267200800019C; the National Center for Research Resources, through Clinical Translational Science Awards UL1 RR024131, UL1 RR024139, UL1 RR024153, UL1 RR024975, UL1 RR024982, UL1 RR025744, UL1 RR025761, UL1 RR025780, UL1 RR029890, UL1 RR031986, UL1 TR001872, and General Clinical Research Center Award M01 RR00400.