2666-P: Multimodal Analysis of Pancreas from Donors with Islet Autoantibodies in Human Pancreas Analysis Program-Type 2 Diabetes (HPAP-T2D)

Introduction and Objective: Some individuals with T2D have islet autoantibodies (aab). To determine if the presence of autoantibodies represents a form of islet-directed autoimmunity, we integrated and compared serologic, functional, genetic, and histologic data from HPAP-T2D donors with (T2Daab+, n=6) or without (T2Daab-, n=47) aab, and donors with no diabetes (ND, N=96). Methods: Donor clinical and demographic data, islet perifusion results, genetic risk scores (GRS), and multiplex immunofluorescent images (CODEX) are available on the HPAP website, PancDB. Immunofluorescent images were quantified using AI-assisted segmentation and classification algorithms in QuPath software. Statistical significance (p0.05) was tested by ANOVA. Results: Compared to ND donors, T2D donors had higher BMI and T2D-GRS, lower residual C-peptide, but no difference in relative pancreas weight (RPW). Compared to T2Daab-, T2Daab+ (4 GADA+, 2 IA2+) individuals were similar in age, BMI, disease duration, T1D-GRS, and T2D-GRS. T2Daab+ individuals had reduced islet function, with lower C-peptide levels (1.2±0.3 vs 3.7±0.5 ng/mL, p=0.001), lower glucose-stimulated insulin release from isolated islets (1.2±0.1 vs 1.6±0.2 stimulation index, p=0.07), and higher HbA1c (8.8±0.5 vs 7.4±0.3 %, p=0.03) than T2Daab-. RPW of T2Daab+ individuals was intermediate between T2Daab- and HPAP-T1D donors (0.86±0.08 vs 1.03±0.07 vs 0.68±0.04 g/kg, p=0.001). In pancreatic sections, the T cell/islet cell ratio was higher in T2Daab+ than in ND controls (0.38±0.09 vs 0.11±0.02; p=0.03), but was not different between T2Daab- and controls. Sections from one of six T2Daab+ donors was amyloid positive, compared to 24/41 T2Daab-donors being amyloid positive. Conclusion: Among T2D donors, the presence of islet autoantibodies was associated with histologic evidence of latent autoimmunity, reduced islet function, and decreased pancreas size, suggesting that autoimmune processes play a role in their diabetes. Disclosure M.M. Wimalarathne: None. A. Eskaros: None. S. Spearman: None. F. Feng: None. A.L. Hopkirk: None. K.S. Lee: None. P.B. Jackson: None. J. Haynes: None. R. Jenkins: None. R.A. Brantley: None. A. Pandey: None. S.A. Sharp: None. H. Sun: None. E. Manduchi: None. R. O’Flynn: None. N.M. Doliba: None. J. Cartailler: None. S. Shapira: None. C. Dai: None. P. Wilson: None. D.C. Saunders: None. M. Brissova: None. A.L. Gloyn: Speaker's Bureau; Ended; Novo Nordisk. Other - Spouse is an employee and holds stock options in Roche; Current; Genentech, Inc. A. Naji: None. K. Kaestner: None. A.C. Powers: None. J. Wright: None. Funding National Institutes of Health (DK112217, DK123594, DK123716, DK112232), Veterans Administration (BX005910, BX000666)