Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development
Abstract
Type 1 diabetes (T1D) affects millions worldwide, yet few non-invasive biomarkers detect immune-mediated {beta}-cell dysfunction during the presymptomatic phase, a critical window for therapeutic intervention. Previously, we identified reduced double C2-like domain containing beta protein (DOC2B) levels in circulating platelets as a marker of reduced {beta}-cell function in early-onset T1D cohorts and nonobese diabetic (NOD) mice. Here, we assessed whether plasma DOC2B could serve as a sensitive early biomarker of T1D progression risk in the autoantibody-positive pediatric cohort (progressors vs non-progressors) from the longitudinal Diabetes Evaluation in Washington (DEW-IT) study; T1D patients and non-diabetic cohorts from the DEW-IT study served as controls. At pre-onset, progressors showed a decline in DOC2B that preceded measurable changes in random C-peptide and HbA1c levels, while non-progressors maintained stable levels. These observations were further supported by our analysis in prediabetic NOD mice. Comparisons of plasma levels pre- and post-clinical islet transplantation in long-standing T1D patients highlights its potential utility as a reporter of {beta}-cell functional mass. Together, these findings suggest that DOC2B decline may precede C-peptide decline in early presymptomatic T1D progression. This work could have significant future implications for clinical trial stratification and assessing response outcomes to disease-modifying or cell replacement therapies.
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D., E., E., O., J., H., D., C. B., M., M. E., J., H., F., K., H., R., W., H., T., J., C., T. D. (2025). Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development. arXiv preprint arXiv:10.64898/2025.12.28.696610.
Esparza, D., Oh, E., Hwang, J., Chatterjee Bhowmick, D., McCown, E. M., Hacker-Stratton, J., Kandeel, F., Reijonen, H., Hagopian, W., Jovanovic-Talisman, T., and Thurmond, D. C.. "Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development." arXiv preprint arXiv:10.64898/2025.12.28.696610 (2025).