Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development

Esparza, D.; Oh, E.; Hwang, J.; Chatterjee Bhowmick, D.; McCown, E. M.; Hacker-Stratton, J.; Kandeel, F.; Reijonen, H.; Hagopian, W.; Jovanovic-Talisman, T.; Thurmond, D. C.

doi:10.64898/2025.12.28.696610

bioRxiv · 10.64898/2025.12.28.696610

Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development

Esparza, D.·Oh, E.·Hwang, J.·Chatterjee Bhowmick, D.·McCown, E. M.·Hacker-Stratton, J.·Kandeel, F.·Reijonen, H.·Hagopian, W.·Jovanovic-Talisman, T.·Thurmond, D. C.

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Abstract

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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Esparza, D., Oh, E., Hwang, J., Chatterjee Bhowmick, D., McCown, E. M., Hacker-Stratton, J., Kandeel, F., Reijonen, H., Hagopian, W., Jovanovic-Talisman, T., Thurmond, D. C.. 2025-12-29. Loss of Exocytosis Protein DOC2B is an Early Event in Type 1 Diabetes Development. https://doi.org/10.64898/2025.12.28.696610

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