Small things matter: Lack of extra-islet beta cells in Type 1 diabetes

Murrall, K.; Luckett, T.; Lekka, C.; Flaxman, C. S.; Wyatt, R.; Akhbari, P.; Kusmartseva, I.; Hunter, S. L.; Leete, P.; Burn, I.; Osokina, E.; EXE-T1D Consortium,; Shaw, J. A. M.; Morgan, N. G.; Richardson, S. J.

doi:10.1101/2025.04.11.648319

bioRxiv · 10.1101/2025.04.11.648319

Small things matter: Lack of extra-islet beta cells in Type 1 diabetes

Murrall, K.·Luckett, T.·Lekka, C.·Flaxman, C. S.·Wyatt, R.·Akhbari, P.·Kusmartseva, I.·Hunter, S. L.·Leete, P.·Burn, I.·Osokina, E.·EXE-T1D Consortium,·Shaw, J. A. M.·Morgan, N. G.·Richardson, S. J.

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Abstract

Recent 3D analyses reported abundant, small beta-cell-rich endocrine objects (EOs) in the human pancreas. Here, we assessed morphological parameters of >262,000 EOs in pancreas sections from 220 donors with or without type 1 diabetes (T1D), ranging in age and disease duration. We observe many insulin (Ins)+/glucagon (Gluc)-EOs in donors without diabetes. Their relative contribution to the total endocrine area is greatest in early life (0-2y) but reduces thereafter. Strikingly, we show the virtual absence of Ins+Gluc- EOs in individuals with T1D, where only the medium and large EOs retain beta cells. We also report a lower EO density in T1D, especially in individuals diagnosed in early life. These findings suggest that extra-islet beta cells are impacted in the development of T1D, and their early loss is a characteristic feature. This new understanding has important implications for defining beta-cell mass, which may inform future screening and treatment strategies in T1D. HighlightsO_LIThe present extensive 2D studies confirm and extend recent 3D analyses of human pancreata, demonstrating that 50% of endocrine objects (EOs) are much smaller than classical islets of Langerhans and consist predominantly of beta cells (Ins+). C_LIO_LISmall insulin+ EOs comprise the largest proportion of the total endocrine area in early childhood and persist throughout the life course in donors without diabetes. C_LIO_LIThere is a shift towards larger EO size with increasing age, with the most pronounced changes in size occurring in the first few years of life. C_LIO_LISmall Ins+ EOs are virtually absent in individuals with type 1 diabetes, while the persisting EOs with beta cells are larger, suggesting a selective destruction of beta cells in small EOs. C_LIO_LIDevelopment of type 1 diabetes, particularly at an early age, is associated with fewer larger EOs in adulthood. This implies that the lack or early destruction of small Ins+ EOs may be detrimental to the generation of larger EOs. C_LI

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Murrall, K., Luckett, T., Lekka, C., Flaxman, C. S., Wyatt, R., Akhbari, P., Kusmartseva, I., Hunter, S. L., Leete, P., Burn, I., Osokina, E., EXE-T1D Consortium,, Shaw, J. A. M., Morgan, N. G., Richardson, S. J.. 2025-04-17. Small things matter: Lack of extra-islet beta cells in Type 1 diabetes. https://doi.org/10.1101/2025.04.11.648319

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