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.

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.