1453-P: Possible Delta- to Beta-Cell Transdifferentiation in Aged Diabetic Mutant CRY1 Transgenic Mice

Cysteine414 (zinc-binding site of mCRY1) -alanine mutant mCRY1 transgenic mice (TG) show diabetes characterized by the reduction of β-cell proliferation due to the characters of senescence-associated secretory phenotype (SASP) in β-cells as we have reported at ADA Scientific Sessions in 2015. We also showed that various structural remodeling progresses in the islets of TG age-dependently: the increase of the population ratios of α-cell to β-cell and of ∂-cell to β-cell as well as fibrillation, angiogenesis and also the generation of mucin-producing atypical intra-islet ducts. Also, we revealed that trefoil factor family 2 (TFF2) is up-regulated in the β-cell of aged TG (Okano S. et al., ADA Scientific Sessions in 2020). To explore the mechanisms of keeping of the amount of β-cells under hyperglycemia for prolonged period in TG, we further conducted detailed double immune-staining experiments in the pancreatic sections of various ages (approximately 1, 10, and 19 months) of TG. The results demonstrated that, somatostatin and insulin double-positive cells were observed exclusively in aged TG (19 months of age). In wild-type mice (WT) of all stages, the double-positive cells were not observed. No glucagon and insulin double-positive cell was observed in islets of both TG and WT of all stages. In addition, scrutinized analyses demonstrated that not only β-cells but also small portion of somatostatin-positive cells express TFF2 in islets of aged TG. Taken together, these results suggest the possible ∂-cell to β-cell transdifferentiation in aged TG, that is, ∂-cells may play some role as the source for β-cells to supply new β-cells for islets in TG.