Intra-Islet Duct Formation and Gastric-Type Metaplasia in CRY1 C414A Transgenic Mice: Association with Endocrine Cell Plasticity and α-Cell Localization

Background: Transgenic mice expressing the C414A-mutant cryptochrome 1 (CRY1 C414A) develop diabetes with progressive β-cell senescence and the formation of mucinous intra-islet ductal lesions. These lesions exhibit features resembling metaplasia; however, their molecular basis and the potential involvement of endocrine cells remain unclear. This study aimed to define the metaplasia-like program in intra-islet ducts and to characterize endocrine cell phenotypes in this context. Methods: Gene expression microarrays were analyzed using islets from aged CRY1 C414A transgenic and wild-type mice. Histological analyses included Alcian blue staining, lectin labeling, and immunostaining for markers of mucin production, metaplasia, and endocrine differentiation. Marker expression in intra-islet ductal lesions was evaluated to assess their progression and cellular composition. Results: Transgenic islets exhibited upregulated expression of metaplasia-associated genes, including mucin 6, trefoil factor 2, and gastrokine 3. Intra-islet ducts, particularly smaller lesions, showed strong mucin production and co-expression of metaplasia-related markers. Tuft cell–associated markers were detected in both intra-islet lesions and pancreatic duct glands. In addition, subsets of insulin-positive cells adjacent to lesions exhibited reduced insulin granularity and expression of metaplasia markers, while glucagon-positive cells were prominent in early lesions. Conclusions: Intra-islet ductal lesion formation in CRY1 C414A transgenic mice is associated with activation of a pyloric/SPEM-like metaplastic program and endocrine cell plasticity. These findings provide a framework linking intra-islet duct formation to established metaplastic processes and suggest a potential relationship β-cell dedifferentiation and broader endocrine cell plasticity under chronic islet stress.