Characterization of age‐associated alterations of islet function and structure in diabetic mutant cryptochrome 1 transgenic mice

Abstract Aims/Introduction In earlier reports, we described that transgenic ( T g) mice ubiquitously expressing cryptochrome1 ( CRY 1) with a mutation in cysteine414 ( CRY 1‐ AP   T g mice) show an early‐onset insulin‐secretory defect of diabetes mellitus resembling human maturity‐onset diabetes of the young ( MODY ). To clarify the yet undiscovered molecular pathogenesis of diabetes mellitus in which the mutant of CRY 1 is involved, we examined age‐dependent characteristics of islets of CRY 1‐ AP   T g mice. Materials and Methods Immunohistochemical analyses of islets were carried out for 2‐, 4‐ and 19‐week‐old mice. Insulin contents in the pancreas and glucose‐stimulated insulin secretion of isolated islets of mice were measured at 4 weeks. Real‐time polymerase chain reaction analyses using pancreases of mice at 4 and 21 weeks‐of‐age were carried out. Results Already at a young stage, the proliferation of β‐cells was reduced in CRY 1‐ AP   T g mice. Insulin contents and the levels of glucose‐stimulated insulin secretion were lower than those of wild‐type controls in CRY 1‐ AP   T g mice at the young stage. The expression of insulin and glucose‐sensing genes was reduced at the young stage. At the mature stage, altered distribution and hyperplasia of α‐cells were observed in the islets of CRY 1‐ AP   T g mice. Conclusions Architectural abnormality in islets progressed with age in CRY 1‐ AP   T g mice. The reduced expression of insulin and glucose‐sensing genes, along with the lowered proliferation of β‐cells from an early stage, is a possible primary cause of early‐onset insulin‐secretory defect in CRY 1‐ AP   T g mice. Our results suggest that CRY 1 is crucial for the maintenance of β‐cell function.