Characterization of age-associated alterations of islet function and structure in diabetic mutant cryptochrome 1 transgenic mice
Article first published online: 26 APR 2013
© 2013 Asian Association for the Study of Diabetes and Wiley Publishing Asia Pty Ltd
Journal of Diabetes Investigation
Volume 4, Issue 5, pages 428–435, September 2013
How to Cite
(J Diabetes Invest, doi: 10.1111/jdi.12080, 2013)
- Issue published online: 13 SEP 2013
- Article first published online: 26 APR 2013
- Manuscript Accepted: 12 FEB 2013
- Manuscript Revised: 10 FEB 2013
- Manuscript Received: 21 AUG 2012
- Grants-in-Aid. Grant Numbers: 21590429, 24590473
Vol. 4, Issue 6, 681, Article first published online: 27 NOV 2013
- Insulin secretion;
- Islet architecture;
In earlier reports, we described that transgenic (Tg) mice ubiquitously expressing cryptochrome1 (CRY1) with a mutation in cysteine414 (CRY1-AP Tg 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 CRY1 is involved, we examined age-dependent characteristics of islets of CRY1-AP Tg 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.
Already at a young stage, the proliferation of β-cells was reduced in CRY1-AP Tg mice. Insulin contents and the levels of glucose-stimulated insulin secretion were lower than those of wild-type controls in CRY1-AP Tg 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 CRY1-AP Tg mice.
Architectural abnormality in islets progressed with age in CRY1-AP Tg 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 CRY1-AP Tg mice. Our results suggest that CRY1 is crucial for the maintenance of β-cell function.