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


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 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.


CONCLUSIONS
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.
Research Laboratory for Molecular Genetics Yamagata Japan.
Satoshi
S
Okano
Department of Pediatrics Yamagata University School of Medicine Yamagata Japan.
Kiyoshi
K
Hayasaka
Yamagata City Hospital Saiseikan Yamagata Japan.
Masahiko
M
Igarashi
Research Laboratory for Molecular Genetics Yamagata Japan.
Yoshiyuki
Y
Togashi
Research Laboratory for Molecular Genetics Yamagata Japan.
Osamu
O
Nakajima
Insulin secretion; Islet architecture; β‐Cell