Diminished pancreatic beta-cell mass in securin-null mice is caused by beta-cell apoptosis and senescence.

Pituitary tumor transforming gene encodes a securin protein critical in regulating chromosome separation. mice exhibit pancreatic beta-cell hypoplasia and insulinopenic diabetes. We tested whether deletion causes beta-cell senescence, resulting in diminished beta-cell mass. We examined beta-cell mass, proliferation, apoptosis, neogenesis, cell size, and senescence in and WT mice from embryo to young adulthood before diabetes is evident. The roles of cyclin-dependent kinase inhibitors and DNA damage in the pathogenesis of diabetes in duanyu1547G(-/-) mice were also addressed. Relative beta-cell mass in duanyu1547G(-/-) mice began to decrease at 2-3 wk, whereas beta-cell proliferation rate was initially normal but decreased in duanyu1547G(-/-) mice beginning at 2 months. Apoptosis was also much more evident in duanyu1547G(-/-) mice. At 1 month, beta-cell neogenesis was robust in wild-type mice but was absent in duanyu1547G(-/-) mice. In addition, the size of beta-cells became larger and macronuclei were prominent in duanyu1547G(-/-) animals. Senescence-associated beta-galactosidase was also active in duanyu1547G(-/-) beta-cells at 1 month. Cyclin-dependent kinase inhibitor p21 was progressively up-regulated in duanyu1547G(-/-) islets, and p21 deletion partially rescued duanyu1547G(-/-) mice from development of diabetes. mRNA array showed that DNA damage-associated genes were activated in duanyu1547G(-/-) islets. We conclude that beta-cell apoptosis and senescence contribute to the diminished beta-cell mass in duanyu1547G(-/-) mice, likely secondary to DNA damage. Our results also suggest that ductal progenitor beta-cells are exhausted by excessive neogenesis induced by apoptosis in duanyu1547G(-/-) mice.

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