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

Abstract

Pituitary tumor transforming gene (PTTG) encodes a securin protein critical in regulating chromosome separation. PTTG-null (PTTG-/-) mice exhibit pancreatic β-cell hypoplasia and insulinopenic diabetes. We tested whether PTTG deletion causes β-cell senescence, resulting in diminished β-cell mass. We examined β-cell mass, proliferation, apoptosis, neogenesis, cell size, and senescence in PTTG-/- 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 PTTG-/- mice were also addressed. Relative β-cell mass in PTTG-/- mice began to decrease at 2-3 wk, whereas β-cell proliferation rate was initially normal but decreased in PTTG-/- mice beginning at 2 months. Apoptosis was also much more evident in PTTG -/- mice. At 1 month, β-cell neogenesis was robust in wild-type mice but was absent in PTTG-/- mice. In addition, the size of β-cells became larger and macronuclei were prominent in PTTG-/- animals. Senescence-associated β-galactosidase was also active in PTTG -/- β-cells at 1 month. Cyclin-dependent kinase inhibitor p21 was progressively up-regulated in PTTG-/- islets, and p21 deletion partially rescued PTTG-/- mice from development of diabetes. mRNA array showed that DNA damage-associated genes were activated in PTTG -/- islets. We conclude that β-cell apoptosis and senescence contribute to the diminished β-cell mass in PTTG-/- mice, likely secondary to DNA damage. Our results also suggest that ductal progenitor β-cells are exhausted by excessive neogenesis induced by apoptosis in PTTG-/- mice. Copyright © 2009 by The Endocrine Society.