Poly (ADP-Ribose) Transferase/Polymerase-1-Deficient Mice Resistant to Age-Dependent Decrease in β-Cell Proliferation

Abstract

Basal and adaptive β-cell regeneration capacity declines with old age, but the underlying molecular mechanisms remain incompletely understood. Poly (adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP-1) is considered a multifunctional enzyme and transcription factor that regulates pancreatic β-cell death, regeneration and insulin secretion. We analyzed the capacity of β-cell regeneration in 2-month-old (young) and 12-month-old (old) wild-type (WT) and PARP-1^−/− mice before and after low-dose streptozotocin (STZ), a stimulus of β-cell regeneration and the underlying mechanism. Before STZ administration, young WT and PARP-1^−/− mice showed similar β-cell proliferation. By contrast, old WT but not old PARP-1^−/− mice showed severely restricted β-cell proliferation. In further assessment of the adaptive β-cell regeneration capacity with age, we observed that with a single low dose of STZ, young WT and PARP-1^−/− mice showed a similar increase in β-cell proliferation, with few changes in old WT mice. Surprisingly, adaptive β-cell proliferation capacity was significantly higher in old PARP-1^−/− mice than old WT mice after STZ administration. The ability of β-cell mass to expand was associated with increased levels of the regenerating (Reg) genes RegI and RegII but not RegIV. Therefore, PARP-1 is a key regulator in β-cell regeneration with advancing age in mice.