Poly (ADP-ribose) transferase/polymerase-1-deficient mice resistant to age-dependent decrease in ß-cell proliferation.

Basal and adaptive ß-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 ß-cell death, regeneration and insulin secretion. We analyzed the capacity of ß-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 ß-cell regeneration and the underlying mechanism. Before STZ administration, young WT and PARP-1⁻/⁻ mice showed similar ß-cell proliferation. By contrast, old WT but not old PARP-1⁻/⁻ mice showed severely restricted ß-cell proliferation. In further assessment of the adaptive ß-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 ß-cell proliferation, with few changes in old WT mice. Surprisingly, adaptive ß-cell proliferation capacity was significantly higher in old PARP-1⁻/⁻ mice than old WT mice after STZ administration. The ability of ß-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 ß-cell regeneration with advancing age in mice.