Pancreatic β-Cell Death, Regeneration and Insulin Secretion: Roles of Poly(ADP-Ribose) Polymerase and Cyclic ADP-Ribose

In the early 1980s, we proposed a unifying model for β-cell damage (The OKAMOTO model), in which poly(ADP-ribose) synthetase/ polymerase (PARP) activation plays an essential role in the consumption of NAD+, which leads to energy depletion and necrotic cell death. In 1984, we demonstrated that the administration of PARP inhibitors to 90% depancreatized rats induces islet regeneration. From the regenerating islet-derived cDNA library we isolated Reg (Regenerating Gene) and demonstrated that Reg protein induces βcell replication via the Reg receptor and ameliorates experimental diabetes. More recently, we showed that the combined addition of IL-6 and dexamethasone induces the Reg gene expression in β-cells and that PARP inhibitors enhance the expression. In 1993, we found that cyclic ADP-ribose (cADPR), a product synthesized from NAD+, is a second messenger for intracellular Ca+ mobilization for insulin secretion by glucose, and proposed a novel mechanism of insulin secretion, the CD38-cADPR signal system. Therefore, PARP inhibitors prevent β-cell necrosis, induce β-cell replication and maintain insulin secretion. In this paper, we would like to present a perspective view based on our studies concerning cell death, cell regeneration, and cell function, especially on insulin-producing pancreatic βcells, in the processes of which poly(ADPribose) synthetase/polymerase (PARP) and cyclic ADP-ribose (cADPR) are functioning.