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 Ca2+ 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.
