<p>This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.</p> <p>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<sup>+</sup>,
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 <italic>Reg</italic> (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 <italic> Reg</italic> 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<sup>+</sup>, is a second messenger for
intracellular Ca<sup>+</sup> mobilization for insulin secretion
by glucose, and proposed a novel mechanism
of insulin secretion, the CD38-cADPR signal
system.</p> <p>
Therefore, PARP inhibitors prevent β-cell
necrosis, induce β-cell replication and maintain
insulin secretion. </p> <p> 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.</p>
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Int J Exp Diabetes Res. 2002; 3(2):79-96