In 1981, we proposed that maintenance of the cellular NAD+ level in pancreatic β-cells of the islets of Langerhans is essential for the synthesis and secretion of insulin and for the repair of β-cell injuries, and presented a unifying model for β-cell damage and its prevention, in which poly(ADP-ribose) synthetase/polymerase (PARP) activation plays an essential role in the depletion of NAD+. 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 β-cell replication via the Reg receptor and ameliorates experimental diabetes. Recently, we showed that PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex by the stimulation with IL-6 and dexamethasone. The formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors stabilize the complex formation for Reg gene transcription. In 1993, we found that cyclic ADP-ribose (cADPR), a metabolite of 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 death, induce β-cell replication, and maintain the insulin secretion.
|Journal||Folia Pharmacologica Japonica|
|Issue number||SUPPL. 1|
|Publication status||Published - 2001|
- Cyclic ADP-ribose
- Poly(ADP-ribose) synthetase/polymerase (PARP)
- Reg gene
ASJC Scopus subject areas