Pancreatic β-cell death, regeneration and insulin secretion: Roles of poly(ADP-ribose) polymerase and cyclic ADP-ribose

Shin Takasawa, Hiroshi Okamoto

Research output: Contribution to journalReview article

33 Citations (Scopus)

Abstract

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 β-cell 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.

Original languageEnglish
Pages (from-to)79-96
Number of pages18
JournalInternational Journal of Experimental Diabetes Research
Volume3
Issue number2
DOIs
Publication statusPublished - 2002

Keywords

  • Cyclic ADP-ribose
  • Necrosis
  • Poly(ADP-ribose) synthetase/polymerase (PARP)
  • Reg gene
  • The Okamoto model

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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