Recent advances in physiological and pathological significance of NAD+ metabolites: roles of poly(ADP-ribose) and cyclic ADP-ribose in insulin secretion and diabetogenesis.
Poly(ADP-ribose) synthetase/polymerase (PARP) activation causes NAD+ depletion in pancreatic beta-cells, which results in necrotic cell death. On the other hand, ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase (CD38) synthesizes cyclic ADP-ribose from NAD+, which acts as a second messenger, mobilizing intracellular Ca2+ for insulin secretion in response to glucose in beta-cells. PARP also acts as a regenerating gene (Reg) transcription factor to induce beta-cell regeneration. This provides the new concept that NAD+ metabolism can control the cellular function through gene expression. Clinically, PARP could be one of the most important therapeutic targets; PARP inhibitors prevent cell death, maintain the formation of a second messenger, cyclic ADP-ribose, to achieve cell function, and keep PARP functional as a transcription factor for cell regeneration.
Okamoto
Hiroshi
H
Department of Biochemistry and Advanced Biological Sciences for Regeneration (Kotobiken Medical Laboratories) Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan. okamotoh@mail.tains.tohoku.ac.jp
Takasawa
Shin
S