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 β-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 β-cells. PARP also acts as a regenerating gene (Reg) transcription factor to induce β-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.