TY - JOUR
T1 - Recent advances in physiological and pathological significance of tryptophan-NAD+ metabolites
T2 - Lessons from insulin-producing pancreatic β-cells
AU - Okamoto, Hiroshi
PY - 2003
Y1 - 2003
N2 - In the early 1980s we found that streptozotocin and alloxan, typical diabetogenic agents, induce pancreatic β-cell DNA strand breaks through the formation of free radicals. The breaks induce DNA repair involving the activation of poly(ADP-ribose) polymerase (PARP), which uses NAD+ as a substrate. As a result, the intracellular levels of NAD+ fall dramatically. The fall in NAD+ inhibits cellular functions including insulin synthesis and secretion, and thus the β-cell ultimately dies. We subsequently proposed that maintenance of the NAD+ level is essential for the synthesis and secretion of insulin, and presented a unifying model for β-cell damage and its prevention (The Okamoto model), in which PARP activation plays an essential role. Recently, the model was reconfirmed by experiments using PARP knockout mice and has been recognized as providing the basis for necrotic death of various cells and tissues. 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. Recently, various physiological phenomena from animal to plant cells become understandable in terms of this signal system. 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 found a novel β-cell growth factor gene, Reg (Regenerating Gene), and elucidated the mechanism of Reg gene expression in β-cells, in which PARP acts as a transcription factor for Reg gene expression. PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex. The complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance and stabilize the complex formation for Reg gene transcription. Reg protein acts as an autocrine/paracrine growth factor to induce β-cell replication via the Reg receptor and ameliorates experimental diabetes.
AB - In the early 1980s we found that streptozotocin and alloxan, typical diabetogenic agents, induce pancreatic β-cell DNA strand breaks through the formation of free radicals. The breaks induce DNA repair involving the activation of poly(ADP-ribose) polymerase (PARP), which uses NAD+ as a substrate. As a result, the intracellular levels of NAD+ fall dramatically. The fall in NAD+ inhibits cellular functions including insulin synthesis and secretion, and thus the β-cell ultimately dies. We subsequently proposed that maintenance of the NAD+ level is essential for the synthesis and secretion of insulin, and presented a unifying model for β-cell damage and its prevention (The Okamoto model), in which PARP activation plays an essential role. Recently, the model was reconfirmed by experiments using PARP knockout mice and has been recognized as providing the basis for necrotic death of various cells and tissues. 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. Recently, various physiological phenomena from animal to plant cells become understandable in terms of this signal system. 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 found a novel β-cell growth factor gene, Reg (Regenerating Gene), and elucidated the mechanism of Reg gene expression in β-cells, in which PARP acts as a transcription factor for Reg gene expression. PARP bound to the cis-element of Reg promoter and formed the active transcriptional DNA/protein complex. The complex formation was inhibited depending on the autopoly(ADP-ribosyl)ation of PARP in the complex. Thus, PARP inhibitors enhance and stabilize the complex formation for Reg gene transcription. Reg protein acts as an autocrine/paracrine growth factor to induce β-cell replication via the Reg receptor and ameliorates experimental diabetes.
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U2 - 10.1007/978-1-4615-0135-0_28
DO - 10.1007/978-1-4615-0135-0_28
M3 - Article
C2 - 15206738
AN - SCOPUS:1042268014
VL - 527
SP - 243
EP - 252
JO - Advances in Experimental Medicine and Biology
JF - Advances in Experimental Medicine and Biology
SN - 0065-2598
ER -