Recent Advances in Physiological and Pathological Significance of tryptophan-Nad+Metabolites: lessons from insulin-producing pancreatic ß-Cells

  • Hiroshi Okamoto
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 527)


In the early 1980s we found that streptozotocin and alloxan, typical diabetogenic agents, induce pancreatic 13-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 (3-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 3-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 Ca’ 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.


Insulin Secretion Pancreatic Islet PARP Inhibitor Kynurenic Acid PARP Activation 
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Copyright information

© Springer Science+Business Media New York 2003

Authors and Affiliations

  • Hiroshi Okamoto
    • 1
  1. 1.Department of BiochemistryTohoku University Graduate School of MedicineMiyagiJapan

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