Okamoto model for necrosis and its expansions, CD38-cyclic ADP-ribose signal system for intracellular Ca ²⁺ mobilization and Reg ( Re generating g ene protein)-Reg receptor system for cell regeneration

Abstract

In pancreatic islet cell culture models and animal models, we studied the molecular mechanisms involved in the development of insulin-dependent diabetes. The diabetogenic agents, alloxan and streptozotocin, caused DNA strand breaks, which in turn activated poly(ADP-ribose) polymerase/synthetase (PARP) to deplete NAD ⁺, thereby inhibiting islet β-cell functions such as proinsulin synthesis and ultimately leading to β-cell necrosis. Radical scavengers protected against the formation of DNA strand breaks and inhibition of proinsulin synthesis. Inhibitors of PARP prevented the NAD ⁺ depletion, inhibition of proinsulin synthesis and β-cell death. These findings led to the proposed unifying concept for β-cell damage and its prevention (the Okamoto model). The model met one proof with PARP knockout animals and was further extended by the discovery of cyclic ADP-ribose as the second messenger for Ca ²⁺ mobilization in glucose-induced insulin secretion and by the identification of Reg ( Re generating g ene) for β-cell regeneration. Physiological and pathological events found in pancreatic β-cells have been observed in other cells and tissues.