Most studies dealing with the pathogenesis of IDDM have emphasized the immune assault against β-cells. In this perspective, we review the data that suggest that the β-cell destruction of IDDM depends on a balance between β-cell damage and repair. The progressive β-cell damage leading to IDDM seems to follow markedly different temporal courses in individual patients. Some individuals at high risk for developing IDDM, and presenting with impaired β-cell function, appear to recover β-cell function when followed prospectively. Moreover, after the clinical onset of IDDM, most patients experience a transitory period of improved insulin secretion. In vitro and in vivo experimental data suggest that β-cells are indeed able to repair themselves after damage. Dispersed β-cells or whole islets can survive and regain their function after a toxic assault. Furthermore, the abnormal insulin release and glucose oxidation of islets isolated from NOD mice during the prediabetic period is completely restored after 1 wk in tissue culture. Finally, treatment of NOD mice with monoclonal antibodies directed against infiltrating T-cells reverses the altered glucose metabolism of β-cells. Note that β-cell repair after exposure to different toxic agents can be enhanced both in vivo and in vitro. Potential enhancers of β-cell repair are nicotinamide, glucose, protein-rich diets, and branched chain amino acids. A basic question that remains to be answered is the nature of the repair mechanisms triggered by β-cells. Some of the β-cell responses to injury include expression of heat shock proteins 32,000, 65,000, 70,000, and 90,000 Mr, activation of the enzyme poly(ADP-ribose) polymerase, induction of the growth arrest and DNA damage inducible genes 45 and 153, and enhanced manganese superoxide dismutase activity. The heat shock protein 70 is of special interest because it has been shown to be both induced by interleukin-1 and protective of β-cells against the deleterious effects of this cytokine. The findings mentioned above suggest that repair mechanisms activated after β-cell injury are an important component of the IDDM disease process. It is conceivable that a detailed characterization of the cellular and molecular mechanisms involved in β-cell repair may contribute to the development of early preventive therapy for IDDM.

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