REPAIR OF PANCREATIC BETA-CELLS - A RELEVANT PHENOMENON IN EARLY IDDM

Most studies dealing with the pathogenesis of IDDM have emphasized the immune assault against beta-cells. In this perspective, we review the data that suggest that the beta-cell destruction of IDDM depends on a balance between beta-cell damage and repair. The progressive beta-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 beta-cell function, appear to recover beta-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 beta-cells are indeed able to repair themselves after damage. Dispersed beta-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 beta-cells. Note that beta-cell repair after exposure to different toxic agents can be enhanced both in vivo and in vitro. Potential enhancers of beta-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 beta-cells. Some of the beta-cell responses to injury include expression of heat shock proteins 32,000, 65,000, 70,000, and 90,000 M(r) 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 beta-cells against the deleterious effects of this cytokine. The findings mentioned above suggest that repair mechanisms activated after beta-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 beta-cell repair may contribute to the development of early preventive therapy for IDDM.