Prevention of beta cell dysfunction and apoptosis activation in human islets by adenoviral gene transfer of the insulin-like growth factor I

Interleukin-1 beta is a potent pro-inflammatory cytokine that has been show n to inhibit islet beta cell function as well as to activate Fas-mediated a poptosis in a nitric oxide-dependent manner. Furthermore, this cytokine is effective in recruiting lymphocytes that mediate beta cell destruction in I DDM onset. The insulin-like growth factor I (IGF-I) has been shown to block IL-1 beta actions in vitro. We hypothesized that gene transfer of the insu lin-like growth factor I to intact human islets could prevent IL-1 beta -in duced beta cell dysfunction and sensitization to Fas-triggered apoptosis ac tivation. intact human islets were infected with adenoviral vectors encodin g IGF-I as well as beta -galactosidase and enhanced green fluorescent prote in as controls. Adenoviral gene transfer of human IGF-I prevented IL-1 beta -mediated nitric oxide production from human islets in vitro as well as th e suppression of beta cell function as determined by glucose-stimulated ins ulin production. Moreover, IGF-I gene transfer prevented IL-1 beta -induced , Fas-mediated apoptosis. These results suggest that locally produced IGF-I from cultured islets may be beneficial in maintaining beta cell function a nd promoting islet survival before and following islet transplantation as a potential therapy for type I diabetes.