Transient Oxidative Stress Damages Mitochondrial Machinery Inducing Persistent β-Cell Dysfunction

Transient exposure of beta-cells to oxidative stress interrupts the transduction of signals normally coupling glucose metabolism to insulin secretion. We investigated putative persistence of effects induced by one transient oxidative stress (200 mu M H2O2, 10 min) on insulin secreting cells following recovery periods of days and weeks. Three days after oxidative stress INS-1E cells and rat islets exhibited persistent dysfunction. In particular, the secretory response to 15 mM glucose was reduced by 40% in INS-1E cells stressed 3 days before compared with naive cells. Compared with non-stressed INS-1E cells, we observed reduced oxygen consumption (-43%) and impaired glucose-induced ATP generation (-46%). These parameters correlated with increased mitochondrial reactive oxygen species formation (+60%) accompanied with down-regulation of subunits of the respiratory chain and decreased expression of genes responsible for mitochondrial biogenesis (TFAM, -24%; PGC-1 alpha, -67%). Three weeks after single oxidative stress, both mitochondrial respiration and secretory responses were recovered. Moreover, such recovered INS-1E cells exhibited partial resistance to a second transient oxidative stress and up-regulation of UCP2 (+78%) compared with naive cells. In conclusion, one acute oxidative stress induces beta-cell dysfunction lasting over days, explained by persistent damages in mitochondrial components.