Reactive oxygen intermediates (ROI) may be involved in the destruction of pancreatic beta-cells during the development of insulin-dependent diabetes mellitus (IDDM). To investigate the possible role of lysosomes in this process, normal mouse beta-cells were cultured as monolayers at D-glucose concentrations of 1.6 (pronounced crinophagy), 11 or 28 mM (minimal crinophagy), subjected to a low level of oxidative stress and returned to standard culture conditions. Some cultures were exposed to desferrioxamine (Des) before the oxidative stress. As a result of such stress, many of the cells' lysosomes ruptured with consequent apoptosis or necrosis. Cells kept at 1.6 mM glucose were rich in secretory granules, showed crinophagy/autophagy, were very sensitive to oxidative stress, and had the least stable lysosomes. Cells kept at 28 mM glucose did not show crinophagy, contained fewer secretory granules, were less sensitive to oxidative stress, and had more stable lysosomes. Des-treated cells behaved almost as cells not exposed to oxidative stress at all. The findings suggest that iron may occur together with zinc within the secretory granules and that it sensitizes crinophagic lysosomes to oxidative stress. The stress that was applied in this study may be comparable to what occurs within the vicinity of activated macrophages during autoimmune insulitis.