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OBJECTIVE - The role of NOX2-containing NADPH oxidase in the development of diabetes is not fully understood. We hypothesized that NOX2 deficiency decreases reactive oxygen species (ROS) production and immune response and protects against streptozotocin (STZ)-induced β-cell destruction and development of diabetes in mice. RESEARCH DESIGN AND METHODS - Five groups of mice-wild-type (WT), NOX2-/-, WT treated with apocynin, and WT adoptively transferred with NOX2-/- or WT splenocytes - were treated with multiple-low-dose STZ. Blood glucose and insulin levels were monitored, and an intraperitoneal glucose tolerance test was performed. Isolated WT and NOX2-/- pancreatic islets were treated with cytokines for 48 h. RESULTS - Significantly lower blood glucose levels, higher insulin levels, and better glucose tolerance was observed in NOX2-/- mice and in WT mice adoptively transferred with NOX2-/- splenocytes compared with the respective control groups after STZ treatment. Compared with WT, β-cell apoptosis, as determined by TUNEL staining, and insulitis were significantly decreased, whereas β-cell mass was significantly increased in NOX2 -/- mice. In response to cytokine stimulation, ROS production was significantly decreased, and insulin secretion was preserved in NOX2 -/- compared with WT islets. Furthermore, proinflammatory cytokine release induced by concanavalin A was significantly decreased in NOX2 -/- compared with WT splenocytes. CONCLUSIONS - NOX2 deficiency decreases β-cell destruction and preserves islet function in STZ-induced diabetes by reducing ROS production, immune response, and β-cell apoptosis. © 2010 by the American Diabetes Association.