Insulin dependent diabetes mellitus (IDDM) is a multifactorial disease characterized by pancreatic β cell death. Although the cellular mechanisms leading to IDDM remain unknown, free radical (FR) mediated destruction of the β cells may be the central event. Thus, changes in FR defenses should affect the susceptibility to IDDM. We have used a multifactorial approach to manipulate the activity of CuZnSOD, a key FR defense protein and determined susceptibility to IDDM. Activity of CuZnSOD was altered 1) via genetic manipulation with the use of transgenic mice with enhanced CuZnSOD activity (TgHS and RIPSOD) and mice with compromised CuZnSOD (G93A and SOD1-/-) 2) via developmental increases in CuZnSOD activity with age and 3) via dietary manipulation using Zn or Cu deficient diets. IDDM was induced in animals using alloxan (100mg, 150mg & 200mg/kg i.p., saline as control). Fasting blood glucose levels (FBG) were monitored for 1 week. We hypothesize that manipulation of CuZnSOD through these distinct interventions will alter the susceptibility to alloxan-induced diabetes. Strains with enhanced CuZnSOD activity had lower FBG in response to alloxan compared to non-transgenic controls, and mice with compromised CuZnSOD activity had acute sensitivity to alloxan. Increasing age was correlated with increased hepatic and pancreatic CuZnSOD activity, and also reduced alloxan-induced hyperglycemia. Zn deficiency decreased hepatic and pancreatic CuZnSOD activity and caused an increase in FBG. Conversely, Cu deficient diet did not affect CuZnSOD or FBG. Each of the distinct interventions altered the activity of CuZnSOD and affected the susceptibility to alloxan as shown by FBG. These findings provide further evidence that free radicals may be the central event in the etiology of IDDM.