There is growing evidence that reactive oxygen species are responsible for the destruction of the beta cells that occurs in Type I, insulin-dependent diabetes mellitus(IDDM). We have used RIPSOD, a transgenic murine model that overexpresses CuZnSOD exclusively in the pancreas to compare the effects of genetic variation and dietary manipulation on the susceptibility to Type I diabetes. Weanling RIPSOD(homozygotes), RIPSODxCdl (hétérozygotes) and Cd1 (control) mice were fed a complete diet or a copper deficient diet for three weeks, and then injected with I50mg/kg i.p. of alloxan dissolved in saline, or with a saline control. The RIPSOD animals had the lowest increase in fasting blood glucose ranging from 1.7-2.5x saline controls. The RIPSODx Cd1 group increased 2.9 to 3.4 and the Cd1 group increased 3.4-4.0.X over saline controls. The Cu-deficient animals of all three strains showed a trend towards higher fasting blood glucose, but this was not significant. These results suggest that genotype is more important than dietary manipulation in predicting the response to chemically-induced IDDM. (Supported by NSERC, Canada, and JDF International).