Enhanced alloxan-induced beta-cell damage and delayed recovery from hyperglycemia in mice lacking extracellular-superoxide dismutase

Alloxan is a diabetogenic agent which apparently acts through formation of superoxide radicals formed by redox cycling. Superoxide radicals are also f ormed by a variety of mechanisms in hyperglycemia. We exposed extracellular -superoxide dismutase (EC-SOD) null mutant and wild-type mice to alloxan, a nd followed up both the initial diabetes induction and the long-term course of the hyperglycemia. The null mutant mice responded with a modestly enhan ced hyperglycemia compared to the wild type controls. In the long-term foll ow-up all mice eventually regained glycemic control, although it took longe r for individuals with higher initial hyperglycemia. This delaying effect o f the hyperglycemia was much more pronounced in the null mutant mice. These data suggest that the difference in initial diabetes induction between the groups is due to interception by EC-SOD of extracellular superoxide radica ls produced by alloxan. The delayed recovery in the null mutant mice sugges ts that superoxide radicals released as a result of hyperglycemia impair be ta-cell regeneration and that EC-SOD provides some protection. Mouse islets were found to contain Little EC-SOD, whereas the content of the cytosolic Cu- and Zn-containing SOD was very high. This low EC-SOD activity may contr ibute to the high alloxan susceptibility of beta-cells, and may also cause a high susceptibility to superoxide radicals produced by activated inflamma tory leukocytes and in hyperglycemia. (C) 1999 Elsevier Science Inc.