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 formed by a variety of mechanisms in hyperglycemia. We exposed extracellular-superoxide dismutase (EC-SOD) null mutant and wild-type mice to alloxan, and followed up both the initial diabetes induction and the long-term course of the hyperglycemia. The null mutant mice responded with a modestly enhanced hyperglycemia compared to the wild type controls. In the long-term follow-up all mice eventually regained glycemic control, although it took longer for individuals with higher initial hyperglycemia. This delaying effect of 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 radicals produced by alloxan. The delayed recovery in the null mutant mice suggests that superoxide radicals released as a result of hyperglycemia impair beta-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 contribute to the high alloxan susceptibility of beta-cells, and may also cause a high susceptibility to superoxide radicals produced by activated inflammatory leukocytes and in hyperglycemia.
Sentman
M L
ML
Department of Clinical Chemistry, Umeå University, Sweden.
Jonsson
L M
LM
Marklund
S L
SL
D000496:Alloxan / Q000494:pharmacology*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced; D005260:Female; D005609:Free Radicals / Q000378:metabolism; D006943:Hyperglycemia / Q000139:chemically induced*; D007515:Islets of Langerhans / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D013482:Superoxide Dismutase / Q000172:deficiency*; D013481:Superoxides / Q000494:pharmacology
D001786:Blood Glucose; D005609:Free Radicals; D013481:Superoxides; D000496:Alloxan; D013482:Superoxide Dismutase