Resistance of ALR/Lt islets to free radical-mediated diabetogenic stress is inherited as a dominant trait.

Abstract

ALS/Lt and ALR/Lt are inbred mouse strains selected for susceptibility and resistance to alloxan (AL)-induced diabetes. Within 24-h after AL administration in vivo, ALS/Lt islets were distinguished from ALR/Lt islets by more extensive necrotic changes. Within 7 days post-AL, ALS/Lt mice exhibited hyperglycemia and hypoinsulinemia, whereas ALR/Lt mice maintained normal plasma insulin and glucose levels. We have recently shown that resistance in ALR/Lt correlated with constitutively elevated systemic (and pancreatic) free radical defense status. In the present report, we examined whether ability to detoxify free radical stress extended to the level of ALR/Lt pancreatic islets. Cultured ALS/Lt islets exposed for 5 min to increasing (0-3 mmol/l) AL concentrations in vitro exhibited an 80% decline in numbers of intact islets after a subsequent 6-day culture period, as well as a 75% reduction in islet insulin content and a 94% decrease in glucose-stimulated insulin secretory capacity. In contrast, ALR/Lt islets remained viable and retained glucose-stimulated insulin secretory capacity as well as normal insulin content. This ALR/Lt islet resistance extended to hydrogen peroxide, a free radical generator whose entry into beta-cells is not dependent on glucose transporters. The elevated antioxidant defenses previously found in ALR/Lt pancreas were extended to isolated islets, which exhibited significantly higher glutathione and Cu-Zn superoxide dismutase 1 levels compared with ALS/Lt islets. A dominant genetic trait from ALR/Lt controlling this unusual AL resistance was indicated by the finding that reciprocal F1 mice of both sexes were resistant to AL administration in vivo. A backcross to ALS/Lt showed 1:1 segregation for susceptibility/resistance, indicative of a single gene controlling the phenotype. In conclusion, the ALR/Lt mouse may provide important insight into genetic mechanisms capable of rendering islets strongly resistant to free radical-mediated damage.