Resistance of ALR/Lt islets to free radical-mediated diabetogenic stress is inherited as a dominant trait.
| Autor: | Mathews, Clayton E., Leiter, Edward H., Mathews, C E, Leiter, E H |
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| Předmět: |
ALLOXAN
DIABETES ISLANDS of Langerhans ANIMAL experimentation BLOOD sugar BODY weight COMPARATIVE studies DISEASE susceptibility FREE radicals GENES GENETIC techniques GLUCOSE HETEROCYCLIC compounds HUMAN reproduction IMMUNITY INSULIN RESEARCH methodology MEDICAL cooperation MICE PEROXIDES RESEARCH EVALUATION research GENOTYPES |
| Zdroj: | Diabetes; Nov99, Vol. 48 Issue 11, p2189-2196, 8p, 1 Black and White Photograph, 1 Diagram, 3 Charts, 4 Graphs |
| Abstrakt: | 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. [ABSTRACT FROM AUTHOR] |
| Databáze: | Complementary Index |
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