Amelioration Of Multiple Low Doses Of Streptozotocin Induced Diabetes By Inhibition Of Aldose Reductase

TypeⅠdiabetes mellitus is an islet-specific autoimmune disease resulting from the specific destruction of insulin-producing pancreaticβ-cells,culminating in a state of hypoinsulinemia and hyperglycemia.Inhibition of aldose reductase have been shown to modulate a number of immune functions,including suppression of nuclear factor-κB mediated transcription in lipopolysaccharide treated cells of macrophage, and further reduction of the production of interleukin -1 and tumor necrosis factor-α. The aim of this study was to determine the effect of inhibition of aldose reductase on type 1 diabetes mellitus.Administration of multiple low doses of streptozotocin(40 mg/kg intraperitoneally for 5 consecutive days) to mice resulted in phenotypes similar to that of typeⅠdiabetes mellitus.Together with the injection of streptozotocin,mice were co-treated with inhibitor of aldose reductase(50 mg/kg/day) or not for 10 days. Blood glucose level was assayed periodically.Serum insulin level was determined at the end of experiment using insulin Enzyme-linked immunosorbent assay kit.Western blot was performed with serum samples to determinded the antibodies level in serum. Aldehyde fuchsin staining and hematoxylin and eosin staining were used for histopathological examination of pancreas.20 days after the initiation of streptozotocin treatment,mice receiving both streptozotocin and inhibitor of aldose reductase treatments had significant lower blood glucose levels than the streptozotocin treated but inhibitor of aldose reductase untreated mice.At the end of experiment,the serum insulin level for inhibitor of aldose reductase and streptozotocin co-treated mice was almost 2 folds as much as that of the streptozotocin treated but inhibitor of aldose reductase untreated group.The total antibodies in serum for inhibitor of aldose reductase and streptozotocin co-treated mice were greatly reduced than that of the streptozotocin treated but inhibitor of aldose reductase untreated group.Pancreatic hematoxylin and eosin staining and aldehyde fuchsin staining showed that multiple low doses of streptozotocin treatment caused significant pancreatitis,islets atrophy,and significant reduction of the number of pancreaticβ-cells.These histological lesions,however,was significantly alleviated by inhibitor of aldose reductase treatment.We further investigated the effect of inhibition of aldose reductase on the immune response of mouse peritoneal macrophage.Mouse peritoneal macrophage was isolation from wild type mice and aldose reductase knockout type mice. Lipopolysaccharide was added to stimulate mouse peritoneal macrophage to increase its immune response.Neutral red test and reverse transcription-polymerase chain reaction for tumor necrosis factor-αwere done to value the immune ability of macrophage.Both of inhibitor of aldose reductase treatment and knockout of aldose reductase can decrease the lipopolysaccharide stimulated increase of tumor necrosis factor-αmRNA level and also the phagocytosis of macrophage.Our results indicate that inhibition of aldose reductase may ameliorate multiple low doses of streptozotocin induced diabetes through suppressing immune response.