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Hyperglycemia exerts negative effects on B-cell functions that may involve oxidative stress. This was tested for by investigating effects of D-α-tocopherol (vitamin E), known as a free radical scavenger, on B-cell functions. For in vivo testing, rat pancreatic islets were transplanted syngeneically under the kidney capsule in streptozotocin-induced diabetic rats. Transplanted rats were treated with D-α-tocopherol (40 mg/kg, intraperitoneally injected every other day) or soybean oil for 2 or 6 weeks. Graft-bearing kidneys were then perfused and insulin release was measured after stimulation sequentially with glucose (27 mmol/L) and L-arginine (10 mmol/L). D-α-tocopherol treatment for 2 or 6 weeks failed to restore glucoseinduced insulin secretion, whereas treatment for 2 but not for 6 weeks enhanced basal insulin release (by 24%, p < 0.05) and arginine-induced release (by 79%, p < 0.05). Treatment did not affect graft content of preproinsulin mRNA. The presence of D-α-tocopherol (50 μg/ml) in vitro enhanced glucose (27 mmol/L)-stimulated insulin release from batch-type incubated islets by 33% (p < 0.05). Exposing islets to D-α-tocopherol for 1 day in the presence of 38 mmol/L glucose enhanced glucosestimulated insulin release (by 25%, p < 0.05), L-argininestimulated release (by 37%, p < 0.05) and elevated islet insulin content (by 20%, p < 0.05). These effects of exposure to D-α-tocopherol were lost when the culture period was extended up to 3 weeks. It is concluded that D-α-tocopherol exerts moderate beneficial effects on B-cell functions during short to intermediate length of high glucose exposure. These effects are, however, insufficient to support a major role for oxidative stress behind glucotoxicity toward B cells.