Amelioration of the beta-cell dysfunction in diabetic APA hamsters by antioxidants and AGE inhibitor treatments.

Background: In our recent report, probucol treatment ameliorated glucose intolerance and increased the insulin-positive area in the pancreas of streptozotocin (SZ)-induced diabetic APA hamsters. The data suggested that the beneficial effects of probucol treatment on beta-cell function might result from its additive effect as an antioxidant. Here, we examined the antioxidant effects on the beta-cell function in SZ-induced diabetic APA hamsters treated with three different agents, N-acetyl-L-cysteine (NAC), aminoguanidine (AG) and pyridoxamine (PM).

Methods: The control (CB group) and diabetic (SZ group) hamsters were treated with NAC, AG or PM for four weeks from several days after SZ injection.

Results: Non-fasting plasma glucose and glycoalbumin levels were significantly reduced in SZ animals by NAC or PM treatment. Glucose tolerance test revealed that fasting plasma glucose levels of SZNAC and SZPM animals were low, similar to the corresponding control animals. Thirty minutes after glucose injection, amelioration in the plasma glucose levels of SZNAC and SZPM animals was observed. Immunohistochemistry revealed that the pancreata of SZNAC, SZAG and SZPM animals showed significantly higher percentages of insulin-positive area than those of non-treated SZ animals. The plasma 8OHdG and malondialdehyde plus 4-hydroxy-2-nonenal (4HNE) levels were significantly decreased especially in SZNAC and SZPM animals. 4HNE-positive cells stained by anti-4HNE antibody were reduced in the islets of each agent-treated animal. SZNAC and SZPM animals showed significantly increased beta-cell proliferation determined by insulin and BrdU double staining. All SZ groups treated with NAC, AG or PM had the high expression levels of Reg and INGAP, which are known to be expressed in regenerating islets.

Conclusions: These data suggest that NAC and PM treatment of SZ-injected diabetic hamsters reduces oxidative stress and restores beta-cell function, but that AG treatment has little beneficial effect on the diabetic conditions of SZ-injected hamsters.