Reduction of oxidative stress by a new low-molecular-weight antioxidant improves metabolic alterations in a non-obese mouse diabetes model

OBJECTIVES: We have previously established a nonobese diabetes mouse model characterized by moderate hyperglycemic levels, like those usually occurring in human type 2 diabetes. As oxidative stress is considered a major mechanism of progressive beta-cell damage in diabetes, we tested in this model the protective effects of a new low-molecular-weight antioxidant, namely, bis(1-hydroxy-2,2,6,6-tetramethyl-4-piperidinyl)decandioate dihydrochloride (IAC). METHODS: Diabetes was induced in C57Bl/6J mice by streptozotocin (STZ) and nicotinamide (NA) administration. Two weeks later, STZ-NA mice were treated for 5 weeks with different doses of IAC (15 or 30 mg/kg per day intraperitoneally) and monitored for glycemia, insulinemia, glucose tolerance, and pancreatic insulin content. RESULTS: Streptozotocin-NA mice showed moderate hyperglycemia, hypoinsulinemia, glucose intolerance, growth impairment, and markedly reduced pancreatic insulin content (22% of controls). IAC-treated STZ-NA mice showed clear-cut reduction of hyperglycemia and attenuation of glucose intolerance, associated to higher residual pancreatic insulin content with respect to untreated diabetic animals. Plasma nitrotyrosine levels (an index of oxidative stress), enhanced 3-fold in diabetic mice, were significantly reduced by IAC treatment. Significant correlations were found between plasma nitrotyrosine values and either blood glucose levels or pancreatic insulin content. CONCLUSIONS: In the STZ-NA diabetic mouse model, the new antioxidant, IAC, improves diabetic metabolic alterations, likely by counteracting beta-cell dysfunction and loss associated with oxidative stress.