N-Acetyl-L-Cysteine inhibits the development of glucose intolerance and hepatic steatosis in diabetes-prone mice

Oxidative stress is associated with different pathological conditions, including glucose intolerance and type 2 diabetes (T2D), however studies had failed to prove the benefits of antioxidants in T2D. Aim: On the assumption that the failure to demonstrate such anti-diabetic effects is a result of sub-optimal or excessive antioxidant dosage, we aimed to clarify the dose-response effect of the antioxidant N-Acetyl-L-Cysteine (NAC) on the progression of T2D in-vivo. Methods: Experiments were conducted on KK-Ay mice and HFD-fed mice given NAC at different concentrations (200-1800 and 60-600 mg/kg/day, respectively). Glucose and insulin tolerance tests were performed and plasma insulin and lipid peroxidation were measured. Insulin signaling pathway was followed in muscle and liver. Hepatic TG accumulation and mRNA expression of genes involved in glucose metabolism were measured. Results: While 600-1800 mg/kg/day NAC all improved glucose tolerance in KK-Ay mice, only the 1200 mg/kg/day treatment increased insulin sensitivity. Hepatic function was not affected, however; microsteatosis rather than macrosteatosis was observed in NAC-treated mice compared to control. Glucose tolerance was improved in NAC-treated HFD-fed mice as well; the best results obtained with a dose of 400 mg NAC/kg/day. This was followed by lower weight gain and hepatic TG. Plasma lipid peroxidation was not correlated with the glucose-lowering effects of NAC in either model. Conclusion: Identification of the optimal dose of NAC and the population that would benefit the most from such intervention is essential in order to apply preventive and/or therapeutic use of NAC and similar agents in the future.