Complexity of NAC action in the treatment of diabetes: opposing effects of oxidative and reductive stress on insulin secretion and insulin signaling

The involvement of oxidative stress in type 2 diabetes (T2D) pathogenesis is well-known. Unfortunately, most clinical studies failed to prove the benefits of antioxidants in the treatment of this disease.

In our studies we demonstrated the potential and the challenge of antioxidants in T2D treatment. The benefits of antioxidant were observed among pre-diabetic and diabetic mice, treated by N-acetyl cysteine (NAC). However, an inverted U-shape curve was observed in regard to NAC effect on insulin sensitivity. Moreover, NAC impaired insulin signaling in healthy mice, suggesting that in addition to the need to define the minimal dose that neutralize oxidative stress, avoidance of a reductive stress is also required. While the adverse effects of oxidative stress on T2D are established, the potential harms of reductive stress are unclear, and were further investigated by us.

We characterized the effects of oxidant (H₂O₂) and antioxidant (NAC) on different tissues involved in the regulation of blood glucose. Pancreatic islets were vulnerable for the development of oxidative stress, while insulin signaling in adipocytes and myotubes was impaired by NAC, reflecting the development of a reductive stress. Protein S-glutathionylation was reduced in NAC-treated myotubes, with high representation of glycolytic and other energy-metabolizing enzymes, suggesting a mechanism for inhibition of insulin signaling.

These results mirror the role of reactive oxygen species in both the physiology and pathophysiology of glucose homeostasis. The study demonstrated tissue-specific effects of NAC, and emphasizes the need to preserve a delicate redox balance and the challenge of implementing antioxidant therapy in the clinic.