Department of Molecular Biology, Ariel University, Ariel 4070000, Israel.
Department of Nutritional Studies, Ariel University, Ariel 4070000, Israel.
Int J Mol Sci. 2022 Mar 9;23(6):2965. doi: 10.3390/ijms23062965.
Dysregulated redox balance is involved in the pathogenesis of type 2 diabetes. While the benefit of antioxidants in neutralizing oxidative stress is well characterized, the potential harm of antioxidant-induced reductive stress is unclear. The aim of this study was to investigate the dose-dependent effects of the antioxidant N-acetylcysteine (NAC) on various tissues involved in the regulation of blood glucose and the mechanisms underlying its functions. HO was used as an oxidizing agent in order to compare the outcomes of oxidative and reductive stress on cellular function. Cellular death in pancreatic islets and diminished insulin secretion were facilitated by HO-induced oxidative stress but not by NAC. On the other hand, myotubes and adipocytes were negatively affected by NAC-induced reductive stress, as demonstrated by the impaired transmission of insulin signaling and glucose transport, as opposed to HO-stimulatory action. This was accompanied by redox balance alteration and thiol modifications of proteins. The NAC-induced deterioration of insulin signaling was also observed in healthy mice, while both insulin secretion and insulin signaling were improved in diabetic mice. This study establishes the tissue-specific effects of NAC and the importance of the delicate maintenance of redox balance, emphasizing the challenge of implementing antioxidant therapy in the clinic.
氧化还原平衡失调与 2 型糖尿病的发病机制有关。虽然抗氧化剂在中和氧化应激方面的益处已得到充分证实，但抗氧化剂诱导的还原应激的潜在危害尚不清楚。本研究旨在探讨抗氧化剂 N-乙酰半胱氨酸（NAC）对参与血糖调节的各种组织的剂量依赖性影响及其作用机制。HO 被用作氧化剂，以便比较氧化和还原应激对细胞功能的影响。HO 诱导的氧化应激促进胰岛细胞死亡和胰岛素分泌减少，但 NAC 没有。另一方面，肌管和成脂细胞受到 NAC 诱导的还原应激的负面影响，如胰岛素信号和葡萄糖转运受损，而不是 HO 的刺激作用。这伴随着氧化还原平衡的改变和蛋白质的巯基修饰。NAC 诱导的胰岛素信号恶化也在健康小鼠中观察到，而在糖尿病小鼠中，胰岛素分泌和胰岛素信号均得到改善。本研究确立了 NAC 的组织特异性作用和精细维持氧化还原平衡的重要性，强调了在临床中实施抗氧化治疗的挑战。
