No abstract

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. H2O2 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 H2O2-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 H2O2-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.

Exposure to certain environmental factors during the early stages of development was found to affect health in adulthood. Among other environmental factors, oxidative stress has been suggested to be involved in fetal programming, leading to elevated risk for metabolic disorders, including type 2 diabetes; however, the possibility that antioxidant consumption during early life may affect the development of diabetes has scarcely been studied. The aim of this study was to investigate the effects of N-acetyl-l-cysteine (NAC) given during pregnancy and lactation on the susceptibility of offspring to develop glucose intolerance at adulthood. C57bl6/J mice were given NAC during pregnancy and lactation. High fat diet (HFD) was given to offspring at an age of 6 weeks for an additional 9 weeks, till the end of the study. Isolated islets of NAC-treated offspring (6 weeks old, before HFD feeding) had an increased efficacy of glucose-stimulated insulin secretion and a higher resistance to oxidative damage. Following HFD feeding, glucose tolerance and insulin sensitivity of NAC-treated offspring were improved. In addition, islet diameter was lower in male offspring of NAC-treated mice compared to their HFD-fed littermates. NAC consumption during early life improves glucose tolerance in adulthood in mice.

Oxidative stress is an important factor in the development of type 2 diabetes (T2D) and associated complications. Unfortunately, most clinical studies have failed to provide sufficient evidence regarding the benefits of antioxidants (AOXs) in treating this disease. Based on the known complexity of reactive oxygen species (ROS) functions in both the physiology and pathophysiology of glucose homeostasis, it is suggested that inappropriate dosing leads to the failure of AOXs in T2D treatment. To support this hypothesis, the role of oxidative stress in the pathophysiology of T2D is described, together with a summary of the evidence for the failure of AOXs in the management of diabetes. A comparison of preclinical and clinical studies indicates that suboptimal dosing of AOXs might explain the lack of benefits of AOXs. Conversely, the possibility that glycemic control might be adversely affected by excess AOXs is also considered, based on the role of ROS in insulin signaling. We suggest that AOX therapy should be given in a personalized manner according to the need, which is the presence and severity of oxidative stress. With the development of gold-standard biomarkers for oxidative stress, optimization of AOX therapy may be achieved to maximize the therapeutic potential of these agents.