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.
Highlights
Type 2 diabetes (T2D) is a chronic disease, recognized to be a risk factor for several severe morbidities, such as cardiovascular disease, stroke, neuropathy, nephropathy and retinopathy
Oxidative stress is involved in the pathological processes leading to T2D by the activation of stress signals that attenuate the transmission of insulin signaling [3]
The intimate link between oxidative stress and T2D is well established by a large number of studies [2]
Summary
Type 2 diabetes (T2D) is a chronic disease, recognized to be a risk factor for several severe morbidities, such as cardiovascular disease, stroke, neuropathy, nephropathy and retinopathy. T2D is primarily characterized by insulin resistance, as the disease progresses, the dysfunction and destruction of pancreatic beta cells occur, leading to the deterioration of the ability to maintain glucose and lipids homeostasis. The resulting insulin resistance and beta-cell dysfunction lead to hyperglycemia which, along with accompanying metabolic inflammation, intensify the severity of oxidative stress. This stress worsens the pathology further with the additional deterioration of insulin sensitivity and its secretion. Oxidative stress is developed by the metabolic defects leading to T2D, but it aggravates the defects and contributes to diabetic damages [7]
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