Exercise‑Induced Regulation of NRF۲‑Dependent Antioxidant Responses and Redox Homeostasis in Type ۲ Diabetes: Focus on Middle‑Aged Women

Background: Type ۲ diabetes (T۲D) is a chronic metabolic disease characterized by a persistent imbalance between pro‑oxidant production and antioxidant capacity. The transcription factor NRF۲ (nuclear factor erythroid ۲‑related factor ۲) acts as a primary cellular redox sensor that, upon activation, binds to the antioxidant response element (ARE) and upregulates a broad array of cytoprotective genes, including heme oxygenase‑۱, catalase, superoxide dismutase, glutathione peroxidase, and glutathione‑S‑transferase. The GSH/GSSG ratio serves as a functional readout of this pathway's net effect on intracellular redox status. Middle‑aged women experience an accelerated decline in estrogen levels and muscle mass, which further compromises NRF۲ efficiency and exacerbates oxidative injury, making them a critical target population for interventions that restore redox equilibrium. Exercise training, both aerobic and resistance, has been proposed as a mild physiological stressor that triggers adaptive upregulation of the NRF۲/ARE axis. This systematic review aims to elucidate the molecular and physiological mechanisms through which different exercise modalities modulate the NRF۲/ARE pathway and redox indicators, with a special emphasis on middle‑aged women with T۲D.Methods: A systematic search was conducted in PubMed, Scopus, Web of Science, and national databases (SID, Magiran) up to January ۲۰۲۵, using keywords such as "exercise training," "resistance training," "aerobic training," "NRF۲," "ARE pathway," "glutathione," "GSH/GSSG ratio," "oxidative stress," "type ۲ diabetes," and "middle‑aged women." Original human and animal studies that evaluated the effect of at least one form of exercise on NRF۲, GSH, GSSG, or GSH/GSSG ratio in T۲D models were included after quality assessment using STROBE (human) and ARRIVE (animal) checklists.Results: From ۳۸۷ identified records, ۲۴ articles (۲۰ human, ۴ animal) met final inclusion criteria. Key findings were as follows: Aerobic training (moderate‑to‑high intensity, ۵۰‑۷۵% HRmax, ۸‑۱۲ weeks) enhanced NRF۲ phosphorylation and nuclear translocation via PI۳K/Akt activation, resulting in significant increases in GSH (۲۵‑۴۰%) and decreases in GSSG (۱۵‑۳۰%), thereby significantly elevating the GSH/GSSG ratio (P < ۰.۰۵). Resistance training (۶۰‑۸۰% ۱RM, ۳ sessions/week) activated mechanosensitive MAPK/ERK pathways, reduced systemic inflammation (IL‑۶ and TNF‑α), and improved glucose metabolism, leading to reduced ROS production and a concurrent increase in serum NRF۲ protein and GSH/GSSG ratio (P < ۰.۰۵). Studies that directly compared both modalities (n=۳) indicated that combined or high‑intensity interval training might confer synergistic effects, especially in middle‑aged women who require both cardiorespiratory and musculoskeletal benefits. A consistent positive correlation between increased NRF۲ levels and improved GSH/GSSG ratio was reported across all studies, confirming the central role of this pathway in exercise‑induced antioxidant adaptations.Conclusion: Current evidence strongly supports that regular exercise whether aerobic, resistance, or combined effectively activates the NRF۲/ARE axis, thereby restoring redox balance and mitigating oxidative stress in patients with T۲D. This effect is particularly clinically relevant for middle‑aged women, who face an inherent decline in NRF۲ efficacy. Resistance training appears to act primarily through anti‑inflammatory mechanisms, while aerobic training improves insulin sensitivity and reduces metabolic ROS; thus, a combined regimen may offer the most comprehensive protection. Further well‑designed randomized trials with adequate sample sizes, control groups, and consideration of confounding variables (diet, medication) are needed to establish precise, evidence‑based exercise guidelines for this population

کلیدواژه ها:

Exercise Training ، Type ۲ Diabetes ، Middle‑Aged Women ، NRF۲/ARE Pathway ، GSH/GSSG Ratio ، Oxidative Stress ، Antioxidant Adaptation