Comparative Efficacy of Resistance versus Aerobic Training on NRF۲/ARE Axis Modulation and Redox Status Markers in Middle Aged Women with Type ۲ Diabetes: A Systematic Review

Background: Type ۲ diabetes mellitus (T۲DM) is a progressive metabolic disorder characterized by insulin resistance, chronic hyperglycemia, and elevated systemic oxidative stress. The NRF۲/ARE (nuclear factor erythroid ۲‑related factor ۲ / antioxidant response element) pathway serves as a master regulator of cellular antioxidant defense, governing the expression of phase‑II detoxifying and antioxidant enzymes, including glutathione‑S‑transferase and glutathione peroxidase. The reduced‑to‑oxidized glutathione ratio (GSH/GSSG) is a sensitive and reliable indicator of intracellular redox balance. Middle‑aged women are particularly vulnerable to T۲DM complications due to hormonal shifts and age‑related muscle loss (sarcopenia), which exacerbate oxidative damage. Both resistance training (RT) and aerobic training (AT) have been individually suggested to modulate NRF۲ signaling; however, a direct comparative synthesis in this specific population is lacking. This systematic review aims to compare the effects of RT versus AT on serum NRF۲ protein concentration and the GSH/GSSG ratio in middle‑aged women with T۲DM.Methods: This systematic review was conducted following PRISMA guidelines. A comprehensive literature search was performed in PubMed, Scopus, Web of Science, Google Scholar, and SID up to January ۲۰۲۵ using Persian and English keywords, including "resistance training," "aerobic training," "type ۲ diabetes," "middle‑aged women," "NRF۲," "GSH/GSSG ratio," and "oxidative stress." Original clinical trials and quasi‑experimental studies that evaluated the effect of either RT or AT (or directly compared both) on the target variables were included. Study quality was assessed using the PEDro scale.Results: Out of ۴۵۲ initial records, ۱۸ studies met inclusion criteria (۹ RT, ۷ AT, and ۲ head‑to‑head comparative trials). Both RT (۶۰‑۸۰% of ۱RM, ۳ sessions/week) and AT (۵۰‑۷۵% of maximum heart rate, ۳‑۵ sessions/week for ۸‑۱۲ weeks) significantly increased serum NRF۲ levels and improved the GSH/GSSG ratio (P < ۰.۰۵). However, indirect comparisons suggested that RT was more effective in reducing systemic inflammation (lowering IL‑۶ and TNF‑α) and increasing muscle mass, while AT showed a greater impact on enhancing insulin sensitivity and reducing reactive oxygen species (ROS) production derived from chronic hyperglycemia. Mechanistically, both modalities activated PI۳K/Akt and MAPK/ERK pathways in response to mechanical (RT) or metabolic (AT) stress, leading to increased NRF۲ phosphorylation, nuclear translocation, and subsequent upregulation of NRF۲‑dependent antioxidant enzymes. The two comparative studies indicated a potential superiority of combined (RT + AT) training over either modality alone, though this finding requires further confirmation.Conclusion: Both resistance and aerobic training are effective non‑pharmacological strategies for enhancing NRF۲‑mediated antioxidant defense and improving redox balance (GSH/GSSG ratio) in middle‑aged women with T۲DM. The choice between them should be individualized based on patient goals (glycemic control vs. muscle preservation). Preliminary evidence suggests that combined training may offer additive benefits. Future head‑to‑head randomized controlled trials with dose‑response designs are warranted to establish precise exercise prescriptions for this high‑risk population

کلیدواژه ها:

Resistance Training ، Aerobic Training ، Type ۲ Diabetes ، Middle‑Aged Women ، NRF۲ ، GSH/GSSG Ratio ، Oxidative Stress