Redox-sensitive miRNAs and Humanin could mediate effects of exercise and astaxanthin on oxidative stress and inflammation in type 2 diabetes.

Type 2 diabetes mellitus (T2DM) is driven by oxidative stress (OS) and inflammation (IF), accelerating disease progression. This study examined whether combined aerobic and resistance training (CT) and astaxanthin (AST) supplementation synergistically improve oxidant and inflammatory status as well as metabolic indices in T2DM, focusing on the mediatory role of Humanin (HN) and microRNAs (miRNA-122, miRNA-126-3p, and miRNA-146a). Ninety women with T2DM were randomly assigned to six groups (n = 15 each): control (C), placebo (P), AST supplementation (S), combined training (CT), CT + placebo (CT + P), and CT + AST supplementation (CT + S). CT, CT + P and CT + S groups underwent an 8-week training program (eight exercises, three sessions per week). Groups and CT + S groups received 8 mg/day of AST. OS markers, inflammatory cytokines, HN levels, miRNAs expression, fasting blood glucose (FBG), insulin resistance (HOMA-IR), lipid profile, and hemoglobin A1c (HbA1c) were assessed. Both CT and AST enhanced antioxidant defenses and reduced IF, with CT + S showing the best effects. HN levels increased significantly in CT and CT + S (p < 0.05). MiRNA-126-3p and miRNA-146a were upregulated, while miRNA-122 was downregulated in CT + S compared to other groups. Lipid profile improved with both interventions, with CT + S yielding the highest increases in HDL and triglycerides. FBG, IR, and HbA1c improved significantly in CT groups but remained unchanged with S group. The metabolic and anti-inflammatory benefits of CT and AST in T2DM may mediated by the effects of HN on mitochondrial function and insulin signaling, together with miRNA-mediated regulation of lipid metabolism, endothelial health, and innate immunity. Targeting these molecular pathways may improve therapeutic strategies for diabetes management.