Intensity-Dependent Effects of Interval Training on Brain Mitophagy, Metabolic Signaling Pathways, and Neuroinflammation in a Mouse Model of Type 2 Diabetes

Introduction Type 2 diabetes mellitus impairs brain metabolic and mitochondrial homeostasis, yet the intensity‑dependent neuroprotective effects of exercise remain poorly defined. Objective This study examined the intensity‑dependent effects of interval training on brain mitophagy, metabolic signaling, oxidative stress, and neuroinflammation in a type 2 diabetes model. Methods In this experimental study, 50 male mice were assigned to five groups: 1) Healthy control (HC), 2) Diabetic control (DC), 3) Diabetic + low-intensity interval training (LIIT), 4) Diabetic + moderate-intensity interval training (MIIT), and 5) Diabetic + high-intensity interval training (HIIT) (n = 10 per group). Following the intervention, hippocampal and cortical tissues were analyzed for metabolic signaling markers (AMPK, ULK1, mTOR), mitophagy-related proteins (PINK1, Parkin, LC3 II/I, p62), oxidative stress and antioxidant indices (MDA, SOD, CAT, TAC), pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lipid peroxidation (4-hydroxynonenal; 4-HNE). Statistical analyses were performed with the significance level set at p < 0.05. Results MIIT and HIIT activated AMPK–ULK1 signaling and suppressed mTOR in the hippocampus and cortex, leading to enhanced mitophagy, particularly in the hippocampus. These adaptations were accompanied by improved redox balance, reduced lipid peroxidation, and attenuated neuroinflammation, with effects increasing in an intensity‑dependent manner (LIIT < MIIT < HIIT). Conclusion Interval training induces neuroprotective adaptations in the diabetic brain in an intensity‑dependent manner. Moderate‑ and high‑intensity protocols more effectively activate AMPK‑driven mitophagy, suppress neuroinflammation, and reduce lipid peroxidation than low‑intensity training, highlighting exercise intensity as a key determinant of brain metabolic resilience in type 2 diabetes.