Combination of selenium and metformin mitigated testicular damage from diabetes mellitus by enhancing glycolysis via AMPK/ SIRT1 pathway.

BACKGROUND: Male reproductive dysfunction, particularly testicular impairment and diminished sperm quality, represents a prevalent yet inadequately addressed complication of type 2 diabetes mellitus (T2DM). Selenium (Se), an essential trace element, is integral to antioxidant defense and male fertility. Its potential synergistic effect with metformin, a first-line antidiabetic drug, in alleviating diabetic testicular lesions has not been fully clarified.

OBJECTIVE: This study investigated the therapeutic efficacy and underlying mechanism of combined selenium and metformin administration against diabetes-induced testicular damage, with a focus on energy metabolism and the AMPK/SIRT1 signaling axis.

METHODS: A murine model of T2DM was established in male C57BL/6 N mice using a high-fat diet combined with streptozotocin (STZ). Diabetic mice were subsequently treated for four weeks with sodium selenite (0.4 mg/kg/d), metformin (200 mg/kg/d), or their combination. Metabolic parameters, semen quality, testicular histology, selenium homeostasis, oxidative stress markers, glycolytic metabolism, and key protein expression were comprehensively analyzed.

RESULTS: Diabetic mice exhibited hyperglycemia, insulin resistance, impaired spermatogenesis, and disrupted testicular architecture. These pathologies were associated with a systemic selenium deficit, elevated oxidative stress, suppressed testicular glycolysis (evidenced by reduced GLUT1/3/8 expression and ATP levels), and inhibition of the AMPK/SIRT1/PGC-1α pathway. Monotherapy with either selenium or metformin provided partial amelioration. Strikingly, the combined treatment most effectively restored systemic and testicular selenium status, normalized redox balance, enhanced glycolytic flux and lactate transporter (MCT4/CD147) regulation, and robustly activated the AMPK/SIRT1 signaling cascade. Consequently, it conferred superior protection against testicular structural damage, spermatogenic failure, and sperm dysfunction.

CONCLUSION: The co-administration of selenium and metformin synergistically alleviates diabetes-induced testicular injury and spermatogenic dysfunction in mice. This protective effect is mechanistically linked to the restoration of selenium-dependent antioxidant capacity and the AMPK/SIRT1 pathway-mediated enhancement of testicular glycolytic metabolism. Our findings propose a novel, combinatory nutritional-pharmacological strategy for managing diabetic male sperm quality and testicular function. The co-administration of selenium and metformin synergistically alleviates diabetes-induced testicular injury and spermatogenic dysfunction in mice. This protective effect is mechanistically associated with the restoration of selenium-dependent antioxidant capacity and the AMPK/SIRT1 pathway-mediated enhancement of testicular glycolytic metabolism. These findings provide preclinical evidence supporting a combinatory nutritional-pharmacological strategy warranting further investigation for managing diabetic male reproductive dysfunction. Clinical translation will require validation in human studies.