Synergistic effect of glutathione and metformin mitigates testicular apoptosis by ameliorating gonadotropin hormones and gene expression in streptozotocin-induced diabetic male mice

Context Diabetes mellitus (DM) is a metabolic disorder that impairs the body’s ability to regulate blood sugar levels, leading to cellular damage and apoptosis. Metformin (Met) and glutathione (GSH) are key antioxidants that prevent damage to mitochondrial DNA and proteins by modulating oxidative stress in testicular cells. Aims This study assessed concomitant therapy with GSH and Met to mitigate testicular apoptosis in diabetic male mice. Methods Six- to eight-week-old male BALB/c mice were randomly divided into four groups (n = 6): DM control, DM + Met (200 mg/kg), DM + GSH (15 mg/kg), and DM + Met (200 mg/kg) + GSH (15 mg/kg). Diabetes was induced by i.p. injection of 50 mg/kg body weight (BW) streptozotocin for five consecutive days. The DM control group served as a baseline to evaluate the effects of treatments. GSH was administered weekly (i.p.), and Met was administered orally daily for 35 consecutive days. Key results BW and fasting blood glucose levels were monitored on Day 0 and Day 44. The fasting blood glucose levels were reduced (P 0.05, P 0.01, P 0.001) while BW, the number of Bax-positive cells, Bax mRNA expression, and Bax : Bcl-2 ratio were restored in all treatment groups (P 0.05, P 0.01, P 0.001). In contrast, FSH, LH, testosterone, the number of Bcl-2 positive cells, Bcl-2 mRNA expression, and mitochondrial genes were increased in all treatment groups (P 0.05, P 0.01, P 0.001). Conclusion These findings suggest that GSH combined with Met restores apoptotic and mitochondrial dynamics, potentially mitigating diabetes-associated testicular damage by modulating the expression of genes involved in apoptotic and mitochondrial processes, thus positioning GSH as a promising complementary therapy. Implications Combined GSH and Met therapy may offer a novel synergistic strategy to protect male fertility in diabetes condition by targeting cellular stress pathways. Further studies are warranted to translate these findings into clinical applications.