Background: Testicular injury is one of the most serious problems of Diabetes mellitus. The present study aims to compare the effect of two different doses of nobiletin and the probable mechanisms against diabetes-induced testicular impairment in rats. Methods and Results: Streptozotocin injection was used to induce diabetes. Diabetic rats received nobiletin (10 mg/kg) or (25 mg/kg) daily and orally for 30 days. Diabetic rats displayed a significant elevation in glucose, glycosylated hemoglobin

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... (HbA1c), homeostasis model of insulin resistance (HOMA-IR), and pro-inflammatory cytokines. Levels of serum insulin, testosterone, luteinizing hormone (LH), and follicle-stimulating hormone (FSH) were significantly reduced. Histological changes with positive caspase-3 and decreased Androgen receptors (AR) immunoexpressions were observed in diabetic rats. Both doses of nobiletin improved hyperglycemia, reduced pro-inflammatory cytokines, and augmented insulin, testosterone, LH, and FSH levels. Gene and protein manifestation of LH and FSH receptors and cytochrome P450 17 α-hydroxylase (CYP17A1) was markedly down-regulated in testicular tissues of diabetic group, an effect which was markedly increased with both doses of nobiletin. In addition, both doses significantly reduced lipid peroxidation, and caspase-3 immuno-expression and improved the activity of the antioxidant enzymes and AR in testicular tissues of diabetic group. Conclusion: Both doses showed protective effects against diabetes-induced testicular injury by diminution of oxidative stress, hyperglycemia, inflammation, caspase-3 and up-regulation of the hypophysis-gonadal axis and androgen receptors. The high dose of nobiletin was more effective than the lower dose.