Synergistic Effects of Vitamin D and Exercise on Diabetes-induced Gonadotoxicity in Male Wistar Rats: Role of Xanthine Oxidase/Uric Acid and Nrf2/NfkB Signaling

Type 2 Diabetes mellitus (T2DM) is one of the oldest known chronic diseases, characterized by elevated fasting blood sugar (FBS). T2DM is a metabolic disorder that can distort the activities of multiple physiological systems, including the reproductive system. Although different drugs have been designed for managing this disorder, these drugs have been reported to have negative side effects. Hence, this study was designed to explore the possible synergistic effect of vitamin D and exercise on T2DM-induced testicular dysfunction. Thirty-six male Wistar rats were randomized into six (6) groups: control, diabetes untreated, diabetes treated with 1000 IU/kg of vitamin D, diabetes treated with 5 min/day of physical exercise, diabetes treated with vitamin D and exercise, diabetes treated with 180 mg/kg of metformin. T2DM induction led to a significant increase in FBS, lactate, and lactate dehydrogenase, and was reversed by vitamin D supplementation and exercise. Also, vitamin D and exercise synergistically blunted T2DM-induced oxido-inflammatory response evidenced by a significant decrease in testicular malondialdehyde, interleukin 1β, interleukin 6, and tumor necrosis factor alpha, and an increase in superoxide dismutase, catalase, glutathione peroxidase, and interleukin 10. These events were associated with a decrease in T2DM-induced increase in XO, UA, and Nf-κb and an increase in T2DM-induced decrease in Nrf2. Also, vitamin D and EX reversed the observed impairment in sperm quality and testicular histology following T2DM-induction. This study revealed the synergistic effect of vitamin D and exercise on T2DM-induced testicular dysfunction. Graphical abstract