Impacts of the DPP-4 Inhibitor Saxagliptin and SGLT-2 Inhibitor Dapagliflozin on the Gonads of Diabetic Mice

Abstract

Diabetes mellitus is a metabolic disease that can cause systemic problems, including testicular dysfunction. Several diabetes medications have demonstrated potential adverse effects on the male reproductive system; however, the effects of saxagliptin and dapagliflozin have not been sufficiently examined. This investigation studied the impacts of saxagliptin and dapagliflozin treatments on the gonads in a male mouse model of diabetes. Testicular disturbances were assessed by sperm DNA damage, diakinesis-metaphase I chromosome examination, and spermiogram analysis. Our results showed more sperm DNA damage, more spermatocyte chromosome aberrations, lower sperm motility/count, and more sperm morphological anomalies in diabetic mice than in the control mice. Dapagliflozin significantly restored all examined measures to the control values in diabetic mice, unlike saxagliptin, which exacerbated the reduction in sperm count and motility. Both drugs significantly restored the gonadal redox imbalances in diabetic mice by decreasing reactive oxygen species accumulation and increasing glutathione levels. In conclusion, our study presents preliminary evidence for the safety and efficacy of dapagliflozin in alleviating testicular abnormalities induced by diabetes, making it a promising candidate drug for patients with diabetes in their reproductive age. As saxagliptin may have negative effects on fertility, its prescription should be avoided in young male diabetic patients.

Keywords: chromosomal aberration; hyperglycemia; metabolism; oxidative stress; reproduction.

Figure 1

DNA damage in sperm cells of treated and untreated animals (mean ± SD, N = 6). Sperm cells were collected 24 h following the last dose of saxagliptin or dapagliflozin (10 mg/kg/d for 35 d) or cyclophosphamide. Group 1, non-diabetic control animals; Group 2, non-diabetic animals treated with saxagliptin; Group 3, non-diabetic animals treated with dapagliflozin; Group 4, diabetic mice; Group 5, diabetic animals treated with saxagliptin; Group 6, diabetic animals treated with dapagliflozin; Group 7, non-diabetic animals administered cyclophosphamide (40 mg/kg). * p < 0.05, ** p < 0.01 vs. control animals (Kruskal–Wallis test). ^a p < 0.05, ^b p < 0.01 vs. diabetic animals and ^## p < 0.01 vs. untreated non-diabetic animals (Mann–Whitney U Test).

Figure 2

Sperm ROS levels in treated and untreated animals (mean ± SD, N = 6). Sperm cells were collected 24 h following the last dose of saxagliptin or dapagliflozin (10 mg/kg/d for 35 d). Group 1, non-diabetic control animals; Group 2, non-diabetic animals administered saxagliptin; Group 3, non-diabetic animals administered dapagliflozin; Group 4, diabetic animals; Group 5, diabetic animals administered saxagliptin; Group 6, diabetic animals administered dapagliflozin. * p < 0.05, ** p < 0.01 vs. control animals and ^a p < 0.05, ^b p < 0.01 vs. untreated diabetic animals (ANOVA test).

Figure 3

Sperm ROS and testicular GSH levels in treated and untreated animals (mean ± SD, N = 6). Sperm cells were collected 24 h following the last dose of saxagliptin or dapagliflozin (10 mg/kg/d for 35 d). Group 1, non-diabetic control animals; Group 2, non-diabetic animals administered saxagliptin; Group 3, non-diabetic animals administered dapagliflozin; Group 4, diabetic animals; Group 5, diabetic animals administered saxagliptin; Group 6, diabetic animals administered dapagliflozin. * p < 0.05, ** p < 0.01 vs. control animals and ^a p < 0.05, ^b p < 0.01 vs. untreated diabetic animals (ANOVA test).