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Abstract

Volume 25, Issue 3 (May 2023) 25, 331–338; 10.4103/aja202242

The protective effects and underlying mechanisms of dapagliflozin on diabetes-induced testicular dysfunction

Zhi-Chao Luo1, Zi-Run Jin1, Ya-Fei Jiang2, Tian-Jiao Wei2, Ya-Lei Cao1, Zhe Zhang1,3, Rui Wei2, Hui Jiang1,3

1 Department of Urology, Peking University Third Hospital, Beijing 100191, China
2 Department of Endocrinology and Metabolism, Peking University Third Hospital, Beijing 100191, China
3 Department of Reproductive Medicine Center, Peking University Third Hospital, Beijing 100191, China

Correspondence: Dr. H Jiang (jianghui55@163.com) or Dr. R Wei (weirui@bjmu.edu.cn)

15-Jul-2022

Abstract

Male diabetic individuals present a marked impairment in fertility; however, knowledge regarding the pathogenic mechanisms and therapeutic strategies is unsatisfactory. The new hypoglycemic drug dapagliflozin has shown certain benefits, such as decreasing the risk of cardiovascular and renal events in patients with diabetes. Even so, until now, the effects and underlying mechanisms of dapagliflozin on diabetic male infertility have awaited clarification. Here, we found that dapagliflozin lowered blood glucose levels, alleviated seminiferous tubule destruction, and increased sperm concentrations and motility in leptin receptor-deficient diabetic db/db mice. Moreover, the glucagon-like peptide-1 receptor (GLP-1R) antagonist exendin (9–39) had no effect on glucose levels but reversed the protective effects of dapagliflozin on testicular structure and sperm quality in db/db mice. We also found that dapagliflozin inhibited the testicular apoptotic process by upregulating the expression of the antiapoptotic protein B-cell lymphoma 2 (BCL2) and X-linked inhibitor of apoptosis protein (XIAP) and inhibiting oxidative stress by enhancing the antioxidant status, including total antioxidant capacity, total superoxide dismutase (SOD) activity, and glutathione peroxidase (GPx) activity, as well as decreasing the level of 4-hydroxynonenal (4-HNE). Exendin (9–39) administration partially reversed these effects. Furthermore, dapagliflozin upregulated the glucagon-like peptide-1 (GLP-1) level in plasma and GLP-1R expression by promoting AKT8 virus oncogene cellular homolog (Akt) phosphorylation in testicular tissue. Exendin (9–39) partially inhibited Akt phosphorylation. These results suggest that dapagliflozin protects against diabetes-induced spermatogenic dysfunction via activation of the GLP-1R/phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Our results indicate the potential effects of dapagliflozin against diabetes-induced spermatogenic dysfunction.

Keywords: dapagliflozin; diabetes; glucagon-like peptide-1 receptor; male infertility; oxidative stress

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Asian Journal of Andrology CN 31-1795/R ISSN 1008-682X  Copyright © 2023  Shanghai Materia Medica, Chinese Academy of Sciences.  All rights reserved.