Dapagliflozin ameliorates diabetes-induced spermatogenic dysfunction by modulating the adenosine metabolism along the gut microbiota-testis axis.

Male infertility is one of the most common complications of diabetes mellitus (DM). Dapagliflozin is widely used to manage the type II DM. This study aimed to assess the dapagliflozin's effects on the spermatogenesis by administering either dapagliflozin (Dapa) or vehicle (db) to male db/db mice, and using littermate male db/m mice as the control (Con). We further performed the integrative analyses of the cecal shotgun metagenomics, cecal/plasmatic/testicular metabolomics, and testicular proteomics. We found that dapagliflozin treatment significantly alleviated the diabetes-induced spermatogenic dysfunction by improving sperm quality, including the sperm concentration and sperm motility. The overall microbial composition was reshaped in Dapa mice and 13 species (such as Lachnospiraceae bacterium 3-1) were regarded as potential beneficial bacteria. Metabolites exhibited modified profiles, in which adenosine, cAMP, and 2'-deoxyinosine being notably altered in the cecum, plasma, and testis, respectively. Testicular protein expression patterns were similar between the Dapa and Con mice. In vivo results indicated that when compared with db group, dapagliflozin treatment alleviated apoptosis and oxidative stress in testis tissues by down-regulating 2'-deoxyinosine. This was further validated by in vitro experiments using GC-2 cells. Our findings support the potential use of dapagliflozin to prevent the diabetes-induced impaired sperm quality and to treat diabetic male infertility.

The effect of metformin on homocysteine levels in patients with polycystic ovary syndrome: A systematic review and meta-analysis.

PURPOSE: Metformin is widely used as an insulin sensitizer in polycystic ovary syndrome (PCOS) patients. However, previous studies have found that the effect of metformin on the level of homocysteine were not consistent in PCOS patients. The aim of this review was to analyze the effect of metformin on homocysteine levels in patients with PCOS patients. METHODS: The Cochrane Library, Pubmed, and Web of Science were searched according to predefined search terms. There is no restriction for publication time and language. RESULTS: Eleven studies were included and the data were extracted. The homocysteine level in PCOS patients was significantly increased after taking metformin (mean difference [MD] -1.33; 95% confidence interval [CI] -2.16 to -0.49, p = 0.002). Subgroup analysis showed that the level of homocysteine was generally increased in PCOS patients with body mass index (BMI) ≥25 after taking metformin alone (MD -1.82; 95% CI -2.56 to -1.07, p < 0.00001). There was no significant change in homocysteine level in PCOS patients with BMI <25 (MD 0.69; 95% CI -0.41 to 1.79, p = 0.22). Subgroup analysis showed that there was no significant difference when taking metformin >3 months or taking metformin ≤3 months (p = 0.84). Taking metformin ≥1700 mg/days significantly increased homocysteine levels in PCOS patients (MD -2.05; 95% CI -2.40 to -1.70, p < 0.00001). When taking metformin <1700 mg/days, there was no significant difference in homocysteine level in PCOS patients (MD 0.15; 95% CI -1.06 to 1.37, p = 0.80). The difference between the two subgroups was significant (p = 0.0006). There was no significant difference in vitamin B12 level before and after metformin treatment (MD 24.70; 95% CI -22.54 to 71.93, p = 0.31). There was a decrease in serum folic acid level after metformin administration (MD 1.03; 95% CI 0.80 to 1.26, p < 0.00001). CONCLUSION: Taking metformin alone increased homocysteine levels and decreased folic acid levels in nonpregnant PCOS patients. And, it was suggested that the dosage of metformin should be less than 1700 mg/days. The supplement of folic acid and B vitamins during metformin administration may be essential in nonpregnant PCOS patients. We should pay much attention to the potential effect of metformin in PCOS patients.