The link between diabetes and male infertility: mechanisms and implications

Diabetes mellitus (DM) is a growing global health crisis affecting male reproductive function, yet the enhanced combined effects of diabetes with pre-existing fertility abnormalities remain poorly understood. This study aims to investigate the individual and combined effects of diabetes and abnormal semen parameters on male reproductive function and the underlying apoptotic mechanisms. Thirty-nine men were enrolled and stratified into two phases: a validation cohort (nondiabetic vs. diabetic; fertile vs. abnormally infertile) and a four-group mechanistic study (normal nondiabetic (n = 10), abnormal nondiabetic (n = 11), normal diabetic (n = 10), and abnormal diabetic (n = 8)). We assessed HbA1c, FSH, LH, testosterone, semen parameters, sperm apoptosis (Annexin V/PI flow cytometry), DNA fragmentation (diphenylamine), and expression of apoptotic markers (caspase-3, cytochrome c, Bax, and Bcl-2) at gene and protein levels. Diabetic patients had significantly higher HbA1c (9.6 ± 2.31% vs. 5.49 ± 0.42%, p < 0.001), elevated FSH and LH, and reduced testosterone. Abnormal infertile patients showed impaired motility and morphology. The abnormal diabetic group had the most severe dysfunction: lowest rapid progressive motility (11.3 ± 3.10%, p < 0.001 vs. control) and highest early apoptosis (58.9 ± 8.79%, p < 0.0001). Protein analysis showed a pro-apoptotic shift with an elevated Bax/Bcl-2 ratio (3.64), increased cytochrome-c, and caspase-3 activation exclusively in this group (p < 0.0001). Diabetes and abnormal semen parameters exert enhanced combined detrimental effects on male fertility via enhanced activation of the intrinsic mitochondrial apoptotic pathway. Diabetic men with pre-existing fertility abnormalities exhibit the most severe phenotype and require prioritized clinical intervention.