Glucagon-like Peptide-1 Acts as Signaling Mediator to Modulate Human Sperm Performance via Targeting Akt, JNK and IRS-1 Cell Signaling Cascades: Novel Insights into Sperm Physiopathology

Recent evidence suggests that the male gonad is a potential target of glucagon-like peptide-1 (GLP-1). We investigated the effects of glucagon-like peptide-1 (GLP-1) on sperm function and the molecular mechanisms through which it may act. Semen samples of healthy men were incubated in the presence or absence of a GLP-1 mimetic analog, exendin-4 (Exe). In a different analysis, sperm were exposed to tumor necrosis factor (TNF-a) alone and, in some tubes, TNF-a was added after previous exposure to exendin-4 (Exe). Sperm parameters and protein-kinase B (p-Akt), insulin receptor substrate-1 (p-IRS-1 Ser312), and c Jun N-terminal protein kinase (p-JNK Thr183/Tyr185) were considered and evaluated. Sperm parameters, when incubated for 4 h in a simple defined balanced salt solution lacking protein, declined progressively with incubation time. The maximum decline was associated with a significant decrease in phosphorylated protein kinase B (p-Akt), concomitantly to an increase in insulin receptor substrate-1 (p-IRS-1 Ser312) and c Jun N-terminal protein kinase (p-JNK Thr183/Tyr185). Preincubation with exendin-4 (Exe) prevented this decline and maintained sperm motility (progressive-PM and total-TM). TNF-a exposure resulted in decreased sperm motility (PM and TM) and viability (V) in a concentration-dependent manner. Exe addition attenuated this TNF-a negative effect on sperm parameters. Glucagon-like peptide-1 (GLP-1) also acts by reducing levels of the negative kinases p-IRS-1Ser312 and p-JNK. An imbalance involving these three kinases in sperm, as it occurs in somatic cells, is a novel scenario that may participate in sperm physiopathology.

Automated summary

Recent evidence suggests that the male gonad is a potential target of glucagon-like peptide-1 (GLP-1). This study investigated the effects of GLP-1 on sperm function and the molecular mechanisms involved. Incubation of semen samples with a GLP-1 mimetic analog prevented a decline in sperm motility and attenuated the negative effects of tumor necrosis factor (TNF-a) on sperm parameters. GLP-1 also reduced levels of negative kinases in sperm, suggesting a potential role in sperm physiopathology.