Tang Zonghao, Zheng Youkun
Basic Medicine Research Innovation Center for Cardiometabolic Diseases, Ministry of Education, Southwest Medical University, Luzhou 646000, China.
Cells. 2025 Sep 4;14(17):1376. doi: 10.3390/cells14171376.
The maturation of testicular Leydig cells during the prepubertal stage is crucial for establishing male fertility. While diabetes is recognized as a significant detrimental factor affecting male testicular function, its impact specifically during the prepubertal period remains largely unknown. We hypothesized that prepubertal diabetes may impair testicular development by disrupting Leydig cell maturation. Using streptozotocin (STZ) administration, we established a prepubertal diabetic rat model and investigated the effects of diabetes on testicular development 2 and 4 weeks post-STZ treatment. Diabetes significantly hampered testicular development, manifesting as a decreased testicular weight, structural abnormalities, reduced testosterone levels, and increased inflammatory responses. As anticipated, prepubertal diabetes stagnated Leydig cell maturation and increased Leydig cell apoptosis. Mechanistic studies revealed that autophagy is essential for maintaining homeostasis and facilitating differentiation in immature Leydig cells but is significantly inhibited by hyperglycemia. Dysregulation of autophagy impaired the mitochondrial network, triggering inflammatory responses, suppressing steroidogenic capacity, and accumulating reactive oxygen species (ROS). Elevated ROS levels exacerbated the inflammatory response in the Leydig cells in an NLRP3-dependent manner. Inhibition of NLRP3 ameliorated the hyperglycemia-induced inflammation and decline in steroidogenic ability. Collectively, these findings demonstrate that hyperglycemia suppresses autophagy induction and enhances ROS accumulation in Leydig cells. This cascade promotes inflammation and inhibits steroidogenesis, thereby impeding testicular development in prepubertal diabetic rats.
青春期前阶段睾丸间质细胞的成熟对于建立男性生育能力至关重要。虽然糖尿病被认为是影响男性睾丸功能的一个重要有害因素，但其在青春期前阶段的具体影响仍 largely 未知。我们假设青春期前糖尿病可能通过破坏间质细胞成熟来损害睾丸发育。通过给予链脲佐菌素（STZ），我们建立了青春期前糖尿病大鼠模型，并研究了糖尿病在 STZ 治疗后 2 周和 4 周对睾丸发育的影响。糖尿病显著阻碍了睾丸发育，表现为睾丸重量减轻、结构异常、睾酮水平降低和炎症反应增加。正如预期的那样，青春期前糖尿病使间质细胞成熟停滞并增加了间质细胞凋亡。机制研究表明，自噬对于维持未成熟间质细胞的稳态和促进分化至关重要，但被高血糖显著抑制。自噬失调损害了线粒体网络，引发炎症反应，抑制类固醇生成能力，并积累活性氧（ROS）。升高的 ROS 水平以 NLRP3 依赖的方式加剧了间质细胞中的炎症反应。抑制 NLRP3 改善了高血糖诱导的炎症和类固醇生成能力的下降。总体而言，这些发现表明高血糖抑制自噬诱导并增强间质细胞中 ROS 的积累。这一级联反应促进炎症并抑制类固醇生成，从而阻碍青春期前糖尿病大鼠的睾丸发育。
