Glucagon Receptor Blockade Protects Spermatogenesis in Diabetic and Aged Mice by Enhancing PFKFB3-Mediated Lactate Production

Male fertility is globally declining, with diabetes and aging being significant contributors to reduced sperm production and testicular dysfunction. While elevated glucagon signaling is known to drive diabetic complications, its specific impact on male reproductive function has remained largely uncharacterized. Current interventions for age- or diabetes-related male infertility are often limited, highlighting a critical need for novel therapeutic targets that can restore testicular health and spermatogenesis by addressing underlying metabolic dysregulation.

Researchers investigated the role of glucagon signaling in male fertility using streptozotocin-induced type 1 diabetic mice and naturally aged mice. Both groups, alongside healthy young controls, received either a glucagon receptor (GCGR) monoclonal antibody or a control. Key endpoints included sperm quality, testicular histology, oxidative stress, and apoptosis. Further, global Gcgr knockout mice were compared to wild-type controls. In vitro studies involved treating mouse spermatogonia, spermatocytes, Leydig, and Sertoli cells with glucagon, a GCGR antibody, or a GLP-1R antagonist to assess proliferation, lactate content, LDH activity, and expression of glycolysis-associated genes like PFKFB3.

In diabetic mice, GCGR antibody treatment significantly increased sperm concentration (P < 0.001) and reduced testicular oxidative stress and apoptosis. Aged mice treated with the GCGR antibody showed improved progressive sperm motility. Global Gcgr knockout mice exhibited enhanced sperm parameters and testicular function compared to wild-type controls. In vitro, glucagon treatment inhibited Sertoli cell proliferation and maturation, while GCGR blockade reversed these effects and enhanced blood-testis barrier (BTB) integrity. The mechanism involved PFKFB3: >GCGR antibody treatment significantly increased lactate production and PFKFB3 levels in Sertoli cells, a key glycolytic regulator, which was critical for maintaining Sertoli cell function and spermatogenesis. Overexpression of Pfkfb3 rescued glucagon-induced impairments in Sertoli cells, while Pfkfb3 heterozygous knockout mice showed impaired lactate production and Sertoli cell function.