Tirzepatide Attenuates Diabetes-Associated Testicular Inflammation and Sperm DNA Fragmentation in Obese Diabetic Mice: Potential Pleiotropic Effects Beyond Glycemic Control
Abstract
Abstract Background Diabetes is increasingly recognized as a contributor to male infertility. We previously reported that diabetic mice exhibit testicular macrophage accumulation and impaired spermatogenesis, and that glucose-dependent insulinotropic polypeptide receptor (GIPR) activation suppresses macrophage inflammatory responses. Here, we investigated whether and how tirzepatide, a dual GIP/glucagon-like peptide-1 receptor (GLP-1R) agonist used for type 2 diabetes and obesity, ameliorates diabetes-associated testicular injury and sperm damage. Methods Obese diabetic KK-Ay mice were treated with vehicle or tirzepatide at a metabolically effective or sub-effective dose (1.00 or 0.16 nmol/kg/day, respectively) for 8 weeks. Testicular histology, macrophage accumulation, inflammatory gene expression, sperm parameters, oxidative stress, and sperm DNA fragmentation were assessed. A separate exploratory experiment with empagliflozin was performed to examine whether a glucose-lowering intervention could affect these testicular and sperm parameters. Results Tirzepatide at 1.00 nmol/kg/day significantly reduced glycated hemoglobin A1c levels, whereas 0.16 nmol/kg/day did not. Tirzepatide at both doses reduced seminiferous tubule vacuolation, testicular macrophage accumulation and oxidative stress, and attenuated sperm oxidative stress and DNA fragmentation. Sperm motility improved only with the higher dose. Gipr expression was abundant in the testis, whereas Glp-1r expression was…
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