Tirzepatide ameliorates type 2 diabetes–associated male reproductive dysfunction via modulation of the Nrf2/Keap1 pathway

Type 2 diabetes mellitus is closely associated with male reproductive dysfunction driven by oxidative stress, hormonal imbalance, and testicular cell damage. This study evaluated the effects of tirzepatide, a dual agonist of the glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptors, on diabetes-induced reproductive impairment in male Wistar rats, compared with metformin. Sixty rats were allocated into control, diabetic control, tirzepatide-treated diabetic, metformin-treated diabetic, and pair-fed diabetic control groups to distinguish weight-dependent from weight-independent effects. Diabetes was induced using a high-fat diet combined with low-dose streptozotocin, and treatments were administered for eight wk. Metabolic, hormonal, sperm, oxidative stress, histological, and gene-expression parameters were assessed. Diabetic rats exhibited hyperglycemia, insulin resistance, reduced reproductive hormones, impaired sperm quality, increased lipid peroxidation, and downregulation of antioxidant and steroidogenic genes. Tirzepatide markedly improved glucose homeostasis, restored testosterone and gonadotropin levels, enhanced antioxidant defenses via activation of the Nrf2/Keap1 pathway, normalized steroidogenic gene expression, preserved testicular architecture, increased PCNA expression, and reduced caspase-3-mediated apoptosis. These effects were superior to those of metformin and largely independent of weight reduction. Overall, tirzepatide ameliorates diabetes-associated male reproductive dysfunction through coordinated metabolic, antioxidant, and steroidogenic mechanisms.