¹Manisa Celal Bayar University, Faculty of Medicine, Department of Physiology, TR-45140 Manisa - TÜRKİYE DOI : 10.9775/kvfd.2025.35321 Diabetes mellitus is a rapidly increasing global health concern, and neuropathy constitutes one of its significant complications. In animal models of diabetic neuropathy, invasive electromyography (EMG) is a widely applied approach. However, the choice of anesthetic agent represents a critical methodological factor, as it can directly modulate nerve conduction and muscle responses, thereby influencing the reliability of electrophysiological outcomes. This study investigated the comparative effects of ketamine-xylazine and urethane anesthesia on EMG parameters in streptozotocin-induced diabetic rats. Electrophysiological assessments of the gastrocnemius muscle demonstrated that urethane anesthesia produced markedly higher amplitudes and prolonged compound muscle action potential (CMAP) durations, potentially masking neuropathic deficits. In contrast, ketamine-xylazine anesthesia preserved the expected electrophysiological hallmarks of diabetic neuropathy, including reduced amplitudes and shortened CMAP durations. These findings indicate that urethane is not a pharmacologically inert anesthetic but one that may artificially alter neuromuscular transmission, leading to misleading interpretations in neuropathy models. Conversely, ketamine-xylazine provides more consistent results aligned with the established pathophysiology of diabetic neuropathy. In conclusion, the selection of anesthetic agent has profound implications for both the validity and translational relevance of electrophysiological research. Therefore, in preclinical neuropathy studies, ketamine-xylazine should be preferred over urethane as a more reliable and methodologically appropriate anesthetic protocol. Keywords : Diabetes mellitus, Diabetic neuropathies, Streptozotocin, Wistar rat, Electromyography, Anesthesia, Ketamine, Xylazine, Urethane, Neuromuscular transmission