An optimized low-dose streptozotocin protocol enables rapid induction of diabetic neuropathy with high survival in rats

Background Diabetic neuropathy is one of the most common complications of diabetes mellitus and remains difficult to study due to the prolonged experimental periods and high mortality frequently associated with conventional streptozotocin (STZ)-induced models. We aimed to develop and characterize a rapid, reproducible, and high-survival rat model of early diabetic neuropathy and to identify molecular alterations associated with disease development. Methods Male Wistar rats received three intraperitoneal injections of low-dose STZ (30 mg/kg) on alternating days or vehicle control. Blood glucose and body weight were monitored, and a neurophysiological assessment was performed using M-wave and F-wave recordings. To complement functional characterization, dorsal root ganglion (DRG) microarray datasets from STZ-induced diabetic rats and human DRG gene expression samples were analyzed using differential expression, protein-protein interaction, functional enrichment, and receiver operating characteristic (ROC) analyses. Results STZ-treated animals developed sustained hyperglycemia and significant body weight loss compared with controls. Neurophysiological assessment revealed a marked reduction in F-wave occurrence and prolonged F-wave latency, indicating early peripheral nerve dysfunction. The protocol achieved 91.7% survival while maintaining robust metabolic and neurophysiological features of diabetic neuropathy. Gene expression analysis identified 2,693 differentially expressed genes, with the top 500 enriched in inflammatory, calcium signaling, neuropeptide signaling, and myeloid immune pathways. Network analysis highlighted TNF, HTR2A, CXCL10 , and CXCR2 as hub genes. Validation in an independent human DRG dataset demonstrated significant upregulation of TNF and HTR2A , with strong diagnostic ability (AUC = 0.91 and 0.80, respectively). Conclusions An optimized low-dose STZ regimen rapidly induces neurophysiological features of diabetic neuropathy within four weeks while maintaining high animal survival. This model provides a practical platform for investigating early pathogenic mechanisms and evaluating therapeutic interventions. Integrative transcriptomic analyses further identify TNF and HTR2A as candidate biomarkers with translational relevance for diabetic neuropathy.