Diabetic neuropathy affects nearly half of individuals living with diabetes, yet its underlying biological drivers remain only partially defined. Multiple peripheral and central mechanisms appear to contribute, ranging from metabolic injury to direct neurotoxicity, and these complexities continue to challenge therapeutic development. Preclinical models that more accurately reflect human disease are essential for evaluating new candidates.
Multiple in vivo models are used to examine diabetes-associated nerve injury. Streptozotocin (STZ) remains a well-established approach to induce type I diabetes and related complications, including diabetic peripheral neuropathy. While STZ is widely used to model hyperglycemia-driven neuronal damage, growing evidence indicates that its effects extend beyond glucose elevation.
Several studies propose that nerve injury following STZ exposure may not be exclusively related to the hyperglycemic state. Instead, direct neurotoxic mechanisms appear to contribute. For example, reactive oxygen species have been shown to elevate TRPV1 expression in neurons when dorsal root ganglion tissue is exposed to STZ in vitro. This supports the concept that STZ induces neuronal changes independent of inflammation or vascular impairment.
High-fat diet (HFD) models complement STZ systems by enabling the study of peripheral neuropathy associated with type II diabetes. In these models, food intake, body weight, and glucose levels are monitored to define the onset of metabolic dysfunction. Together, STZ and HFD models provide distinct but complementary views into diabetic neuropathy and its diverse mechanisms.
To strengthen translational relevance, modern neuropathy studies extend beyond behavioral endpoints. Electrophysiology and intraepidermal nerve fiber (IENF) staining are routinely incorporated to quantify structural and functional changes in peripheral nerves. These assessments enable detection of early degeneration, impaired conduction, and small-fiber pathology, hallmarks of human diabetic neuropathy.
The diabetes neurodegeneration in vitro screening assay adds an efficient early-stage component to neuropathy programs. This system uses primary neurons from immature mice or rats conditioned with high glucose. Following treatment with test compounds, cultures are evaluated for their neurodegeneration index. These assays allow rapid screening and prioritization of therapeutic candidates prior to in vivo evaluation.
Diabetes frequently co-occurs with other neurological and cardiovascular conditions, complicating clinical outcomes and influencing treatment response. Stroke provides a clear example: patients are often older, present with comorbid diabetes, and are treated with multiple medications. However, the majority of preclinical stroke studies continue to rely on young, healthy rodents, limiting translational alignment.
Models that incorporate clinically relevant variables, including age, metabolic status, and comorbid conditions, offer a more accurate representation of patient populations. In ischemia studies, for instance, the four-vessel occlusion (4VO) model captures hippocampal vulnerability and cognitive impairment. Spatial memory deficits are evident in Morris Water Maze performance following 4VO, driven by degeneration of CA1 hippocampal neurons.
Notably, therapeutic effects observed in young, healthy animals may diminish or disappear under diabetic conditions. This highlights the importance of considering diabetes not only as a primary disease model, but also as a modifying factor that can fundamentally alter neurological outcomes and treatment efficacy.
Learn more about diabetic neuropathy models in our datasheet here - including STZ and high-fat diet models.
Download our neurodegeneration assay datasheet here.