Diabetic Peripheral Neuropathy

The Diabetes Neurodegeneration in vitro screening assay utilizes primary neurons from immature mice or rats. Following the conditioning phase with high concentrations of glucose, cultures are treated with compounds and evaluated for their neurodegeneration index. 

The assays are ideal for screening compounds prior to efficacy in in vivo studies. 

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STZ is used to induce type I diabetes and diabetes-related complications, including diabetic peripheral neuropathy. There are multiple theories on the mechanism that involves peripheral neuropathy following STZ. Some of the mechanisms suggested are related to the hyperglycemic state of the rats suggesting that following the hyperglycemia, nerve endings are damaged either through an inflammatory process or interfering with blood supply. However, vast studies are also suggesting a mechanism of neuronal damage that occurs following STZ but it is unrelated to the hyperglycemic state of the animals.

These studies suggest direct damage to the nerves. For example, reactive oxygen species (ROS) mediate elevation of TRPV1 in neurons and the DRG is exposed to STZ in vitro. Therefore, the STZ model involves direct changes in the nerves that are not related to the inflammatory process. 

The high fat diet (HFD) model is a diet-induced model of type 2 diabetes and diabetic peripheral neuropathy that develops through prolonged metabolic stress rather than chemical induction. Maintained on a high fat diet, C57BL/6 mice develop weight gain, insulin resistance, and elevated blood glucose, reproducing the metabolic profile that underlies type 2 diabetic neuropathy in patients. Over an 11 to 16 week study, animals go on to develop a clear neuropathy phenotype, including mechanical allodynia and reduced intraepidermal nerve fiber (IENF) density. MD Biosciences characterizes the model using von Frey testing, blood glucose and glucose tolerance testing, and electrophysiology, with histology and IHC, IENF quantification, and cytokine analysis as endpoints, and validates pharmacology against gabapentin and morphine as positive controls. Together these measures provide a clinically relevant, well-characterized readout of type 2 diabetic neuropathy for therapeutic evaluation.

The Zucker Diabetic Fatty (ZDF) rat is a well-characterized, spontaneous model of obese type 2 diabetes that develops progressive hyperglycemia and diabetic peripheral neuropathy without chemical induction. Driven by a leptin receptor mutation, ZDF rats become obese and develop glucose intolerance and sustained hyperglycemia that closely reflect the metabolic profile of human type 2 diabetes. As the disease progresses, animals go on to develop a robust diabetic peripheral neuropathy phenotype, making the model well suited to evaluating both disease modifying and symptomatic therapies. In a 13-week longitudinal characterization against lean Sprague-Dawley controls, MD Biosciences tracked the model across metabolic endpoints, including body weight and glucose tolerance, alongside a panel of sensory and sensorimotor measures, with ZDF rats showing marked mechanical allodynia on von Frey testing, progressively developing thermal hypersensitivity on the hot plate, and clear sensorimotor deficits on adhesive removal. Together these endpoints provide a clinically relevant, reproducible readout of type 2 diabetic neuropathy for therapeutic evaluation.