NONcNZO10 / LtJ and TALLY ‐ HO / JngJ Mice as Novel Models of Diabetic Peripheral Neuropathy

Diabetic peripheral neuropathy (DPN), a severe complication of Type 2 diabetes (T2D), is marked by progressive distal-to-proximal axonal degeneration. Although animal models have advanced our understanding of DPN pathogenesis, preclinical successes rarely translate into effective therapies, underscoring the need for models that more faithfully mirror human disease. In this study, we characterized two polygenic mouse strains, NONcNZO10/LtJ (RCS10) and TALLYHO/JngJ (TH), and found that both models developed obesity, hyperglycemia, dyslipidemia, and DPN by 24 weeks of age. However, hyperinsulinemia was observed only in RCS10 mice. Compared to monogenic and high-fat diet-induced models, the metabolic and neuropathic phenotypes of RCS10 and TH more closely resembled those of human DPN. In the second phase of the study, RCS10 mice were subjected to a calorie-restricted diet (60% of standard intake) for 8 weeks, which improved metabolic health and restored large fiber function, although intraepidermal nerve fiber density remained unchanged. Together, these findings identify RCS10 and TH mice as clinically relevant polygenic models for studying DPN pathogenesis and evaluating targeted therapeutic strategies.