Diabetic peripheral neuropathy (DPN) is a progressive distal-to-proximal axonopathy and a major complication of Type 2 diabetes (T2D). Preclinical models that better reflect the complex, polygenic nature of human T2D may improve translational success. This study characterized two polygenic mouse strains, NONcNZO10/LtJ (RCS10) and TALLYHO/JngJ (TH), to determine whether their metabolic and neuropathic phenotypes resemble human DPN more closely than monogenic or high-fat diet–induced models.
Ten-week-old RCS10, TH and their respective control strains (C57BL/6J for RCS10 and SWR/J for TH) were fed a standard diet and monitored until 24 weeks of age. Body weight (BW) and fasting blood glucose (FBG) were recorded biweekly. Terminal assessments at 24 weeks included BW, FBG, HbA1c, plasma insulin, lipid panels, and DPN phenotyping consisting of motor and sensory nerve conduction velocities (NCVs) and intraepidermal nerve fiber density (IENFD). Data reporting included individual animal values and group means with standard deviations.
By 24 weeks, both RCS10 and TH strains developed key metabolic abnormalities relevant to T2D: increased body weight and hyperglycemia, along with elevated HbA1c. Plasma lipid disturbances were also present. Notably, hyperinsulinemia was observed only in RCS10 mice, indicating metabolic heterogeneity between the two polygenic strains. The presence or absence of hyperinsulinemia is an important distinction when modeling different aspects of human T2D and its complications.
Terminal lipid analyses showed altered circulating lipid species in both RCS10 and TH mice relative to their controls. Measured parameters included non-esterified fatty acids (NEFA), cholesterol, triglycerides (TG), and phospholipids (PPL). The strains demonstrated dyslipidemia consistent with metabolic dysfunction observed in T2D, supporting their relevance for studies linking lipid metabolism to neuropathic outcomes.
Both RCS10 and TH mice exhibited electrophysiologic and structural evidence of DPN at 24 weeks. Motor nerve conduction velocity (MNCV) and sensory nerve conduction velocity (SNCV) were reduced compared with controls, indicating impaired large-fiber function. Intraepidermal nerve fiber density (IENFD), a marker of small fiber integrity, was also decreased in the affected strains. These combined findings show concurrent large- and small-fiber involvement in these polygenic models by mid-adulthood.
The authors note that RCS10 and TH phenotypes—obesity, hyperglycemia, dyslipidemia, and combined large- and small-fiber neuropathy—more closely reflect human DPN than commonly used monogenic or high-fat diet–induced rodent models. This closer resemblance pertains to the multifactorial metabolic context and the presence of polygenic risk factors, which the investigators argue may improve the clinical relevance of preclinical therapeutic testing.
In a second phase, the investigators applied a dietary intervention to RCS10 mice. At 16 weeks of age, a subset of RCS10 animals was switched to a calorie-restricted diet providing 60% of standard intake for eight weeks. The intervention arm included baseline and terminal assessments: glucose tolerance testing (GTT) at baseline and terminal time points, repeated measures of BW and FBG, and terminal analyses of HbA1c, plasma insulin and lipids, body composition, NCVs, and IENFD.
Caloric restriction in RCS10 mice improved metabolic health indicators and led to recovery of large-fiber function as measured by nerve conduction velocities. Despite electrophysiologic improvement, intraepidermal nerve fiber density did not change over the 8-week caloric restriction period, indicating that structural small-fiber loss was not reversed within the timeframe of the study. These results suggest that metabolic rescue can restore functional large-fiber performance while small-fiber structural recovery may require longer duration or additional targeted interventions.
The reported findings derive from the described cohorts evaluated up to 24 weeks of age, with the dietary intervention applied for eight weeks in RCS10 mice. Specific numerical results, statistical values and some group sizes are presented in the article figures and figure legends. Where detailed numerical data is not restated here, those values were reported in the original article. The work was published in FASEB Journal (2026 Sep 15;40(17):e72275) with PMID 42698390, PMCID PMC13545661, and DOI 10.1096/fj.202600848R. The authors declared no conflicts of interest.
Conclusions
RCS10 (NONcNZO10/LtJ) and TH (TALLYHO/JngJ) mice develop obesity, hyperglycemia, dyslipidemia, and diabetic peripheral neuropathy by 24 weeks of age. The strains display metabolic heterogeneity—hyperinsulinemia in RCS10 but not TH—and combine large- and small-fiber neuropathic features. Caloric restriction (60% intake for eight weeks) in RCS10 improved metabolic measures and restored large-fiber function but did not alter IENFD within the study period. The authors propose these polygenic strains as clinically relevant models for studying DPN pathogenesis and for preclinical evaluation of targeted therapies.