Amelioration of Peripheral Neuropathy in Mouse Models of Diabetes by Dietary Reversal

Peripheral neuropathy (PN) is a common complication of prediabetes and type 2 diabetes (T2D). Lifestyle changes, including dietary reversal (DR), can reverse PN, although the mechanisms involved remain unclear. The goal of this study was to identify the mechanisms that underlie PN development in prediabetes and T2D and understand which of these are corrected upon DR. To achieve this, we used two models of PN and looked at the effects of DR on global gene expression and lipid profiles in peripheral nerves. C57BL/6J mice were fed a standard diet (10% kcal fat; SD) or high fat diet (60% kcal fat; HF) from 5 week. A subset of HF mice were injected with STZ at 12 week to induce hyperglycemia, reflecting a more diabetic-like phenotype. At 16 week, subsets of HF and HF-STZ mice were placed on the standard diet for 8 week (HF-DR and HF-STZ-DR, respectively) until 24 week when terminal phenotyping was performed. At baseline and at study completion, sciatic nerve tissue was processed for gene expression by RNAseq or for lipid species profiling by untargeted shotgun lipidomics. HF and HF-STZ mice display PN compared to controls. In contrast, peripheral nerve function of HF-DR and HF-STZ-DR mice was corrected upon DR. Neural gene expression analysis revealed numerous differentially expressed genes (DEG) when comparing SD to HF or HF-STZ mice. Interestingly, a proportion of the genes dysregulated in HF and HF-STZ, were similarly reversed by DR. KEGG enrichment of these genes revealed that lipid metabolism pathways were enriched. Lipidomic analysis revealed a similar pattern of differentially altered lipids that were reversed by DR in HF and HF-STZ mouse models. Lipids reversed by DR include diacylglycerol, a known mediator of insulin resistance. We demonstrate that DR of HF and HF-STZ mice can restore peripheral nerve function. We also show that genes related to lipid function are dysregulated in diseased states and are reversed by DR. This study supports the idea that DR improves peripheral nerve function by restoring lipid homeostasis. Disclosure P.D. O'Brien: None. K. Guo: None. L.M. Hinder: None. J.M. Hayes: None. F. Mendelson: None. M.A. Tabbey: None. J. Hur: None. E.L. Feldman: None.