Transcriptomic analysis of peripheral neuropathy in a high-fat diet-induced mouse model of type 2 diabetes

Peripheral neuropathy (PN) is the most common microvascular complication of type 2 diabetes mellitus (T2D). However, a thorough understanding of the mechanisms underlying PN pathogenesis is currently lacking. Thus, the goal of the current study was to use system biology approaches to investigate the development and progression of PN in a high-fat diet (HFD)-induced mouse model of T2D. Transcriptomic data sets from sciatic nerve (SCN) and dorsal root ganglia (DRG) tissue were collected from 12- and 36-week-old HFD-fed mice and analyzed using self-organizing map and differentially expressed gene analysis with functional enrichment. Consistent with prior literature, pathways related to immune function and inflammation, mTOR signaling, and lipid metabolism were dysregulated in the SCN and DRG of HFD-fed mice. Additionally, cell-type abundance analysis revealed changes in cell composition in the SCN and DRG of HFD-fed T2D mice over time, particularly in the SCN. Comparison of differentially expressed genes from the SCN of HFD-fed mice to transcriptomic data from human sural nerve further supported the role of inflammation, mTOR signaling, and lipid metabolism in PN. Results from this study provide the basis for mechanistic studies investigating nerve damage in T2D and support the development of mechanism-based treatment options for PN.