Diabetic Polyneuropathy Patients Exhibit an Altered Skeletal Muscle Proteome Phenotype

PURPOSE: Diabetic polyneuropathy (DPN) is a debilitating complication of diabetes that affects motor nerves and may impair skeletal muscle health. This study investigated skeletal muscle proteomic alterations associated with DPN compared with type 2 diabetes without DPN (T2D) and healthy controls (CON). EXPERIMENTAL DESIGN: An exploratory proteomic profiling was performed in 15 participants divided into three groups based on clinical and neurophysiological diagnosis (DPN, n = 5; T2D, n = 5; CON, n = 5). Biopsies from the gastrocnemius lateralis muscle were analyzed using LC-MS/MS-based proteomics and pathway enrichment analyses. RESULTS: A total of 265 and 444 proteins were differentially expressed in DPN compared with T2D and CON, respectively (q < 0.05). Enrichment analyses revealed marked alterations in mitochondrial-related pathways, including cellular respiration, distinguishing DPN from both comparison groups. Differences between T2D and CON were present but less pronounced. DPN was characterized by downregulation of glycogen-regulating proteins (phosphorylase kinase G1 and A1) and upregulation of ferritin light chain (FTL), alpha actin 2, and myosin-binding protein H. CONCLUSIONS AND CLINICAL RELEVANCE: DPN is associated with a distinct and progressive skeletal muscle proteomic phenotype, supporting mitochondrial dysfunction as a key feature and providing a basis for future mechanistic and therapeutic studies.