Diabetic Polyneuropathy Patients Exhibit an Altered Skeletal Muscle Proteome Phenotype

Abstract

ABSTRACT 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.