Proteomic Analysis of Skeletal Muscle in Chinese Hamsters with Type 2 Diabetes Mellitus Reveals That OPLAH Downregulation Affects Insulin Resistance and Impaired Glucose Uptake

Type 2 diabetes mellitus (T2DM) is a metabolic disease controlled by a combination of genetic and environmental factors. The Chinese hamster, as a novel animal model of spontaneous T2DM with high phenotypic similarity to human disease, is of great value in identifying potential therapeutic targets for T2DM. Here, we used tandem mass tag (TMT) quantitative proteomics based on liquid chromatography-tandem mass spectrometry to assess the skeletal muscles of a Chinese hamster diabetes model. We identified 38 differentially abundant proteins, of which 14 were upregulated and 24 were downregulated. Further analysis of the differentially abundant proteins revealed that five of them (OPLAH, GST, EPHX1, SIRT5, ALDH1L1) were associated with oxidative stress; these were validated at the protein and mRNA levels, and the results were consistent with the proteomic analysis results. In addition, we evaluated the role of OPLAH in the pathogenesis of T2DM in human skeletal muscle cells (HSKMCs) by silencing it. The knockdown of OPLAH caused an increase in reactive oxygen species content, decreased the GSH content, inhibited the PI3K/Akt/GLUT4 signaling pathway, and reduced glucose uptake. We propose that OPLAH downregulation plays a role in insulin resistance and glucose uptake disorders in HSKMCs possibly via oxidative stress, making it a new therapeutic target for T2DM.