Muscle and liver insulin resistance are associated with distinct plasma protein abundance profiles - A proteomics analysis in the DiOGenes cohort

Context: Insulin resistance (IR) can develop in multiple organs, representing distinct etiologies towards cardiometabolic disease.Objective: This study aimed to investigate which proteins and pathways are specific for liver IR or muscle IR in individuals with overweight or obesity of the Diet, Obesity, and Genes (DiOGenes) cohort (n = 535) (NCT00390637, ClinicalTrials.gov).Methods: First, independent associations between muscle and liver IR and protein abundance levels were assessed. In the analysis we corrected for study centre, sex, BMI and age, whereby the analyses on liver IR were adjusted for muscle IR and vice versa. Differentially abundant proteins were then subjected to pathway enrichment analysis.Results: Muscle IR was associated with 160 proteins and liver IR was associated with 81 proteins. Of these, 12 were shared between both forms of IR. Pathway enrichment analysis identified 51 enriched pathways for muscle IR, characterized by a strong inflammatory profile, including chemokine signalling, IL-6 signalling and complement system related pathways. In contrast, liver IR was associated with 11 enriched pathways, primarily related to the complement system.Conclusion: Understanding the processes underlying these distinct IR phenotypes could inform the development of personalized prevention strategies.