Plasma proteomic profiling deciphers molecular dynamics linking insulin resistance to multiple chronic diseases and mortality.
BACKGROUND Insulin resistance (IR) correlates with a wide spectrum of diseases and death. However, the specific proteomic signatures of IR and their associations with health outcomes remain incompletely understood. METHODS Leveraging data of 2,920 plasma proteins from 19,556 individuals in UK biobank study, we employed the elastic net model to dissect IR-related proteins and construct proteomic signature scores. Cox proportional hazards model was fitted to examine the longitudinal associations of distinct IR indicators and their proteomic signatures with multiple chronic disease and mortality. Mediation analyses were conducted to explore the role of individual proteins and proteomic signatures in IR-disease associations. RESULTS Over a mean follow-up of over 12 years, higher levels of IR surrogate makers were linked to cardiovascular-kidney-metabolic events and mortality, with eGDR outperforming other metrics in predictive discrimination. Furthermore, most IR proteomic signatures were prospectively associated with the incidence of type 2 diabetes mellitus, ischemic heart diseases, stroke, chronic kidney diseases, and mortality. Proteins associated with IR were primarily enriched in inflammation, immune response, and lipid metabolism, with immune-related proteins holding crucial roles. Multiple IR-disease associations were significantly mediated by proteomic signatures and specific proteins, like HAVCR1, CXCL17, and GDF15. CONCLUSION This study probed into the plasma proteomic profiles in IR settings and the associations of relevant protein signatures with multiple chronic diseases and mortality, providing additional guidelines on targeted intervention strategies for cardiovascular-kidney-metabolic outcomes.