Background <p>The pathogenesis of type 2 diabetes (T2DM) remained to be fully understood. Meanwhile, exosome have shown its potential to further advance diabetes research as a rich source of biomarkers. This study aims to explore the proteomic profiles of circulating plasma exosomes in individuals with varying glucose statuses and offer potentially new perspective on the pathogenesis of T2DM.</p> Methods <p>Participants with different glucose status were recruited according to the diagnostic criteria of the American diabetes association. Plasma exosomes were collected and went through data independent acquisition mass spectrometry quantitative proteomics analysis. Differential proteins identified through pairwise group comparisons underwent further analysis like protein-protein interaction (PPI) and gene ontology (GO) to reveal their functions and interactions.</p> Results <p>A total of 75 participants (25 euglycemia; 25 prediabetes; 25 diabetes) were included in this study. Principal coordinates analysis showed that the proteomic patterns of exosomes in groups with prediabetes and diabetes exhibited certain similarities, contrasting with those in euglycemic individuals. From pairwise differential protein comparison, 32 proteins were selected for PPI and functional analysis, of which 7 were deemed significant within the network. GO annotations highlighted a close link between immunity and T2DM. Local STRING clustering, Reactome and KEGG pathway analysis all indicated great significance of complement and coagulation cascades.</p> Conclusion <p>The proteomic patterns of exosomes in groups with different glucose levels exhibited that even before overt diabetes manifests, the circulating exosome cargo signals immune and coagulatory activation distinct from normal physiology.</p>