Quantitative Proteomic Profiling of Plasma Alterations Associated with Thrombotic Risk and Insulin Resistance in Type 1 Diabetes

Type 1 diabetes (T1D) is associated with prothrombotic changes that contribute to an elevated risk of cardiovascular disease. We hypothesised that insulin resistance (IR), increasingly prevalent among individuals with T1D, exacerbates haemostatic abnormalities through distinct proteomic alterations in plasma. In a cross-sectional observational study, citrated plasma was collected from individuals with T1D (with and without IR) and healthy controls. Fibrin clot formation and lysis were assessed using turbidimetric assays. Plasma proteomes were analysed using data-independent acquisition mass spectrometry (DIA-MS), and correlations between protein abundance and clinical parameters were evaluated. T1D plasma exhibited faster clot initiation, increased clot density, and impaired fibrinolysis. Effects on clot lysis were most pronounced in individuals with IR. DIA-MS revealed distinct proteomic signatures, with significant changes in proteins involved in regulating clot structure and breakdown. Notably, clot density correlated positively with fibrinogen gamma-chain abundance. T1D is characterised by prothrombotic alterations that are further intensified by IR. Our findings reveal that these changes are driven by proteomic shifts affecting clot initiation, structural integrity, fibrinolysis, and inflammatory pathways, offering mechanistic insights and potential targets for mitigating cardiovascular risk in this population.