Specific apoCIII proteoform ratios are associated with a healthier cardiometabolic phenotype and lower incidence of type 2 diabetes: a nested case-control study

Background Apolipoprotein CIII (apoCIII) is a key regulator of triglyceride metabolism and an emerging biomarker of cardiometabolic risk. Although elevated total apoCIII concentrations have been associated with type 2 diabetes (T2D) and cardiovascular disease, individual apoCIII proteoforms may exert distinct metabolic effects. We investigated the prospective associations between apoCIII proteoforms and incident T2D in adults at high cardiometabolic risk, as well as their associations with dietary intake. Methods This nested case-control study included 594 incident T2D cases and 594 controls matched for age, sex, intervention group, body mass index, fasting glucose and triglyceride concentrations. Seven apoCIII proteoforms were measured using mass spectrometry-based immunoassay, and total apoCIII concentrations were measured using an immunoturbidimetric assay. Associations between apoCIII proteoforms and metabolic traits, dietary factors, and incident T2D were evaluated using multivariable-adjusted regression models. Results ApoCIII proteoforms showed heterogeneous associations with metabolic risk and incident T2D. Higher CIII2d/CIII1, CIII2/CIII1, and CIII0f/CIII1 ratios were associated with more favourable lipid and glycaemic profiles and lower odds of incident T2D per 1-SD increase (CIII2d/CIII1 OR = 0.77, 95% CI: 0.61–0.97; CIII2/CIII1 OR = 0.81, 95% CI: 0.69–0.96; CIII0f/CIII1 OR = 0.73, 95% CI: 0.55–0.97). Exploratory analyses identified several nominal associations between dietary intake and apoCIII proteoform ratios; however, none remained statistically significant after FDR correction. Conclusions Higher CIII2d/CIII1, CIII2/CIII1, and CIII0f/CIII1 proteoform ratios were associated with healthier lipid and glucose metabolic profiles and lower odds of incident T2D. These findings support further investigation of apoCIII proteoform profiling as a potential biomarker of incident T2D risk.