(A) Left: Overview of clinical cohorts for clinical and serum proteomic longitudinal analyses. Among the healthy participants at the 6-year visit, subpopulations who developed either prediabetes (n = 19) or T2D (n = 9) were labeled as the diabetes-progressors, while nonprogressors stayed healthy at the 10-year visit (n = 41). Right: Progression to diabetes between 6-year and 10-year follow-up visits was associated with increase in BMI and HOMA-IR. The plots show within-participant changes in BMI (top) and HOMA-IR (bottom) with Wilcoxon P values of progressors versus nonprogressors. (B) Protein changes at 10 years versus 6 years within a participant across each subcohorts are represented with individual lines. PON3 (top) and PLTP (bottom) changed most in T2D-progressors between 6 and 10 years. Data represent mean ± SD of each year. *P_adj. < 0.05, **P_adj. < 0.01. (C) Protein change between 6 and 10 years within a participant across each subcohort is displayed in colors corresponding to the mean of the log₂ fold change (10 years/6 years) within a participant. Among the T2D or prediabetes-specific proteins from Figure 1, proteins mostly changed in T2D-progressor or prediabetes-progressor are shown (Supplemental Data File 5). A star is displayed in each cell if abundance of a protein was significantly changed at 10 years compared with 6 years by paired 2-tailed t test. (D) ROC curve and corresponding AUC statistics using random forest model, using a 2-fold stratified cross-validation and repeated process over 5,000 within-class shuffling to differentiate T2D-progressors and prediabetes-progressors from nonprogressors. (E) The 10 most discriminating features of T2D-progressors versus nonprogressors for model training.