Abstract Body: Introduction: Proteomics could improve our understanding of the mechanisms underlying short-term prediabetes progression and remission, i.e., reverting to normoglycemia.

Objective: To identify proteomic predictors of 3-year progression from prediabetes to diabetes and remission.

Method: We used data from the Atherosclerosis Risk in Communities (ARIC) Study visit 2 (1990-2) and visit 3 (1993-5). We examined associations of 4,955 plasma proteins (SOMAScan v4.0) in participants with baseline prediabetes (fasting glucose [FG] 100-125 mg/dL without diabetes). We used multivariable logistic regressions to examine protein associations with 3-year progression from prediabetes to diabetes (physician diagnosis, medication, or FG ≥126 mg/dL) or remission (FG <100 mg/dL). Analyses were adjusted for demographics, cardiometabolic risk factors, and baseline glucose. Statistical significance was based on p<10^-5. We explored biologic pathways enriched among top proteins and calculated the delta-AUC for models with (and without) the associated proteins.

Results: The 3,788 participants with prediabetes were mean aged 57 years (SD:6), 52% were women, 18% self-identified as Black. The 3-year cumulative incidence of diabetes was 6% and was 40% for prediabetes remission. We identified 6 proteins associated with 3-year progression to diabetes (e.g., lower adiponectin [ADIPOQ]) and 8 proteins (e.g., higher insulin growth factor binding protein 2 [IGFBP2], lower complement C3 [C3]) associated with prediabetes remission. Adipogenesis and Jak/STAT signaling were among the pathways enriched in diabetes-associated proteins. Regulation of IGF transport and uptake by IGFBPs and C3/C5 activation were pathways for remission-associated proteins. The 6 proteins collectively improved diabetes progression prediction (covariate only AUC=0.798; delta-AUC=0.03 p<0.001). The 8 proteins collectively improved remission prediction (covariate only AUC=0.722; delta-AUC=0.03 p<0.001).

Conclusions: In persons with prediabetes, we identified known and novel proteins that were associated with 3-year progression to diabetes and remission. Proteins associated with remission relate to reduced inflammation and improved insulin sensitivity.