Proteomic signatures of loss of glycemic control in youth-onset type 2 diabetes in the TODAY study.
CONTEXT Youth-onset type 2 diabetes (T2D) is characterized by accelerated β-cell decline and early treatment failure, and there is an urgent need to improve the understanding of molecular drivers of loss of glycemic control (LOGC). OBJECTIVE To identify multiprotein signatures associated with loss of glycemic control (LOGC) in youth-onset T2D. DESIGN Longitudinal observational study with a mean follow-up of 10.8 ± 3.8 years using data from the TODAY study, with external validation in three youth cohorts and one adult-onset T2D cohort. SETTING Multicenter clinical research study. PARTICIPANTS Participants from the TODAY study (N = 374; age 14 ± 2 years; 37% male), of whom 72% experienced LOGC over 10.8 ± 3.8 years. INTERVENTIONS None. MAIN OUTCOME MEASURE LOGC, defined as HbA1c ≥ 8% for ≥6 months or inability to discontinue insulin after acute metabolic decompensation. RESULTS Plasma proteomics quantified 7604 aptamers representing 6596 proteins using the SomaScan 7 K platform. Sixty-seven proteins were associated with LOGC after false discovery rate correction and multivariable adjustment. Key proteins included plexin-B2 (HR: 1.46 [95% CI: 1.29-1.66]) and semaphorin-6A (HR: 1.31 [1.18-1.47]), which were also associated with glycemic outcomes in independent youth and adult cohorts. Enrichment analyses implicated pathways related to axon guidance, immune response, inflammation, and metabolism. CONCLUSIONS Novel proteins involved in axon guidance, immune response, inflammation, and metabolism associated with LOGC in youth-onset T2D with proteins demonstrating consistent associations across the lifespan and proteomic platforms.