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.