1135-P: Pigment Epithelium–Derived Factor, Diabetic Kidney Disease, and Hypertension—Deciphering the Proteomic Response to Metabolic Bariatric Surgery in Adolescents

Introduction & Objective: This study aims to explore the effects of metabolic bariatric surgery (MBS) on plasma proteins linked to diabetic kidney disease and hypertension in youth with type 2 diabetes (T2D).

Methods: We measured 7604 proteins in 326 plasma samples from severely obese youth, both with and without T2D, in the Teen-LABS study, examining pre- and post-MBS changes (6 month, 1, 2-, 3-, 4-, and 5-year follow-up). This analysis focused on proteins identified in the TODAY cohort as predictors of severe albuminuria (ACR ≥300 mg/g) and hypertension (SBP≥130/80 mm Hg), in youth with T2D (n=374), using Cox proportional hazard models adjusted for age, sex, HbA1c, log-transformed triglycerides and estimated insulin sensitivity. A mixed model evaluated proteomic changes post-MBS, maintaining a 5% false discovery rate with reported q-values.

Results: In Teen-LABS, several proteins associated with a higher risk of severe albuminuria and hypertension in TODAY showed notable post-surgical downregulation. Higher pigment epithelium-derived factor (PEDF) at baseline predicted onset to severe albuminuria (HR: 1.63, 95% CI 1.12, 2.37, per 1 SD increment) and hypertension (HR: 1.41, 95% CI 1.22, 1.63, per 1 SD increment) over 15 years in TODAY after multivariable adjustments. In Teen-LABS, PEDF decreased post-MBS compared to baseline at 6 months follow-up (logFC: -0.30, q-value=1.24x10^-31), year 1 (logFC: -0.28, q-value=2.35x10^-29), year 2 (logFC: -0.32, q-value=1.85x10^-34), year 3 (logFC: -0.28, q-value=6.95x10^-29), year 4 (logFC: -0.30, q-value=4.13x10^-28) and year 5 (logFC: -0.30, q-value=2.78x10^-26).

Conclusion: These analyses show durable attenuation of plasma PEDF after MBS, a protein strongly associated with risk of severe albuminuria and hypertension in youth with T2D. PEDF is implicated in endothelial dysfunction and vascular damage through impaired angiogenesis and endothelial repair mechanisms.