1135-P：色素上皮衍生因子、糖尿病肾病和高血压--解读蛋白质组对青少年代谢减肥手术的反应

IF 6.2 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Diabetes Pub Date : 2024-07-19 DOI:10.2337/db24-1135-p

PHOOM NARONGKIATIKHUN, YE JI CHOI, NHUNG NGUYEN, KELLY NASH, KALIE L. TOMMERDAHL, MATTHIAS KRETZLER, THOMAS INGE, JUSTIN R. RYDER, LAURA PYLE, PETTER BJORNSTAD

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引用次数: 0

摘要

引言& 目的：本研究旨在探讨代谢减重手术（MBS）对2型糖尿病（T2D）患者血浆中与糖尿病肾病和高血压有关的蛋白质的影响。研究方法我们测量了 Teen-LABS 研究中 326 份严重肥胖青少年血浆样本中的 7604 种蛋白质，其中既有 T2D 患者，也有非 T2D 患者，并检查了减重手术前后（6 个月、1 年、2 年、3 年、4 年和 5 年随访）的变化。这项分析的重点是在 TODAY 队列中发现的可预测患有 T2D 的青少年（人数=374）严重白蛋白尿（ACR ≥300 mg/g）和高血压（SBP ≥130/80 mm Hg）的蛋白质，使用的是经年龄、性别、HbA1c、对数变换甘油三酯和估计胰岛素敏感性调整的 Cox 比例危险模型。混合模型评估了MBS后蛋白质组的变化，报告的q值保持了5%的误发现率。结果在 Teen-LABS 中，与 TODAY 中严重白蛋白尿和高血压风险较高相关的几种蛋白质在手术后出现了明显的下调。经多变量调整后，基线色素上皮衍生因子（PEDF）越高，预示 TODAY 15 年后会出现严重白蛋白尿（HR：1.63，95% CI 1.12，2.37，每 1 SD 增量）和高血压（HR：1.41，95% CI 1.22，1.63，每 1 SD 增量）。在 Teen-LABS 中，MBS 后与基线相比，PEDF 在 6 个月随访（logFC：-0.30，q-value=1.24x10-31）、第 1 年（logFC：-0.28，q-value=2.35x10-29）、第 2 年（logFC：-0.32，q-value=1.85x10-34）、第 3 年（logFC：-0.28，q-value=6.95x10-29）、第 4 年（logFC：-0.30，q-value=4.13x10-28）和第 5 年（logFC：-0.30，q-value=2.78x10-26）。结论这些分析表明，血浆中的 PEDF 在 MBS 后会持续减少，而这种蛋白质与患有 T2D 的青少年出现严重白蛋白尿和高血压的风险密切相关。PEDF 与血管生成和内皮修复机制受损导致的内皮功能障碍和血管损伤有关。披露 P. Narongkiatikhun：无。Y. Choi：无。N. Nguyen：无：无。K. Nash：无。K.L. Tommerdahl：无。M. Kretzler：研究资助；勃林格殷格翰、Certa、Traveere 制药公司、Maze Therapeutics、罗氏制药、阿斯利康、诺和诺德、Moderna 公司、Chinook Therapeutics 公司、angion、礼来糖尿病、Renalytix、吉利德科学公司、Regeneron 制药公司、杨森制药公司。T. Inge：顾问；美敦力、礼来公司、Brainstorm Therapeutics。股票/股东；Standard Bariatrics。顾问；Teleflex。J.R. Ryder：无。L. Pyle：无：无。P. Bjornstad：顾问；阿斯利康、勃林格殷格翰。顾问团；礼来糖尿病、诺和诺德、拜耳公司、Horizon Therapeutics plc。资助国立卫生研究院

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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. Disclosure P. Narongkiatikhun: None. Y. Choi: None. N. Nguyen: None. K. Nash: None. K.L. Tommerdahl: None. M. Kretzler: Research Support; Boehringer-Ingelheim, Certa, Traveere Pharmaceuticals, Maze Therapeutics, Roche Pharmaceuticals, AstraZeneca, Novo Nordisk, Moderna, Inc., Chinook Therapeutics Inc., angion, Lilly Diabetes, Renalytix, Gilead Sciences, Inc., Regeneron Pharmaceuticals Inc., Janssen Pharmaceuticals, Inc. T. Inge: Consultant; Medtronic, Eli Lilly and Company, Brainstorm Therapeutics. Stock/Shareholder; Standard Bariatrics. Consultant; Teleflex. J.R. Ryder: None. L. Pyle: None. P. Bjornstad: Consultant; AstraZeneca, Boehringer-Ingelheim. Advisory Panel; Lilly Diabetes, Novo Nordisk, Bayer Inc., Horizon Therapeutics plc. Funding National Institutes of Health

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来源期刊

Diabetes 医学-内分泌学与代谢

CiteScore

12.50

自引率

2.60%

发文量

1968

审稿时长

1 months

期刊介绍： Diabetes is a scientific journal that publishes original research exploring the physiological and pathophysiological aspects of diabetes mellitus. We encourage submissions of manuscripts pertaining to laboratory, animal, or human research, covering a wide range of topics. Our primary focus is on investigative reports investigating various aspects such as the development and progression of diabetes, along with its associated complications. We also welcome studies delving into normal and pathological pancreatic islet function and intermediary metabolism, as well as exploring the mechanisms of drug and hormone action from a pharmacological perspective. Additionally, we encourage submissions that delve into the biochemical and molecular aspects of both normal and abnormal biological processes. However, it is important to note that we do not publish studies relating to diabetes education or the application of accepted therapeutic and diagnostic approaches to patients with diabetes mellitus. Our aim is to provide a platform for research that contributes to advancing our understanding of the underlying mechanisms and processes of diabetes.