Targeted Proteomics Reveals Functional Targets for Early Diabetes Susceptibility in Young Adults.

IF 6 2区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS Circulation: Genomic and Precision Medicine Pub Date : 2024-02-01 Epub Date: 2024-02-07 DOI:10.1161/CIRCGEN.123.004192

Ravi V Shah, Jiawei Zhong, Lucas Massier, Kahraman Tanriverdi, Shih-Jen Hwang, Jeffrey Haessler, Matthew Nayor, Shilin Zhao, Andrew S Perry, John T Wilkins, Aladdin H Shadyab, JoAnn E Manson, Lisa Martin, Daniel Levy, Charles Kooperberg, Jane E Freedman, Mikael Rydén, Venkatesh L Murthy

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Abstract

Background: The circulating proteome may encode early pathways of diabetes susceptibility in young adults for surveillance and intervention. Here, we define proteomic correlates of tissue phenotypes and diabetes in young adults.

Methods: We used penalized models and principal components analysis to generate parsimonious proteomic signatures of diabetes susceptibility based on phenotypes and on diabetes diagnosis across 184 proteins in >2000 young adults in the CARDIA (Coronary Artery Risk Development in Young Adults study; mean age, 32 years; 44% women; 43% Black; mean body mass index, 25.6±4.9 kg/m²), with validation against diabetes in >1800 individuals in the FHS (Framingham Heart Study) and WHI (Women's Health Initiative).

Results: In 184 proteins in >2000 young adults in CARDIA, we identified 2 proteotypes of diabetes susceptibility-a proinflammatory fat proteotype (visceral fat, liver fat, inflammatory biomarkers) and a muscularity proteotype (muscle mass), linked to diabetes in CARDIA and WHI/FHS. These proteotypes specified broad mechanisms of early diabetes pathogenesis, including transorgan communication, hepatic and skeletal muscle stress responses, vascular inflammation and hemostasis, fibrosis, and renal injury. Using human adipose tissue single cell/nuclear RNA-seq, we demonstrate expression at transcriptional level for implicated proteins across adipocytes and nonadipocyte cell types (eg, fibroadipogenic precursors, immune and vascular cells). Using functional assays in human adipose tissue, we demonstrate the association of expression of genes encoding these implicated proteins with adipose tissue metabolism, inflammation, and insulin resistance.

Conclusions: A multifaceted discovery effort uniting proteomics, underlying clinical susceptibility phenotypes, and tissue expression patterns may uncover potentially novel functional biomarkers of early diabetes susceptibility in young adults for future mechanistic evaluation.

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靶向蛋白质组学揭示年轻人早期糖尿病易感性的功能靶点

背景：循环蛋白质组可能编码青壮年糖尿病易感性的早期途径，以便进行监测和干预。在此，我们定义了组织表型与青壮年糖尿病的蛋白质组相关性：方法：我们使用惩罚模型和主成分分析方法，根据表型和糖尿病诊断，在 CARDIA（年轻人冠状动脉风险发展研究；平均年龄 32 岁；44% 女性；43% 黑人；平均体重指数 25.6±4.9kg/m2）研究中超过 2,000 名年轻人的 184 个蛋白质中生成了糖尿病易感性的蛋白质组特征，并在 FHS（弗雷明汉心脏研究）和 WHI（妇女健康倡议）研究中超过 1,800 名糖尿病患者中进行了验证：在 CARDIA 超过 2,000 名年轻成人的 184 种蛋白质中，我们发现了糖尿病易感性的 2 种蛋白质型--促炎症脂肪蛋白质型（内脏脂肪、肝脏脂肪、炎症生物标志物）和肌肉蛋白质型（肌肉质量），这两种蛋白质型与 CARDIA 和 WHI/FHS 的糖尿病有关。这些蛋白型明确了早期糖尿病发病的广泛机制，包括跨器官沟通、肝脏和骨骼肌应激反应、血管炎症和止血、纤维化和肾损伤。利用人体脂肪组织单细胞/核 RNA-seq，我们在转录水平上证明了脂肪细胞和非脂肪细胞类型（如成纤维前体、免疫细胞和血管细胞）中相关蛋白质的表达。通过在人体脂肪组织中进行功能测试，我们证明了编码这些相关蛋白的基因的表达与脂肪组织代谢、炎症和胰岛素抵抗的关系：结论：将蛋白质组学、潜在的临床易感性表型和组织表达模式结合起来的多方面发现工作可能会发现年轻成人早期糖尿病易感性的潜在新型功能性生物标记物，以便将来进行机理评估。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Circulation: Genomic and Precision Medicine Biochemistry, Genetics and Molecular Biology-Genetics

CiteScore

9.20

自引率

5.40%

发文量

144

期刊介绍： Circulation: Genomic and Precision Medicine is a distinguished journal dedicated to advancing the frontiers of cardiovascular genomics and precision medicine. It publishes a diverse array of original research articles that delve into the genetic and molecular underpinnings of cardiovascular diseases. The journal's scope is broad, encompassing studies from human subjects to laboratory models, and from in vitro experiments to computational simulations. Circulation: Genomic and Precision Medicine is committed to publishing studies that have direct relevance to human cardiovascular biology and disease, with the ultimate goal of improving patient care and outcomes. The journal serves as a platform for researchers to share their groundbreaking work, fostering collaboration and innovation in the field of cardiovascular genomics and precision medicine.