Circulating epigenetic signatures classifying brain insulin resistance in humans

IF 14.6 1区医学 Q1 CELL BIOLOGY

Science Translational Medicine Pub Date : 2025-08-06 DOI:10.1126/scitranslmed.adv7834

Stephanie Kullmann, Amandeep Singh, Ratika Sehgal, Fabian Eichelmann, Leontine Sandforth, Britta Wilms, Markus Jähnert, Andreas Peter, Svenja Meyhöfer, Dirk Walther, Hubert Preissl, Hans-Ulrich Häring, Matthias B. Schulze, Martin Heni, Andreas L. Birkenfeld, Annette Schürmann, Meriem Ouni

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Abstract

Brain insulin action plays an important role in metabolic and cognitive health, but there is no biomarker available to assess brain insulin resistance in humans. Here, we developed a machine learning framework based on blood DNA methylation profiles of participants who did not have type 2 diabetes with and without brain insulin resistance and detailed metabolic phenotyping. We identified 540 DNA methylation sites (CpGs) as classifiers of brain insulin resistance in a discovery cohort ( n = 167), results that were validated in two replication cohorts ( n = 33 and 24) with high accuracy (83 to 94%). All 540 CpGs were differentially methylated and annotated to 445 genes mapping to neuronal development and axonogenesis processes. Methylation patterns of 98 of 540 CpGs exhibited a strong and significant ( P < 0.05) blood-brain correlation, indicating that blood cells are a reliable proxy to capture brain-specific DNA methylation changes. These blood-based epigenetic signatures could potentially serve in the future for the early detection of individuals with brain insulin resistance in a broad clinical setting.

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分类人类脑胰岛素抵抗的循环表观遗传特征

脑胰岛素作用在代谢和认知健康中起着重要作用，但没有可用的生物标志物来评估人类脑胰岛素抵抗。在这里，我们开发了一个机器学习框架，该框架基于没有2型糖尿病的参与者的血液DNA甲基化谱，这些参与者有或没有脑胰岛素抵抗和详细的代谢表型。我们在一个发现队列（n = 167）中鉴定出540个DNA甲基化位点（CpGs）作为脑胰岛素抵抗的分类器，结果在两个重复队列（n = 33和24）中得到了验证，准确率很高（83 - 94%）。所有540个CpGs都被差异甲基化，并被注释为445个与神经元发育和轴突发生过程相关的基因。在540个CpGs中，有98个的甲基化模式表现出强烈且显著的(P <；0.05)血脑相关性，表明血细胞是捕获脑特异性DNA甲基化变化的可靠代理。这些基于血液的表观遗传特征可能在未来广泛的临床环境中用于早期检测脑胰岛素抵抗个体。

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

Science Translational Medicine CELL BIOLOGY-MEDICINE, RESEARCH & EXPERIMENTAL

CiteScore

26.70

自引率

1.20%

发文量

309

审稿时长

1.7 months

期刊介绍： Science Translational Medicine is an online journal that focuses on publishing research at the intersection of science, engineering, and medicine. The goal of the journal is to promote human health by providing a platform for researchers from various disciplines to communicate their latest advancements in biomedical, translational, and clinical research. The journal aims to address the slow translation of scientific knowledge into effective treatments and health measures. It publishes articles that fill the knowledge gaps between preclinical research and medical applications, with a focus on accelerating the translation of knowledge into new ways of preventing, diagnosing, and treating human diseases. The scope of Science Translational Medicine includes various areas such as cardiovascular disease, immunology/vaccines, metabolism/diabetes/obesity, neuroscience/neurology/psychiatry, cancer, infectious diseases, policy, behavior, bioengineering, chemical genomics/drug discovery, imaging, applied physical sciences, medical nanotechnology, drug delivery, biomarkers, gene therapy/regenerative medicine, toxicology and pharmacokinetics, data mining, cell culture, animal and human studies, medical informatics, and other interdisciplinary approaches to medicine. The target audience of the journal includes researchers and management in academia, government, and the biotechnology and pharmaceutical industries. It is also relevant to physician scientists, regulators, policy makers, investors, business developers, and funding agencies.