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Kullmann, S. ; Singh, A.* ; Sehgal, R.* ; Eichelmann, F.* ; Sandforth, L. ; Wilms, B.* ; Jähnert, M.* ; Peter, A. ; Meyhöfer, S.* ; Walther, D.* ; Preissl, H. ; Häring, H.-U. ; Schulze, M.B.* ; Heni, M.* ; Birkenfeld, A.L. ; Schürmann, A.* ; Ouni, M.*

Circulating epigenetic signatures classifying brain insulin resistance in humans.

Sci. Transl. Med. 17:eadv7834 (2025)
Postprint DOI PMC
Open Access Green
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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Publication type Article: Journal article
Document type Scientific Article
Keywords Glucose-uptake; Sad Kinases; Sensitivity; Hyperinsulinemia; Hypothalamus; Overweight; Blood
ISSN (print) / ISBN 1946-6234
e-ISSN 1946-6242
Journal Science Translational Medicine
Quellenangaben Volume: 17, Issue: 810, Pages: , Article Number: eadv7834 Supplement: ,
Publisher American Association for the Advancement of Science (AAAS)
Publishing Place 1200 New York Ave, Nw, Washington, Dc 20005 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes Research and Metabolic Diseases (IDM)
Grants German research Association as a clinician scientist
German research Foundation
German diabetes Society (ddG)
German center for diabetes research
Brandenburg State
German Ministry of Education and Research (BMBF)