PuSH - Publication Server of Helmholtz Zentrum München: Circulating epigenetic signatures classifying brain insulin resistance in humans.

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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)

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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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