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Rhein, S.* ; Costalunga, R.* ; Inderhees, J.* ; Gürtzgen, T.* ; Faupel, T.C.* ; Shaheryar, Z.* ; Arrulo Pereira, A.* ; Othman, A.* ; Begemann, K.* ; Binder, S.* ; Stölting, I.* ; Dorta, V.* ; Nawroth, P.P.* ; Fleming, T.* ; Oexle, K. ; Prévot, V.* ; Nogueiras, R.* ; Meyhöfer, S.* ; Meyhöfer, S.M.* ; Schwaninger, M.*

The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes.

Nat. Commun. 15:5745 (2024)
Publ. Version/Full Text DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Complications of diabetes are often attributed to glucose and reactive dicarbonyl metabolites derived from glycolysis or gluconeogenesis, such as methylglyoxal. However, in the CNS, neurons and endothelial cells use lactate as energy source in addition to glucose, which does not lead to the formation of methylglyoxal and has previously been considered a safer route of energy consumption than glycolysis. Nevertheless, neurons and endothelial cells are hotspots for the cellular pathology underlying neurological complications in diabetes, suggesting a cause that is distinct from other diabetes complications and independent of methylglyoxal. Here, we show that in clinical and experimental diabetes plasma concentrations of dimethylglyoxal are increased. In a mouse model of diabetes, ilvb acetolactate-synthase-like (ILVBL, HACL2) is the enzyme involved in formation of increased amounts of dimethylglyoxal from lactate-derived pyruvate. Dimethylglyoxal reacts with lysine residues, forms Nε-3-hydroxy-2-butanonelysine (HBL) as an adduct, induces oxidative stress more strongly than other dicarbonyls, causes blood-brain barrier disruption, and can mimic mild cognitive impairment in experimental diabetes. These data suggest dimethylglyoxal formation as a pathway leading to neurological complications in diabetes that is distinct from other complications. Importantly, dimethylglyoxal formation can be reduced using genetic, pharmacological and dietary interventions, offering new strategies for preventing CNS dysfunction in diabetes.
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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Journal Nature Communications
Quellenangaben Volume: 15, Issue: 1, Pages: , Article Number: 5745 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants European Research Council (ERC) under the European Union
Deutsche Forschungsgemeinschaft
Deutsche Forschungsgemeinschaft (German Research Foundation)