The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes

Sina Rhein, Riccardo Costalunga, Julica Inderhees, Tammo Gürtzgen, Teresa Christina Faupel, Zaib Shaheryar, Adriana Arrulo Pereira, Alaa Othman, Kimberly Begemann, Sonja Binder, Ines Stölting, Valentina Dorta, Peter P. Nawroth, Thomas Fleming, Konrad Oexle, Vincent Prevot, Ruben Nogueiras, Svenja Meyhöfer, Sebastian M. Meyhöfer and Markus Schwaninger ()
Additional contact information
Sina Rhein: University of Lübeck
Riccardo Costalunga: University of Lübeck
Julica Inderhees: University of Lübeck
Tammo Gürtzgen: University of Lübeck
Teresa Christina Faupel: University of Lübeck
Zaib Shaheryar: University of Lübeck
Adriana Arrulo Pereira: University of Lübeck
Alaa Othman: University of Lübeck
Kimberly Begemann: University of Lübeck
Sonja Binder: University of Lübeck
Ines Stölting: University of Lübeck
Valentina Dorta: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Peter P. Nawroth: University Hospital Heidelberg
Thomas Fleming: University Hospital Heidelberg
Konrad Oexle: Helmholtz
Vincent Prevot: EGID
Ruben Nogueiras: University of Santiago de Compostela-Instituto de Investigación Sanitaria
Svenja Meyhöfer: German Center for Diabetes Research (DZD)
Sebastian M. Meyhöfer: German Center for Diabetes Research (DZD)
Markus Schwaninger: University of Lübeck

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-50089-3

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