1. The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes.
- Author
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Rhein, Sina, Costalunga, Riccardo, Inderhees, Julica, Gürtzgen, Tammo, Faupel, Teresa Christina, Shaheryar, Zaib, Arrulo Pereira, Adriana, Othman, Alaa, Begemann, Kimberly, Binder, Sonja, Stölting, Ines, Dorta, Valentina, Nawroth, Peter P., Fleming, Thomas, Oexle, Konrad, Prevot, Vincent, Nogueiras, Ruben, Meyhöfer, Svenja, Meyhöfer, Sebastian M., and Schwaninger, Markus
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DIACETYL ,DIABETES complications ,DIABETES ,PYRUVATES ,MILD cognitive impairment ,LACTATES - 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. Diabetes complications are attributed to reactive by-products of glycolysis, but cells consuming lactate and pyruvate are not spared. Here, the authors show that the reactive dicarbonyl dimethylglyoxal is formed from pyruvate, rises in diabetes, and potentially causes neurological complications of diabetes. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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