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The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes

Author

Listed:
  • Sina Rhein

    (University of Lübeck
    partner site Hamburg/Lübeck/Kiel)

  • Riccardo Costalunga

    (University of Lübeck
    partner site Hamburg/Lübeck/Kiel
    University of Lübeck)

  • Julica Inderhees

    (University of Lübeck
    partner site Hamburg/Lübeck/Kiel
    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
    ETH Zurich)

  • 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
    German Center for Diabetes Research (DZD))

  • Konrad Oexle

    (Helmholtz
    Technical University of Munich)

  • Vincent Prevot

    (EGID)

  • Ruben Nogueiras

    (University of Santiago de Compostela-Instituto de Investigación Sanitaria)

  • Svenja Meyhöfer

    (German Center for Diabetes Research (DZD)
    University of Lübeck
    University Hospital Schleswig-Holstein Campus Lübeck)

  • Sebastian M. Meyhöfer

    (German Center for Diabetes Research (DZD)
    University of Lübeck)

  • Markus Schwaninger

    (University of Lübeck
    partner site Hamburg/Lübeck/Kiel)

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.

Suggested Citation

  • Sina Rhein & Riccardo Costalunga & Julica Inderhees & Tammo Gürtzgen & Teresa Christina Faupel & Zaib Shaheryar & Adriana Arrulo Pereira & Alaa Othman & Kimberly Begemann & Sonja Binder & Ines Stöltin, 2024. "The reactive pyruvate metabolite dimethylglyoxal mediates neurological consequences of diabetes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-50089-3
    DOI: 10.1038/s41467-024-50089-3
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    References listed on IDEAS

    as
    1. Michael Brownlee, 2001. "Biochemistry and molecular cell biology of diabetic complications," Nature, Nature, vol. 414(6865), pages 813-820, December.
    2. Sheng Hui & Jonathan M. Ghergurovich & Raphael J. Morscher & Cholsoon Jang & Xin Teng & Wenyun Lu & Lourdes A. Esparza & Tannishtha Reya & Le Zhan & Jessie Yanxiang Guo & Eileen White & Joshua D. Rabi, 2017. "Glucose feeds the TCA cycle via circulating lactate," Nature, Nature, vol. 551(7678), pages 115-118, November.
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