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10.1016_j.tem.2019.04.011.pdf (2.82 MB)

Hexokinase-2 Glycolytic Overload in Diabetes and Ischemia–Reperfusion Injury

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submitted on 2024-06-27, 12:47 and posted on 2024-06-27, 12:48 authored by Naila Rabbani, Paul J. Thornalley


Hexokinase-2 (HK2) was recently found to produce increased metabolic flux through glycolysis in hyperglycemia without concurrent transcriptional or other functional regulation. Rather, stabilization to proteolysis by increased glucose substrate binding produced unscheduled increased glucose metabolism in response to high cytosolic glucose concentration. This produces abnormal increases in glycolytic intermediates or glycolytic overload, driving cell dysfunction and vulnerability to the damaging effects of hyperglycemia in diabetes, explaining tissue-specific pathogenesis. Glycolytic overload is also activated in ischemia–reperfusion injury and cell senescence. A further key feature is HK2 displacement from mitochondria by increased glucose-6-phosphate concentration, inducing mitochondrial dysfunction and oxidative stress. This pathogenic mechanism suggested new targets for therapeutics development that gave promising outcomes in initial clinical evaluation.

Other Information

Published in: Trends in Endocrinology & Metabolism
License: http://creativecommons.org/licenses/by-nc-nd/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.tem.2019.04.011

History

Language

  • English

Publisher

Cell Press

Publication Year

  • 2019

License statement

This Item is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • Qatar Biomedical Research Institute - HBKU
  • Diabetes Research Center - QBRI

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