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Challenging the unifying hypothesis: Cellular dysfunction on multiple levels in situations of hyperglycemia despite normal glucose flux

Supervisor (Heidelberg): Thomas Fleming/Peter P. Nawroth
Co-Supervisor (Groningen): Maaike Oosterveer
Graduate: Marta Campos

Project description

Currently it is believed that increased glucose flux and ROS-dependent inhibition of GAPDH results in an overflow of glycolytic intermediates and the activation of different pathways of cellular dysfunction, such as the AGE-RAGE pathway, PKC activation and the pentose-phosphate pathway. These pathways contribute to the development of late diabetic complications. However the catalytic parameters (Km, KD, Kcat) of key regulator enzymes of glycolysis, such as hexokinases are not consistent with this view and also data from in vivo experiments indicate that this unifying hypothesis postulating increased glucose flux as the cause of cellular dysfunction might not be the only underlying mechanism [1-2]. Therefore alternative model(s) have to be developed, explaining cellular dysfunction despite normal glucose flux [1-2].


  1. Brownlee, M. Nature. 2001;414(6865):813-20.
  2. Schaffer, S.W. et al. Vascul Pharmacol. 2012; 57(5-6):139-49.

Methods used

Metabolic flux analysis, proteomics, RNAseq, biochemical and molecular analysis.

Collaboration Partners

  • Hans-Peter Hammes, Mannheim
  • Jens Kroll, Mannheim
  • Markus Hecker, Heidelberg