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@ARTICLE{Schumacher:140821,
author = {D. Schumacher and J. Morgenstern and Y. Oguchi and N. Volk
and S. Kopf and J. B. Groener and P. P. Nawroth$^*$ and T.
Fleming and M. Freichel},
title = {{C}ompensatory mechanisms for methylglyoxal detoxification
in experimental $\&$ clinical diabetes.},
journal = {Molecular metabolism},
volume = {18},
issn = {2212-8778},
address = {Oxford [u.a.]},
publisher = {Elsevier},
reportid = {DKFZ-2018-01585},
pages = {143-152},
year = {2018},
abstract = {The deficit of Glyoxalase I (Glo1) and the subsequent
increase in methylglyoxal (MG) has been reported to be one
the five mechanisms by which hyperglycemia causes diabetic
late complications. Aldo-keto reductases (AKR) have been
shown to metabolize MG; however, the relative contribution
of this superfamily to the detoxification of MG in vivo,
particularly within the diabetic state, remains
unknown.CRISPR/Cas9-mediated genome editing was used to
generate a Glo1 knock-out (Glo1-/-) mouse line.
Streptozotocin was then applied to investigate metabolic
changes under hyperglycemic conditions.Glo1-/- mice were
viable and showed no elevated MG or MG-H1 levels under
hyperglycemic conditions. It was subsequently found that the
enzymatic efficiency of various oxidoreductases in the liver
and kidney towards MG were increased in the Glo1-/- mice.
The functional relevance of this was supported by the
altered distribution of alternative detoxification products.
Furthermore, it was shown that MG-dependent AKR activity is
a potentially clinical relevant pathway in human patients
suffering from diabetes.These data suggest that in the
absence of GLO1, AKR can effectively compensate to prevent
the accumulation of MG. The combination of metabolic,
enzymatic, and genetic factors, therefore, may provide a
better means of identifying patients who are at risk for the
development of late complications caused by elevated levels
of MG.},
cin = {A170},
ddc = {610},
cid = {I:(DE-He78)A170-20160331},
pnm = {311 - Signalling pathways, cell and tumor biology
(POF3-311)},
pid = {G:(DE-HGF)POF3-311},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:30287091},
doi = {10.1016/j.molmet.2018.09.005},
url = {https://inrepo02.dkfz.de/record/140821},
}