TY  - JOUR
AU  - Schumacher, Dagmar
AU  - Morgenstern, Jakob
AU  - Oguchi, Yoko
AU  - Volk, Nadine
AU  - Kopf, Stefan
AU  - Groener, Jan Benedikt
AU  - Nawroth, Peter Paul
AU  - Fleming, Thomas
AU  - Freichel, Marc
TI  - Compensatory mechanisms for methylglyoxal detoxification in experimental </td><td width="150">
TI  - amp; clinical diabetes.
JO  - Molecular metabolism
VL  - 18
SN  - 2212-8778
CY  - Oxford [u.a.]
PB  - Elsevier
M1  - DKFZ-2018-01585
SP  - 143-152
PY  - 2018
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:30287091
DO  - DOI:10.1016/j.molmet.2018.09.005
UR  - https://inrepo02.dkfz.de/record/140821
ER  -