Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes
Objectives - 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...
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| Main Authors: | , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
19 September 2018
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| In: |
Molecular metabolism
Year: 2018, Volume: 18, Pages: 143-152 |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2018.09.005 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.molmet.2018.09.005 Verlag, Volltext: http://www.sciencedirect.com/science/article/pii/S2212877818302047 
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| Author Notes: | Dagmar Schumacher, Jakob Morgenstern, Yoko Oguchi, Nadine Volk, Stefan Kopf, Jan Benedikt Groener, Peter Paul Nawroth, Thomas Fleming, Marc Freichel |
| Summary: | Objectives - 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. - Methods - 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. - Results - 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. - Conclusions - 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. |
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| Item Description: | Gesehen am 28.08.2019 |
| Physical Description: | Online Resource |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2018.09.005 |