Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes

• Verfasst von: Schumacher, Dagmar [VerfasserIn]
• Verfasst von: Morgenstern, Jakob [VerfasserIn]
• Verfasst von: Oguchi, Yoko [VerfasserIn]
• Verfasst von: Volk, Nadine [VerfasserIn]
• Verfasst von: Kopf, Stefan [VerfasserIn]
• Verfasst von: Gröner, Jan [VerfasserIn]
• Verfasst von: Nawroth, Peter Paul [VerfasserIn]
• Verfasst von: Fleming, Thomas [VerfasserIn]
• Verfasst von: Freichel, Marc [VerfasserIn]
• Titel: Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes
• Verf.angabe: Dagmar Schumacher, Jakob Morgenstern, Yoko Oguchi, Nadine Volk, Stefan Kopf, Jan Benedikt Groener, Peter Paul Nawroth, Thomas Fleming, Marc Freichel
• E-Jahr: 2018
• Jahr: 19 September 2018
• Umfang: 10 S.
• Fussnoten: Gesehen am 28.08.2019
• Titel Quelle: Enthalten in: Molecular metabolism
• Ort Quelle: Oxford [u.a.] : Elsevier, 2012
• Jahr Quelle: 2018
• Band/Heft Quelle: 18(2018), Seite 143-152
• ISSN Quelle: 2212-8778
• DOI: doi:10.1016/j.molmet.2018.09.005
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Advanced glycation end products
• Sach-SW: Aldo-keto reductases
• Sach-SW: Diabetic complications
• Sach-SW: Glyoxalase 1
• Sach-SW: Methylglyoxal
• Sach-SW: Reactive metabolites
• K10plus-PPN: 1672329620

Abstract

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.