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.
Keywords: Advanced glycation end products; Aldo-keto reductases; Diabetic complications; Glyoxalase 1; Methylglyoxal; Reactive metabolites.
Copyright © 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.