Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes

摘要

Objectives p id="abspara0010"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 p id="abspara0015"CRISPR/Cas9-mediated genome editing was used to generate a Glo1 knock-out ( Glo1 sup ?/? /sup) mouse line. Streptozotocin was then applied to investigate metabolic changes under hyperglycemic conditions. Results p id="abspara0020" Glo1 sup ?/? /sup 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 sup ?/? /sup 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 p id="abspara0025"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.