Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes

Abstract

ObjectivesThe 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.MethodsCRISPR/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.ResultsGlo1−/− 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.ConclusionsThese 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.

Impairment of methylglyoxal detoxification systems causes mitochondrial dysfunction and schizophrenia-like behavioral deficits

“…For example, other enzymes such as aldehyde dehydrogenase and AKR metabolize MG to pyruvate and hydroxyacetone, respectively 22,23 . Consistent with our findings, in vitro and in vivo studies show that in the absence of Glo1, AKR may compensate concerning MG detoxification, resulting in no MG accumulation 24,25 . We also found no change in gene expression of AKR in the brain of Glo1 KO mice (Fig.…”

The Glyoxalase System—New Insights into an Ancient Metabolism

“…Obviously, compensatory pathways for the glyoxalase system were underestimated in earlier studies. This is supported by the findings that in mammalian models a complete loss of Glo1 does not result in basal MG and MG-H1 elevations, even under high glucose conditions [ 72 , 74 ]. It has to be pointed out that most of the in vitro studies about MG-derived AGEs and DNA adducts had to use exogenously added MG in a supraphysiological range in order to achieve obvious molecular effects [ 64 , 72 , 75 , 76 , 77 ].…”

“…In a mouse models with a global Glo1 KO, others were able to show that the expected damaging effects of Glo1 loss are rather mild or non-existent [ 68 , 74 ]. One group postulated increased levels of MG-H1 due to Glo1 loss, using an obsolete immunoblot technique, but only found this increase in the liver and not in the brain.…”

The combination of loss of glyoxalase1 and obesity results in hyperglycemia

“…In addition to the glyoxalase system, aldo-keto reductase and aldehyde dehydrogenase can detoxify MG (8,9). Recently, aldo-keto reductase and aldehyde dehydrogenase could be shown to efficiently compensate for loss of glyoxalase 1 in cells and mice (10,11).…”

“…Although these findings indicate the important role of MG in the pathogenesis of diabetes mellitus, most studies have only focused on external addition of MG (24) to cells or rodent models; however, the consequences of endogenous MG elevation are still poorly understood. Recently, glo1-knockout flies and mice were reported (11,25,26). Glo1-knockout mice compensate effectively for the loss of glyoxalase 1, whereas the glo1-knockout fly has elevated MG concentrations.…”