Compensatory mechanisms for methylglyoxal detoxification in experimental & clinical diabetes
| Autor: | Dagmar Schumacher, Yoko Oguchi, Peter P. Nawroth, Jakob Morgenstern, Nadine Volk, Marc Freichel, Jan B. Groener, Stefan Kopf, Thomas Fleming |
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| Rok vydání: | 2018 |
| Předmět: |
Glycation End Products
Advanced Male 0301 basic medicine Aldo-Keto Reductases GSSG Glutathione disulfide ALDH Aldehyde dehydrogenase Pharmacology Kidney Reactive metabolites Mice Lactoylglutathione lyase chemistry.chemical_compound MDRD Modification of Diet in Renal Disease Advanced glycation end products GSH Glutathione chemistry.chemical_classification biology Chemistry Methylglyoxal Lactoylglutathione Lyase Advanced Glycation End Products Glyoxalase 1 Reactive Metabolites Diabetic Complications Aldo-keto Reductases Middle Aged AGE Advanced glycation end product Pyruvaldehyde Liver Female Glo2 Glyoxalase 2 medicine.drug lcsh:Internal medicine AKR Aldo-keto reductase MG-H1 arginine-derived hydroimidazalone Nδ-(5-hydro-5-methyl- 4-imidazolon-2-yl)-ornithine UACR Urine Albumine-Creatinine Ratio Brief Communication Diabetes Mellitus Experimental Diabetic complications 03 medical and health sciences Detoxification Diabetes mellitus medicine Animals Humans Distribution (pharmacology) lcsh:RC31-1245 Glo1 Glyoxalase 1 Molecular Biology Aged Aldo-keto reductase STZ Streptozotocin Cell Biology Streptozotocin medicine.disease Mice Inbred C57BL MG Methylglyoxal 030104 developmental biology Enzyme Diabetes Mellitus Type 2 HTA Hemithioacetal biology.protein |
| Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 18, Iss, Pp 143-152 (2018) Mol. Metab. 18, 143-152 (2018) |
| ISSN: | 2212-8778 |
| DOI: | 10.1016/j.molmet.2018.09.005 |
| Popis: | 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, Glyoxalase 1, Reactive metabolites, Methylglyoxal, Diabetic complications, Aldo-keto reductases |
| Databáze: | OpenAIRE |
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