<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism"^^ . "Type-2 diabetes (T2D) is a heterogeneous and multifactorial disorder whose pathophysiology is\r\nnot completely understood. The first impairment seen in individuals suffering from T2D is insulin\r\nresistance resulting from: (i) mitochondrial dysfunction; (ii) lipid-induced insulin resistance; (iii)\r\nendoplasmic reticulum stress; and (iv) inflammation. Methylglyoxal (MG), a potent-glycating agent\r\nproduced in physiological conditions as a by-product of glycolysis, has shown to be associated\r\nwith the activation of the four above-mentioned impairments leading to insulin resistance. The\r\neffects of MG on cellular metabolism have been studied extensively and the modulation of its\r\nmain detoxification enzyme, Glo1, has been used as a strategy to resemble increased levels of\r\nMG in diabetes. The knockdown of Glo1 in experimental murine models has been linked to the\r\ndevelopment of diabetic nephropathy and has shown increased MG levels. Moreover, the\r\ncomplete knockout of Glo1 (Glo1-KO) in Drosophila melanogaster or zebrafish, produced a T2Dphenoype\r\nwith insulin resistance, potentially as a cause of increased levels of MG. In this study,\r\nit was hypothesized that the loss of Glo1 in mice could also recapitulate a T2D-phenotype. To test\r\nthis hypothesis, Glo1-KO C57BL/6 mice were generated and compared to wildtype mice (WT),\r\nas a non-diabetic model, and mice subjected to a long-term high-fat diet (HFD), as a model of\r\nT2D. As expected, mice on a HFD showed increased body weight and blood glucose levels, as\r\nwell as impaired glucose and insulin tolerance as compared to WT-mice. None of these\r\nphysiological alterations, however, were seen in the Glo1-KO mice. Analysis of the liver and\r\nkidneys also showed no changes in the Glo1-KO mice. However, hepatic gene expression\r\nprofiling showed a sex dimorphism in the Glo1-KO mice. The Glo1-KO male mice showed\r\nincreased expression in the complexes of the mitochondrial electron transport chain. Further\r\nexperiments showed a potential impairment in mitochondrial function in male Glo1-KO mice, as\r\nshown by significant increases in the levels of the citric acid cycle intermediates, after insulin\r\nstimulation, as well as an impaired lactate to pyruvate ratio. The impaired mitochondrial function\r\nin Glo1-KO males was also accompanied by reduced AMPK and insulin signalling cascade\r\nactivation, as measured by Akt phosphorylation. Comparison of the hepatic gene expression from\r\nthe female and male WT- and Glo1-KO mice showed an increased expression in the cytochrome\r\nP450 family in female mice. Specifically, an increase in the expression and activity of the\r\nisoenzymes involved in the metabolism of arachidonic acid. In conclusion, this study could show\r\nthat the loss of Glo1 in mice does not recapitulate a T2D phenotype. However, this study did show\r\nthat the effects resulting from the loss of Glo1 are sex dimorphic, in which male mice are more\r\nsusceptible. The increase in arachidonic acid metabolism, in particularly the levels of\r\nepoxyeicosatrienoic acids (EETs), and the beneficial effects that they induce with respect to\r\ninflammation, mitochondrial dysfunction and insulin resistance, is proposed as a protective\r\nmechanism in females from the loss of Glo1."^^ . "2024" . . . . . . . "Marta"^^ . "Campos Campos"^^ . "Marta Campos Campos"^^ . . . . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (PDF)"^^ . . . "Campos_Campos_Marta_01_12_1995_Dissertation.pdf"^^ . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (Other)"^^ . . . . . . "lightbox.jpg"^^ . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (Other)"^^ . . . . . . "preview.jpg"^^ . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (Other)"^^ . . . . . . "medium.jpg"^^ . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (Other)"^^ . . . . . . "small.jpg"^^ . . . "The consequences of the loss of Glyoxalase 1 on cellular metabolism (Other)"^^ . . . . . . "indexcodes.txt"^^ . . "HTML Summary of #33956 \n\nThe consequences of the loss of Glyoxalase 1 on cellular metabolism\n\n" . "text/html" . . . "570 Biowissenschaften, Biologie"@de . "570 Life sciences"@en . . . "610 Medizin"@de . "610 Medical sciences Medicine"@en . .