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Abstract

Type-2 diabetes (T2D) is a heterogeneous and multifactorial disorder whose pathophysiology is not completely understood. The first impairment seen in individuals suffering from T2D is insulin resistance resulting from: (i) mitochondrial dysfunction; (ii) lipid-induced insulin resistance; (iii) endoplasmic reticulum stress; and (iv) inflammation. Methylglyoxal (MG), a potent-glycating agent produced in physiological conditions as a by-product of glycolysis, has shown to be associated with the activation of the four above-mentioned impairments leading to insulin resistance. The effects of MG on cellular metabolism have been studied extensively and the modulation of its main detoxification enzyme, Glo1, has been used as a strategy to resemble increased levels of MG in diabetes. The knockdown of Glo1 in experimental murine models has been linked to the development of diabetic nephropathy and has shown increased MG levels. Moreover, the complete knockout of Glo1 (Glo1-KO) in Drosophila melanogaster or zebrafish, produced a T2Dphenoype with insulin resistance, potentially as a cause of increased levels of MG. In this study, it was hypothesized that the loss of Glo1 in mice could also recapitulate a T2D-phenotype. To test this hypothesis, Glo1-KO C57BL/6 mice were generated and compared to wildtype mice (WT), as a non-diabetic model, and mice subjected to a long-term high-fat diet (HFD), as a model of T2D. As expected, mice on a HFD showed increased body weight and blood glucose levels, as well as impaired glucose and insulin tolerance as compared to WT-mice. None of these physiological alterations, however, were seen in the Glo1-KO mice. Analysis of the liver and kidneys also showed no changes in the Glo1-KO mice. However, hepatic gene expression profiling showed a sex dimorphism in the Glo1-KO mice. The Glo1-KO male mice showed increased expression in the complexes of the mitochondrial electron transport chain. Further experiments showed a potential impairment in mitochondrial function in male Glo1-KO mice, as shown by significant increases in the levels of the citric acid cycle intermediates, after insulin stimulation, as well as an impaired lactate to pyruvate ratio. The impaired mitochondrial function in Glo1-KO males was also accompanied by reduced AMPK and insulin signalling cascade activation, as measured by Akt phosphorylation. Comparison of the hepatic gene expression from the female and male WT- and Glo1-KO mice showed an increased expression in the cytochrome P450 family in female mice. Specifically, an increase in the expression and activity of the isoenzymes involved in the metabolism of arachidonic acid. In conclusion, this study could show that the loss of Glo1 in mice does not recapitulate a T2D phenotype. However, this study did show that the effects resulting from the loss of Glo1 are sex dimorphic, in which male mice are more susceptible. The increase in arachidonic acid metabolism, in particularly the levels of epoxyeicosatrienoic acids (EETs), and the beneficial effects that they induce with respect to inflammation, mitochondrial dysfunction and insulin resistance, is proposed as a protective mechanism in females from the loss of Glo1.