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Why Excess Glucose Is Toxic

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Science's STKE  31 Jan 2006:
Vol. 2006, Issue 320, pp. tw40
DOI: 10.1126/stke.3202006tw40

High concentrations of glucose can be toxic and contribute to diabetic retinopathy, for example. Elevated glucose increases glycolytic flux, which leads to increased production of a highly reactive dicarbonyl, methylglyoxal. Cells eliminate this potentially toxic degradation product by enzymatic conversion to lactate by glyoxylase I (GLO1), glyoxylase II, and glutathione. However, in pathological situations, such as diabetes, or conditions of oxidative stress, methylglyoxal may accumulate and react with DNA or arginine, lysine, or cysteine residues of proteins. Yao et al. show that exposure of retinal Müller cells (rMC-1) to elevated glucose increased the concentration of methylglyoxal and stimulated expression of the angiopoietin-2 (Ang-2) gene. Both of these effects were prevented if the cells were overexpressing GLO1, the mitochondrial uncoupling protein UCP-1, or manganese superoxide dismutase (MnSOD). Promoter analysis defined a glucose-response element in the Ang-2 promoter at the Sp1 site, and chromatin immunoprecipitation experiments revealed that the binding of Sp1 was enhanced under conditions of high glucose, whereas Sp3 binding was decreased, suggesting that glucose triggers a switch in these two transcriptional regulators. Overexpression of GLO1, UCP-1, or MnSOD prevented this glucose-stimulated switch. Sp3 coimmunoprecipitated with the corepressor mSin3A. Elevated glucose increased the methylglyoxal modification of mSin3A and increased the association of mSin3A and Sp3 with O-linked N-acetylglucosamine (O-GlcNAc) transferase (OGT), resulting in O-GlcNAc modification of Sp3. Inhibition of O-GlcNAc modification of proteins by antisense RNA against the rate-limiting enzyme in UDP-GlcNAc formation or by overexpression of an enzyme that removes O-GlcNAc prevented the switch in Sp1 and Sp3-mSin3A at the Ang-2 promoter. These results provide a mechanism for diabetic retinopathy associated with high glucose, because an imbalance in angiogenic signals (elevated Ang-2 without sufficient vascular endothelial growth factor, for example) can lead to endothelial cell death and regression. These results also have implications for the role of glucose in aging and cancer through the actions of methylglyoxal on transcription (see Ramasamy et al.).

D. Yao, T. Taguchi, T. Matsumura, R. Pestell, D. Edelstein, I. Giardino, G. Suske, N. Ahmed, P. J. Thornalley, V. P. Sarthy, H.-P. Hammes, M. Brownlee, Methylglyoxal modification of mSin3A links glycolysis to angiopoietin-2 transcription. Cell 124, 275-286 (2006). [PubMed]

R. Ramasamy, S. F. Yan, A. M. Schmidt, Methylglyoxal comes of AGE. Cell 124, 258-260 (2006). [PubMed]

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