| Autor: |
Lodd E; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Wiggenhauser LM; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Morgenstern J; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany., Fleming TH; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany., Poschet G; Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany., Büttner M; Metabolomics Core Technology Platform, Centre for Organismal Studies, Heidelberg University, Heidelberg, Germany., Tabler CT; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Wohlfart DP; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany., Nawroth PP; Department of Internal Medicine I and Clinical Chemistry, Heidelberg University Hospital, Heidelberg, Germany.; German Center for Diabetes Research (DZD), München-Neuherberg, Germany.; Joint Heidelberg-IDC Translational Diabetes Program, Helmholtz-Zentrum, München, Heidelberg, Germany., Kroll J; Department of Vascular Biology and Tumor Angiogenesis, European Center for Angioscience (ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. |
| Abstrakt: |
The increased formation of methylglyoxal (MG) under hyperglycemia is associated with the development of microvascular complications in patients with diabetes mellitus; however, the effects of elevated MG levels in vivo are poorly understood. In zebrafish, a transient knockdown of glyoxalase 1, the main MG detoxifying system, led to the elevation of endogenous MG levels and blood vessel alterations. To evaluate effects of a permanent knockout of glyoxalase 1 in vivo, glo1-/- zebrafish mutants were generated using CRISPR/Cas9. In addition, a diet-induced-obesity zebrafish model was used to analyze glo1-/- zebrafish under high nutrient intake. Glo1-/- zebrafish survived until adulthood without growth deficit and showed increased tissue MG concentrations. Impaired glucose tolerance developed in adult glo1-/- zebrafish and was indicated by increased postprandial blood glucose levels and postprandial S6 kinase activation. Challenged by an overfeeding period, fasting blood glucose levels in glo1-/- zebrafish were increased which translated into retinal blood vessel alterations. Thus, the data have identified a defective MG detoxification as a metabolic prerequisite and glyoxalase 1 alterations as a genetic susceptibility to the development of type 2 diabetes mellitus under high nutrition intake. |
