The combination of loss of glyoxalase1 and obesity results in hyperglycemia
Elisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Fleming, Gernot Poschet, Michael Büttner, Christoph T. Tabler, David P. Wohlfart, Peter P. Nawroth, Jens Kroll
Elisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Fleming, Gernot Poschet, Michael Büttner, Christoph T. Tabler, David P. Wohlfart, Peter P. Nawroth, Jens Kroll
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Research Article Endocrinology Metabolism

The combination of loss of glyoxalase1 and obesity results in hyperglycemia

Abstract

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.

Authors

Elisabeth Lodd, Lucas M. Wiggenhauser, Jakob Morgenstern, Thomas H. Fleming, Gernot Poschet, Michael Büttner, Christoph T. Tabler, David P. Wohlfart, Peter P. Nawroth, Jens Kroll

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Figure 6

Diet-induced obese glo1–/– zebrafish develop hyperglycemia.

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Diet-induced obese glo1–/– zebrafish develop hyperglycemia. (A) After 8 ...
(A) After 8 weeks of overfeeding, zebrafish in the overfed group have gained significantly more weight than zebrafish in the normal-fed group, whereas there was no difference dependent on the glo1 genotype. Weight was measured at the start and at the end of the feeding period. Results were obtained from 3 independent experiments; n = 9 to 12 fish per group; mean ± SEM. (B) After the overfeeding period, livers of overfed fish show high fed content compared with livers of normal-fed fish and are surrounded by lipid droplets. Images were taken using a light microscope. Frozen liver sections were stained with Oil Red O. Black scale bar: 100 μm. (C) Fasting blood glucose levels are increased in glo1–/– overfed fish in comparison with glo1+/+ normal-fed fish; n = 9 to 12 fish per group; mean ± SEM. One-way ANOVA followed by Sidak’s multiple-comparisons test was applied. *P < 0.05; **P < 0.01; ***P < 0.001. OF, overfed; NF, normal-fed; ns, not significant.