PUBLICATION

A new model of inducible chronic hyperglycemia

Authors
Tucker, T.R., Knitter, C.A., Khoury, D.M., Eshghi, S., Tran, S., Sharrock, A.V., Wiles, T.J., Ackerley, D.F., Mumm, J.S., Parsons, M.J.
ID
ZDB-PUB-230704-41
Date
2023
Source
Disease models & mechanisms   16(8): (Journal)
Registered Authors
Mumm, Jeff, Parsons, Michael
Keywords
Cell-specific ablation, Chronic hyperglycemia, Diabetes, Metronidazole, Nitroreductase
MeSH Terms
  • Metronidazole/pharmacology
  • Metronidazole/therapeutic use
  • Hyperglycemia*/complications
  • Nitroreductases/metabolism
  • Diabetes Mellitus*
  • Zebrafish/metabolism
  • Animals, Genetically Modified
  • Animals
(all 8)
PubMed
37401381 Full text @ Dis. Model. Mech.
Abstract
Transgene driven expression of E. coli nitroreductase (NTR1.0) renders animal cells susceptible to the antibiotic metronidazole (MTZ). Many NTR1.0/MTZ ablation tools have been reported in the zebrafish that have significantly impacted regeneration studies. However, NTR1.0-based tools are not appropriate for modeling chronic cell loss as prolonged application of the required MTZ dose (10 mM) is deleterious to zebrafish health. We established this dose corresponds to the LD50 of MTZ in larval and adult zebrafish and that it induced intestinal pathology. NTR2.0 is a more active NTR engineered from Vibrio vulnificus NfsB that requires substantially less MTZ to induce cell ablation. Here we report on the generation of two new NTR2.0-based zebrafish lines where acute β-cell ablation can be achieved without MTZ-associated intestinal pathology. For the first time, we were able to sustain β-cell loss and maintain elevated glucose levels (chronic hyperglycemia) in larvae and adults. Adult fish showed significant weight loss consistent with the induction of a diabetic state, indicating this paradigm will allow the modeling of diabetes and associated pathologies.
Genes / Markers
Figures
Figure Gallery (7 images)
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Expression
No data available
Phenotype
No data available
Mutations / Transgenics
Allele Construct Type Affected Genomic Region
a9
    		Complex
    ir2018TgTransgenic Insertion
      ir2019TgTransgenic Insertion
        ir2050TgTransgenic Insertion
          jh4TgTransgenic Insertion
            jh10TgTransgenic Insertion
              lmc01TgTransgenic Insertion
                m1018TgTransgenic Insertion
                  w2
                    		Point Mutation
                    1 - 9 of 9
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                    Human Disease / Model
                    No data available
                    Sequence Targeting Reagents
                    No data available
                    Fish
                    No data available
                    Antibodies
                    Name Type Antigen Genes Isotypes Host Organism
                    Ab1-gcgmonoclonal
                      		IgG1Mouse
                      Ab5-insrbpolyclonal
                        		IgGRabbit
                        1 - 2 of 2
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                        Orthology
                        No data available
                        Engineered Foreign Genes
                        Marker Marker Type Name
                        DsRedEFGDsRed
                        EGFPEFGEGFP
                        GFPEFGGFP
                        mCherryEFGmCherry
                        NTREFGNTR
                        PhiYFPEFGPhiYFP
                        TagRFPEFGTagRFP
                        YFPEFGYFP
                        1 - 8 of 8
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                        Mapping
                        No data available
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                        Citation
                        Tucker, T.R., Knitter, C.A., Khoury, D.M., Eshghi, S., Tran, S., Sharrock, A.V., Wiles, T.J., Ackerley, D.F., Mumm, J.S., Parsons, M.J. (2023) A new model of inducible chronic hyperglycemia. Disease models & mechanisms. 16(8):.