PUBLICATION

Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish

Authors
Robertson, M.A., Padgett, L.R., Fine, J.A., Chopra, G., Mastracci, T.L.
ID
ZDB-PUB-200728-33
Date
2020
Source
Islets   12(5): 99-107 (Journal)
Registered Authors
Keywords
Beta cell, DFMO, difluoromethylornithine, imatinib, islet, ornithine decarboxylase, polyamine biosynthesis, regeneration, type 1 diabetes, zebrafish
MeSH Terms
  • Animals
  • Eflornithine/pharmacology
  • Fluorescent Antibody Technique
  • Imatinib Mesylate/pharmacology
  • Insulin-Secreting Cells/drug effects
  • Insulin-Secreting Cells/metabolism
  • Insulin-Secreting Cells/physiology*
  • Polyamines/metabolism*
  • Regeneration/drug effects
  • Zebrafish/embryology
(all 10)
PubMed
32715853 Full text @ Islets
Abstract
Type 1 diabetes (T1D) is a disease characterized by destruction of the insulin-producing beta cells. Currently, there remains a critical gap in our understanding of how to reverse or prevent beta cell loss in individuals with T1D. Previous studies in mice discovered that pharmacologically inhibiting polyamine biosynthesis using difluoromethylornithine (DFMO) resulted in preserved beta cell function and mass. Similarly, treatment of non-obese diabetic mice with the tyrosine kinase inhibitor Imatinib mesylate reversed diabetes. The promising findings from these animal studies resulted in the initiation of two separate clinical trials that would repurpose either DFMO (NCT02384889) or Imatinib (NCT01781975) and determine effects on diabetes outcomes; however, whether these drugs directly stimulated beta cell growth remained unknown. To address this, we used the zebrafish model system to determine pharmacological impact on beta cell regeneration. After induction of beta cell death, zebrafish embryos were treated with either DFMO or Imatinib. Neither drug altered whole-body growth or exocrine pancreas length. Embryos treated with Imatinib showed no effect on beta cell regeneration; however, excitingly, DFMO enhanced beta cell regeneration. These data suggest that pharmacological inhibition of polyamine biosynthesis may be a promising therapeutic option to stimulate beta cell regeneration in the setting of diabetes.
Genes / Markers
No data available
Figures
No images available
Show all Figures
Expression
No data available
Phenotype
Fish Conditions Stage Phenotype Figure
jh1Tg; s950Tgchemical treatment by environment: eflornithineDays 7-13
jh1Tg; s950Tgchemical treatment by environment: eflornithineDays 7-13
jh1Tg; s950Tgchemical treatment by environment: nifurpirinolDay 4
jh1Tg; s950Tgchemical treatment by environment: nifurpirinolDays 7-13
jh1Tg; s950Tgchemical treatment by environment: nifurpirinolDays 7-13
jh1Tg; s950Tgchemical treatment by environment: nifurpirinolDays 7-13
jh1Tg; s950Tgchemical treatment by environment: nifurpirinol, chemical treatment by environment: eflornithineDay 4
jh1Tg; s950Tgchemical treatment by environment: nifurpirinol, chemical treatment by environment: eflornithineDays 7-13
jh1Tg; s950Tgchemical treatment by environment: imatinib, chemical treatment by environment: eflornithineDay 4
jh1Tg; s950Tgchemical treatment by environment: imatinib, chemical treatment by environment: eflornithineDays 7-13
1 - 10 of 10
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Mutations / Transgenics
Allele Construct Type Affected Genomic Region
jh1TgTransgenic Insertion
    s950TgTransgenic Insertion
      1 - 2 of 2
      Show
      Human Disease / Model
      Human Disease Fish Conditions Evidence
      type 1 diabetes mellitusTAS
      1 - 1 of 1
      Show
      Sequence Targeting Reagents
      No data available
      Fish
      Fish
      jh1Tg; s950Tg
      1 - 1 of 1
      Show
      Antibodies
      No data available
      Orthology
      No data available
      Engineered Foreign Genes
      Marker Marker Type Name
      EGFPEFGEGFP
      mCherryEFGmCherry
      NTREFGNTR
      1 - 3 of 3
      Show
      Mapping
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      Citation
      Robertson, M.A., Padgett, L.R., Fine, J.A., Chopra, G., Mastracci, T.L. (2020) Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish. Islets. 12(5):99-107.