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Targeting polyamine biosynthesis to stimulate beta cell regeneration in zebrafish
Morgan A Robertson1, Leah R Padgett1, Jonathan A Fine2
1Indiana Biosciences Research Institute , Indianapolis, IN, USA.
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.
Insights
Difluoromethylornithine (DFMO) promotes beta cell regeneration in zebrafish, offering a potential new therapy for type 1 diabetes (T1D). This finding suggests inhibiting polyamine biosynthesis could reverse beta cell loss in T1D patients.
Area of Science:
- Endocrinology
- Regenerative Medicine
- Pharmacology
Background:
- Type 1 diabetes (T1D) involves the destruction of insulin-producing beta cells, with no current methods to reverse or prevent this loss.
- Previous mouse studies indicated that difluoromethylornithine (DFMO) and Imatinib could preserve beta cell function and reverse diabetes, respectively.
- Clinical trials are underway to repurpose DFMO and Imatinib for T1D, but their direct impact on beta cell regeneration is unknown.
Purpose of the Study:
- To investigate the direct effects of DFMO and Imatinib on beta cell regeneration.
- To determine if pharmacological inhibition of polyamine biosynthesis can stimulate beta cell regrowth.
Main Methods:
- Utilized the zebrafish model system to study beta cell regeneration.
- Induced beta cell death in zebrafish embryos and subsequently treated them with DFMO or Imatinib.
- Assessed the impact of treatments on whole-body growth, exocrine pancreas length, and beta cell regeneration.
Main Results:
- Neither DFMO nor Imatinib affected overall zebrafish growth or exocrine pancreas length.
- Imatinib treatment showed no effect on beta cell regeneration.
- DFMO treatment significantly enhanced beta cell regeneration in zebrafish embryos.
Conclusions:
- Pharmacological inhibition of polyamine biosynthesis using DFMO shows promise for stimulating beta cell regeneration.
- DFMO may represent a novel therapeutic strategy to address beta cell loss in type 1 diabetes.
