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Published on: September 15, 2023
Tamoxifen suppresses pancreatic β-cell proliferation in mice
Surl-Hee Ahn1, Anne Granger1, Matthew M Rankin1
1Pediatric Endocrinology and Diabetes, University of Pennsylvania School of Medicine, Philadelphia, PA, United States of America.
Abstract:
Tamoxifen is a mixed agonist/antagonist estrogen analogue that is frequently used to induce conditional gene deletion in mice using Cre-loxP mediated gene recombination. Tamoxifen is routinely employed in extremely high-doses relative to typical human doses to induce efficient gene deletion in mice. Although tamoxifen has been widely assumed to have no influence upon β-cells, the acute developmental and functional consequences of high-dose tamoxifen upon glucose homeostasis and adult β-cells are largely unknown. We tested if tamoxifen influences glucose homeostasis in male mice of various genetic backgrounds. We then carried out detailed histomorphometry studies of mouse pancreata. We also performed gene expression studies with islets of tamoxifen-treated mice and controls. Tamoxifen had modest effects upon glucose homeostasis of mixed genetic background (F1 B6129SF1/J) mice, with fasting hyperglycemia and improved glucose tolerance but without overt effects on fed glucose levels or insulin sensitivity. Tamoxifen inhibited proliferation of β-cells in a dose-dependent manner, with dramatic reductions in β-cell turnover at the highest dose (decreased by 66%). In sharp contrast, tamoxifen did not reduce proliferation of pancreatic acinar cells. β-cell proliferation was unchanged by tamoxifen in 129S2 mice but was reduced in C57Bl6 genetic background mice (decreased by 59%). Gene expression studies revealed suppression of RNA for cyclins D1 and D2 within islets of tamoxifen-treated mice. Tamoxifen has a cytostatic effect on β-cells, independent of changes in glucose homeostasis, in mixed genetic background and also in C57Bl6 mice. Tamoxifen should be used judiciously to inducibly inactivate genes in studies of glucose homeostasis.
Insights
High-dose tamoxifen, used for gene deletion in mice, unexpectedly inhibits beta-cell proliferation in a dose-dependent manner, impacting glucose homeostasis studies. Researchers advise cautious use of tamoxifen in such research.
Area of Science:
- Endocrinology
- Molecular Biology
- Genetics
Background:
- Tamoxifen is a widely used tool for inducible gene deletion in mice via Cre-loxP recombination.
- High doses of tamoxifen are routinely administered to mice, exceeding typical human therapeutic levels.
- The impact of these high doses on pancreatic beta-cells and glucose homeostasis remains largely uncharacterized.
Purpose of the Study:
- To investigate the effects of high-dose tamoxifen on glucose homeostasis in male mice across different genetic backgrounds.
- To assess the direct consequences of tamoxifen administration on adult pancreatic beta-cell proliferation and turnover.
- To explore the molecular mechanisms underlying tamoxifen's effects on beta-cells.
Main Methods:
- Glucose tolerance tests and fed/fasted glucose measurements were performed on tamoxifen-treated mice.
- Histomorphometry was used to quantify beta-cell and pancreatic acinar cell proliferation.
- Gene expression analysis of pancreatic islets was conducted to identify affected pathways.
Main Results:
- Tamoxifen induced modest glucose homeostasis changes, including fasting hyperglycemia and improved glucose tolerance, in mixed genetic background mice.
- A significant, dose-dependent inhibition of beta-cell proliferation was observed, with up to a 66% reduction at the highest dose.
- Beta-cell proliferation was reduced in C57Bl6 mice but not in 129S2 mice, indicating genetic background sensitivity.
- Tamoxifen suppressed cyclin D1 and D2 RNA expression in islets, suggesting a cytostatic effect on beta-cells.
Conclusions:
- High-dose tamoxifen exerts a cytostatic effect on pancreatic beta-cells, independent of overt changes in glucose homeostasis.
- The observed reduction in beta-cell proliferation is dependent on the tamoxifen dose and the mouse genetic background.
- Tamoxifen should be used with caution in studies involving glucose homeostasis and beta-cell function due to its potential to alter beta-cell dynamics.
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