PUBLICATION
An inhibitor-mediated beta cell dedifferentiation model reveals distinct roles for FoxO1 in glucagon repression and insulin maturation
- Authors
- Casteels, T., Zhang, Y., Frogne, T., Sturtzel, C., Lardeau, C.H., Sen, I., Liu, X., Hong, S., Pauler, F.M., Penz, T., Brandstetter, M., Barbieux, C., Berishvili, E., Heuser, T., Bock, C., Riedel, C.G., Meyer, D., Distel, M., Hecksher-Sørensen, J., Li, J., Kubicek, S.
- ID
- ZDB-PUB-210829-13
- Date
- 2021
- Source
- Molecular metabolism 54: 101329 (Journal)
- Registered Authors
- Distel, Martin, Meyer, Dirk, Sturtzel, Caterina
- Keywords
- Diabetes/Beta Cell Dedifferentiation/FoxO1 inhibitor/Loperamide
- MeSH Terms
-
- Adult
- Animals
- Cell Dedifferentiation
- Cells, Cultured
- Female
- Forkhead Box Protein O1/metabolism*
- Glucagon/metabolism*
- Humans
- Insulin/metabolism*
- Insulin-Secreting Cells/metabolism*
- Male
- Mice
- Middle Aged
- PubMed
- 34454092 Full text @ Mol Metab
Citation
Casteels, T., Zhang, Y., Frogne, T., Sturtzel, C., Lardeau, C.H., Sen, I., Liu, X., Hong, S., Pauler, F.M., Penz, T., Brandstetter, M., Barbieux, C., Berishvili, E., Heuser, T., Bock, C., Riedel, C.G., Meyer, D., Distel, M., Hecksher-Sørensen, J., Li, J., Kubicek, S. (2021) An inhibitor-mediated beta cell dedifferentiation model reveals distinct roles for FoxO1 in glucagon repression and insulin maturation. Molecular metabolism. 54:101329.
Abstract
Objective Loss of FoxO1 signaling in response to metabolic stress contributes to the etiology of type II diabetes, causing the dedifferentiation of pancreatic beta cells to a cell type reminiscent of endocrine progenitors. Lack of methods to easily model this process in vitro, however, have hindered progress into identification of key downstream targets and potential inhibitors. We therefore aimed to establish such an in vitro cellular dedifferentiation model and apply it to identify novel agents involved in the maintenance of beta cell identity.
Methods The murine beta cell line, Min6, was used for primary experiments and high content screening. Screens encompassed a library of small molecule drugs representing the chemical and target space of all FDA-approved small molecules with an automated immunofluorescence read-out. Validation experiments were performed in a murine alpha cell line as well as in primary murine and human diabetic islets. Developmental effects were studied in zebrafish and C. elegans models, while diabetic db/db mouse models were used to elucidate global glucose metabolism outcomes.
Results We show that short-term pharmacological FoxO1 inhibition can model beta cell dedifferentiation by downregulating beta-cell specific transcription factors, resulting in the aberrant expression of progenitor genes and the alpha cell marker glucagon. From a high content screen, we identified loperamide as a small molecule that can prevent FoxO inhibitor-induced glucagon expression and further stimulate insulin protein processing and secretion by altering calcium levels, intracellular pH and FoxO1 localization.
Conclusions Our study provides novel models, molecular targets and drug candidates for studying and preventing beta cell dedifferentiation.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping