PUBLICATION
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells
- Authors
- Xu, J., Jia, Y.F., Tapadar, S., Weaver, J.D., Raji, I.O., Pithadia, D.J., Javeed, N., García, A.J., Choi, D.S., Matveyenko, A.V., Oyelere, A.K., Shin, C.H.
- ID
- ZDB-PUB-181024-5
- Date
- 2018
- Source
- Scientific Reports 8: 15587 (Journal)
- Registered Authors
- Pithadia, Deeti J., Shin, Chong, Xu, Jin
- Keywords
- none
- MeSH Terms
-
- Animals
- Cell Proliferation/drug effects*
- Cinnamates/metabolism
- Humans
- I-kappa B Kinase/metabolism*
- Insulin-Secreting Cells/drug effects*
- Insulin-Secreting Cells/physiology*
- Protein Serine-Threonine Kinases/metabolism*
- Quinolones/metabolism
- Rats, Inbred Lew
- Regeneration/drug effects*
- Zebrafish
- PubMed
- 30349097 Full text @ Sci. Rep.
Citation
Xu, J., Jia, Y.F., Tapadar, S., Weaver, J.D., Raji, I.O., Pithadia, D.J., Javeed, N., García, A.J., Choi, D.S., Matveyenko, A.V., Oyelere, A.K., Shin, C.H. (2018) Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. Scientific Reports. 8:15587.
Abstract
β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-cell regeneration enhancer was a cinnamic acid derivative (E)-3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA), which, acting through the cAMP-dependent protein kinase A (PKA), stimulated β-cell-specific proliferation by increasing cyclic AMP (cAMP) levels and mechanistic target of rapamycin (mTOR) activity. A combination of PIAA and cilostamide, an inhibitor of β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-cells in mammalian islets including human islets with elevation in cAMP levels and insulin secretion. PIAA improved glycemic control in streptozotocin (STZ)-induced diabetic mice with increases in β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass.
Errata / Notes
This article is corrected by ZDB-PUB-220906-186 .
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping