Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

Jin Xu, Yun Fang Jia, Subhasish Tapadar, Jessica D. Weaver, Idris O. Raji, Deeti J. Pithadia, Naureen Javeed, Andrés J. García, Doo Sup Choi, Aleksey V. Matveyenko, Adegboyega K. Oyelere, Chong Hyun Shin

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8 Scopus citations

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.

Original languageEnglish (US)
Article number15587
JournalScientific reports
Volume8
Issue number1
DOIs
StatePublished - Dec 1 2018

ASJC Scopus subject areas

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    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(1), [15587]. https://doi.org/10.1038/s41598-018-33875-0