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

Research output: Contribution to journalArticle

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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

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I-kappa B Kinase
Regeneration
Cell Proliferation
Cyclic AMP
Zebrafish
Cyclic AMP-Dependent Protein Kinases
Phosphotransferases
Insulin
Phosphoric Diester Hydrolases
Sirolimus
Streptozocin
Type 1 Diabetes Mellitus
Pancreas

ASJC Scopus subject areas

  • General

Cite this

Xu, J., Jia, Y. F., Tapadar, S., Weaver, J. D., Raji, I. O., Pithadia, D. J., ... 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

Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. / Xu, Jin; Jia, Yun Fang; Tapadar, Subhasish; Weaver, Jessica D.; Raji, Idris O.; Pithadia, Deeti J.; Javeed, Naureen; García, Andrés J.; Choi, Doo Sup; Matveyenko, Aleksey V; Oyelere, Adegboyega K.; Shin, Chong Hyun.

In: Scientific Reports, Vol. 8, No. 1, 15587, 01.12.2018.

Research output: Contribution to journalArticle

Xu, J, Jia, YF, Tapadar, S, Weaver, JD, Raji, IO, Pithadia, DJ, Javeed, N, García, AJ, Choi, DS, Matveyenko, AV, Oyelere, AK & Shin, CH 2018, 'Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells', Scientific Reports, vol. 8, no. 1, 15587. https://doi.org/10.1038/s41598-018-33875-0
Xu J, Jia YF, Tapadar S, Weaver JD, Raji IO, Pithadia DJ et al. Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. Scientific Reports. 2018 Dec 1;8(1). 15587. https://doi.org/10.1038/s41598-018-33875-0
Xu, Jin ; Jia, Yun Fang ; Tapadar, Subhasish ; Weaver, Jessica D. ; Raji, Idris O. ; Pithadia, Deeti J. ; Javeed, Naureen ; García, Andrés J. ; Choi, Doo Sup ; Matveyenko, Aleksey V ; Oyelere, Adegboyega K. ; Shin, Chong Hyun. / Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. In: Scientific Reports. 2018 ; Vol. 8, No. 1.
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