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

4 Citations (Scopus)

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
Externally publishedYes

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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, 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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