Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells
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...
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doaj-64e8697002f84880b24071507a4860542020-12-08T05:35:24ZengNature Publishing GroupScientific Reports2045-23222018-10-018111410.1038/s41598-018-33875-0Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cellsJin Xu0Yun-Fang Jia1Subhasish Tapadar2Jessica D. Weaver3Idris O. Raji4Deeti J. Pithadia5Naureen Javeed6Andrés J. García7Doo-Sup Choi8Aleksey V. Matveyenko9Adegboyega K. Oyelere10Chong Hyun Shin11School of Biological Sciences and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologyDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicSchool of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologyWoodruff School of Mechanical Engineering and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologySchool of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologySchool of Biological Sciences and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologyDepartment of Physiology and Biomedical Engineering, Mayo ClinicWoodruff School of Mechanical Engineering and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologyDepartment of Molecular Pharmacology and Experimental Therapeutics, Mayo ClinicDepartment of Physiology and Biomedical Engineering, Mayo ClinicSchool of Chemistry and Biochemistry and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologySchool of Biological Sciences and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of TechnologyAbstract 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.https://doi.org/10.1038/s41598-018-33875-0TANK-binding Kinase 1 (TBK1)Transgenic Zebrafish ModelIsoxazolylSupplemental Experimental ProceduresAmlexanox |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
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 |
spellingShingle |
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 Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells Scientific Reports TANK-binding Kinase 1 (TBK1) Transgenic Zebrafish Model Isoxazolyl Supplemental Experimental Procedures Amlexanox |
author_facet |
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 |
author_sort |
Jin Xu |
title |
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells |
title_short |
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells |
title_full |
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells |
title_fullStr |
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells |
title_full_unstemmed |
Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells |
title_sort |
inhibition of tbk1/ikkε promotes regeneration of pancreatic β-cells |
publisher |
Nature Publishing Group |
series |
Scientific Reports |
issn |
2045-2322 |
publishDate |
2018-10-01 |
description |
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. |
topic |
TANK-binding Kinase 1 (TBK1) Transgenic Zebrafish Model Isoxazolyl Supplemental Experimental Procedures Amlexanox |
url |
https://doi.org/10.1038/s41598-018-33875-0 |
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