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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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	TANK-binding Kinase 1 (TBK1) Transgenic Zebrafish Model Isoxazolyl Supplemental Experimental Procedures Amlexanox Medicine R Science Q
Acceso en línea:	https://doaj.org/article/64e8697002f84880b24071507a486054
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spelling	oai:doaj.org-article:64e8697002f84880b24071507a4860542021-12-02T11:40:36ZInhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells10.1038/s41598-018-33875-02045-2322https://doaj.org/article/64e8697002f84880b24071507a4860542018-10-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-33875-0https://doaj.org/toc/2045-2322Abstract 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.Jin XuYun-Fang JiaSubhasish TapadarJessica D. WeaverIdris O. RajiDeeti J. PithadiaNaureen JaveedAndrés J. GarcíaDoo-Sup ChoiAleksey V. MatveyenkoAdegboyega K. OyelereChong Hyun ShinNature PortfolioarticleTANK-binding Kinase 1 (TBK1)Transgenic Zebrafish ModelIsoxazolylSupplemental Experimental ProceduresAmlexanoxMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-14 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	TANK-binding Kinase 1 (TBK1) Transgenic Zebrafish Model Isoxazolyl Supplemental Experimental Procedures Amlexanox Medicine R Science Q
spellingShingle	TANK-binding Kinase 1 (TBK1) Transgenic Zebrafish Model Isoxazolyl Supplemental Experimental Procedures Amlexanox Medicine R Science Q 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
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.
format	article
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
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 Portfolio
publishDate	2018
url	https://doaj.org/article/64e8697002f84880b24071507a486054
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Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells

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