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

Xu, Jin and Jia, Yun-Fang and Tapadar, Subhasish and Weaver, Jessica D. and Raji, Idris O. and Pithadia, Deeti J. and Javeed, Naureen and García, Andrés J. and Choi, Doo-Sup and Matveyenko, Aleksey V. and Oyelere, Adegboyega K. and Shin, Chong Hyun (2018) Inhibition of TBK1/IKKε Promotes Regeneration of Pancreatic β-cells. Scientific Reports, 8 . Art. No. 15587. ISSN 2045-2322. PMCID PMC6197228. http://resolver.caltech.edu/CaltechAUTHORS:20181025-074837881

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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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1038/s41598-018-33875-0DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197228PubMed CentralArticle
ORCID:
AuthorORCID
García, Andrés J.0000-0001-6602-2518
Additional Information:© 2018 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. Received 31 May 2017; Accepted 01 October 2018; Published 22 October 2018. We thank Mi Hyeon Jang, Philipp Gut, Shanthi Srinivasan, Ki Hyun Yoo, and Simon Mwangi for discussions/advice for experimental procedures, and Sun Choi and Sang-Oh Yoon for experimental assistance. We acknowledge the Mayo Clinic Zebrafish Facility and Georgia Tech Physiological Research Laboratory for fish care as well as the Microscopy and Biophotonics core at the Parker H. Petit Institute for Bioengineering and Bioscience at Georgia Tech for technical support. This work was supported in part by the grants from the NIH (K01DK081351 and R56DK111630 to C. H. S.; R01CA131217 to A. K. O.; R01AR062368 to A. J. G.; R01AA018779 to D.-S. C.; R01DK098468 to A. V. M), the NSF (1354837 to C. H. S.), the Juvenile Diabetes Research Foundation (JDRF 2-SRA-2014-287-Q-R to A. J. G.), the Cullen-Peck Fund (to A. K. O.), and the Regenerative Engineering and Medicine Research Center (2731336 and 1411318 to C. H. S.). Author Contributions: C.H.S. conceived and designed the experiments. J.X., J.-Y.F., J.D.W., D.J.P., J.N., and C.H.S. performed the experiments. S.T., I.O.R., and A.K.O. provided reagents/materials and performed molecular docking simulations. J.X., J.-Y.F., J.D.W., A.J.G., D.-S.C., A.V.M., A.K.O., and C.H.S. analyzed the data. A.J.G., D.-S.C., A.V.M., A.K.O., and C.H.S. wrote the paper. The authors declare no competing interests.
Funders:
Funding AgencyGrant Number
NIHK01DK081351
NIHR56DK111630
NIHR01CA131217
NIHR01AR062368
NIHR01AA018779
NIHR01DK098468
NSFIOS-1354837
Juvenile Diabetes Research Foundation2-SRA-2014-287-Q-R
Cullen-Peck FundUNSPECIFIED
Regenerative Engineering and Medicine Research Center2731336
Regenerative Engineering and Medicine Research Center1411318
PubMed Central ID:PMC6197228
Record Number:CaltechAUTHORS:20181025-074837881
Persistent URL:http://resolver.caltech.edu/CaltechAUTHORS:20181025-074837881
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:90409
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:25 Oct 2018 15:03
Last Modified:25 Oct 2018 15:03

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