TBK1 regulates regeneration of pancreatic β-cells

Yun Fang Jia, Subbiah Jeeva, Jin Xu, Carrie Jo Heppelmann, Jin Sung Jang, Michael Q. Slama, Subhasish Tapadar, Adegboyega K. Oyelere, Sang Moo Kang, Aleksey V. Matveyenko, Quinn P. Peterson, Chong Hyun Shin

Research output: Contribution to journalArticlepeer-review

1 Scopus citations


Small-molecule inhibitors of non-canonical IκB kinases TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε) have shown to stimulate β-cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in β-cells in mammalian islets. Proteomic and transcriptome analyses revealed that genetic silencing of TBK1 increased expression of proteins and genes essential for cell proliferation in INS-1 832/13 rat β-cells. Conversely, TBK1 overexpression decreased sensitivity of β-cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of β-cells in a manner dependent on the activity of cAMP-hydrolyzing phosphodiesterase 3 (PDE3). While the mitogenic effect of (E)3-(3-phenylbenzo[c]isoxazol-5-yl)acrylic acid (PIAA) is derived from inhibition of TBK1, PIAA augmented glucose-stimulated insulin secretion (GSIS) and expression of β-cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived β-cells and human islets. TBK1 expression was increased in β-cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and β-cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional β-cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a β-cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional β-cells.

Original languageEnglish (US)
Article number19374
JournalScientific reports
Issue number1
StatePublished - Dec 2020

ASJC Scopus subject areas

  • General


Dive into the research topics of 'TBK1 regulates regeneration of pancreatic β-cells'. Together they form a unique fingerprint.

Cite this