Tbk1 Regulates Regeneration Of Pancreatic Beta-Cells

Small-molecule inhibitors of non-canonical I kappa B kinases TANK-binding kinase 1 (TBK1) and I kappa B kinase epsilon (IKK epsilon) have shown to stimulate beta -cell regeneration in multiple species. Here we demonstrate that TBK1 is predominantly expressed in beta -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 beta -cells. Conversely, TBK1 overexpression decreased sensitivity of beta -cells to the elevation of cyclic AMP (cAMP) levels and reduced proliferation of beta -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 beta -cell differentiation and proliferation markers in human embryonic stem cell (hESC)-derived beta -cells and human islets. TBK1 expression was increased in beta -cells upon diabetogenic insults, including in human type 2 diabetic islets. PIAA enhanced expression of cell cycle control molecules and beta -cell differentiation markers upon diabetogenic challenges, and accelerated restoration of functional beta -cells in streptozotocin (STZ)-induced diabetic mice. Altogether, these data suggest the critical function of TBK1 as a beta -cell autonomous replication barrier and present PIAA as a valid therapeutic strategy augmenting functional beta -cells.