Abstract
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.
Highlights
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
TBK1 expression was induced in β-cells in response to diabetogenic insults, including in human type 2 diabetes (T2D) islets
Being an evolutionarily conserved serine/threonine protein kinase essential for cell proliferation and survival[48], and the essential role of TBK1 in suppressing β-cell replication cell autonomously shown above, we hypothesized that TBK1 represses the cyclic AMP (cAMP)-protein kinase A (PKA)-mTOR complex 1 (mTORC1) signaling axis via activation of phosphodiesterase 3 (PDE3)
Summary
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. 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 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. Adipose-specific deletion of TBK1 (ATKO) attenuates diet-induced obesity with exacerbation in glucose intolerance and insulin resistance, whereas genetic deletion of IKKε increases energy expenditure with improvement in insulin sensitivity on a H FD34,35 These data indicate that TBK1 and IKKε use discrete signaling networks to exert their critical effects on regulating glucose and energy metabolism, while showing high sequence homology with comparable phosphorylation profiling of substrate(s)[42]
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