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

beta-cell proliferation induction is a promising therapeutic strategy to restore beta-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of noncanonical I kappa B kinases (IKKs), TANK-binding kinase 1 (TBK1) and I kappa B kinase epsilon (IKK epsilon), as enhancers of beta-cell regeneration. The most potent beta-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 beta-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 beta-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced beta-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1 beta-cell and beta-cell 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 beta-cell proliferation, beta-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKK epsilon suppression in expanding functional beta-cell mass.