Inhibition of TBK1/IKK? Promotes Regeneration of Pancreatic ?-cells.

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

SUBMITTER: Xu J 

PROVIDER: S-EPMC6197228 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature