School of Biological Sciences and the Parker H. Petit Institute for Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA, 91125, USA.
Sci Rep. 2018 Oct 22;8(1):15587. doi: 10.1038/s41598-018-33875-0.
β-cell proliferation induction is a promising therapeutic strategy to restore β-cell mass. By screening small molecules in a transgenic zebrafish model of type 1 diabetes, we identified inhibitors of non-canonical IκB kinases (IKKs), TANK-binding kinase 1 (TBK1) and IκB kinase ε (IKKε), as enhancers of β-cell regeneration. The most potent β-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 β-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 β-cell-enriched cAMP hydrolyzing enzyme phosphodiesterase (PDE) 3, enhanced β-cell proliferation, whereas overexpression of PDE3 blunted the mitogenic effect of PIAA in zebrafish. PIAA augmented proliferation of INS-1β-cells and β-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 β-cell proliferation, β-cell area, and insulin content in the pancreas. Collectively, these data reveal an evolutionarily conserved and critical role of TBK1/IKKε suppression in expanding functional β-cell mass.
β细胞增殖诱导是恢复β细胞数量的一种很有前途的治疗策略。通过在 1 型糖尿病的转基因斑马鱼模型中筛选小分子，我们发现非典型 IκB 激酶（IKK）、TANK 结合激酶 1（TBK1）和 IκB 激酶 ε（IKKε）的抑制剂可增强β细胞再生。最有效的β细胞再生增强剂是肉桂酸衍生物（E）-3-（3-苯基苯并[c]异噁唑-5-基）丙烯酸（PIAA），它通过激活 cAMP 依赖性蛋白激酶 A（PKA），通过增加环 AMP（cAMP）水平和雷帕霉素（mTOR）活性来刺激β细胞特异性增殖。PIAA 与西洛他唑（一种β细胞丰富的 cAMP 水解酶磷酸二酯酶（PDE）3 的抑制剂）联合使用可增强β细胞增殖，而过表达 PDE3 会削弱 PIAA 在斑马鱼中的促有丝分裂作用。PIAA 可增加 INS-1β细胞和哺乳动物胰岛（包括人胰岛）的增殖，同时增加 cAMP 水平和胰岛素分泌。PIAA 通过增加β细胞增殖、β细胞面积和胰腺中的胰岛素含量来改善链脲佐菌素（STZ）诱导的糖尿病小鼠的血糖控制。总之，这些数据揭示了 TBK1/IKKε 抑制在扩大功能性β细胞数量方面的保守和关键作用。
