Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.
Inhibition of DYRK1A and GSK3B induces human β-cell proliferation.
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DOI：
10.1038/ncomms9372
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发表时间：
2015-10-26
影响因子：
16.6
通讯作者：
Laffitte B
中科院分区：
文献类型：
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作者：
Shen W;Taylor B;Jin Q;Nguyen-Tran V;Meeusen S;Zhang YQ;Kamireddy A;Swafford A;Powers AF;Walker J;Lamb J;Bursalaya B;DiDonato M;Harb G;Qiu M;Filippi CM;Deaton L;Turk CN;Suarez-Pinzon WL;Liu Y;Hao X;Mo T;Yan S;Li J;Herman AE;Hering BJ;Wu T;Martin Seidel H;McNamara P;Glynne R;Laffitte B
胰腺β细胞质量或功能不足导致糖尿病。虽然在调节糖尿病患者的β-细胞的胰岛素分泌方面已经取得了显著进展，但尚未描述增加人类β-细胞复制的药理学试剂。在这里，我们报告了氨基吡嗪化合物，其刺激成人原代胰岛中的稳健β细胞增殖，最有可能是由于DYRK 1A和GSK 3B的联合抑制。氨基吡嗪处理的人胰岛在体外和移植到糖尿病小鼠后保留功能。在糖尿病小鼠中口服这些化合物诱导β细胞增殖，增加β细胞质量和胰岛素含量，并改善血糖控制。生物化学、遗传学和细胞生物学数据表明Dyrk 1a是关键的分子靶点。这项研究支持了用口服疗法治疗糖尿病以恢复β细胞质量的可行性，并强调了未来药物发现工作的易处理途径。 所有形式的糖尿病最终都会导致分泌胰岛素的胰腺β细胞减少。在这里，作者报告了氨基吡嗪衍生物，其诱导啮齿动物以及人类β细胞的增殖，并改善1型糖尿病小鼠模型中的葡萄糖代谢。
Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts. All forms of diabetes eventually lead to a reduction in insulin-secreting pancreatic β-cells. Here, the authors report aminopyrazine derivatives, which induce proliferation of rodent as well as human β-cells and improve glucose metabolism in a mouse model of type 1 diabetes.