Resistance to regeneration of insulin-producing pancreatic β cells is a fundamental challenge for type 1 and type 2 diabetes. Recently, small molecule inhibitors of the kinase DYRK1A have proven effective in inducing adult human β cells to proliferate, but their detailed mechanism of action is incompletely understood. We interrogated our human insulinoma and β cell transcriptomic databases seeking to understand why β cells in insulinomas proliferate, while normal β cells do not. This search reveals the DREAM complex as a central regulator of quiescence in human β cells. The DREAM complex consists of a module of transcriptionally repressive proteins that assemble in response to DYRK1A kinase activity, thereby inducing and maintaining cellular quiescence. In the absence of DYRK1A, DREAM subunits reassemble into the pro-proliferative MMB complex. Here, we demonstrate that small molecule DYRK1A inhibitors induce human β cells to replicate by converting the repressive DREAM complex to its pro-proliferative MMB conformation.

中文翻译：

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破坏 DREAM 复合体可以促进成人胰腺 β 细胞的增殖


产生胰岛素的胰腺 β 细胞的再生抵抗是 1 型和 2 型糖尿病面临的根本挑战。最近，激酶 DYRK1A 的小分子抑制剂已被证明可有效诱导成人 β 细胞增殖，但其详细作用机制尚不完全清楚。我们询问了人类胰岛素瘤和 β 细胞转录组数据库，试图了解为什么胰岛素瘤中的 β 细胞会增殖，而正常的 β 细胞则不会。这项研究揭示了 DREAM 复合物是人类 β 细胞静止的中心调节因子。 DREAM 复合体由转录抑制蛋白模块组成，该模块响应 DYRK1A 激酶活性而组装，从而诱导和维持细胞静止。在 DYRK1A 缺失的情况下，DREAM 亚基重新组装成促增殖 MMB 复合体。在这里，我们证明小分子 DYRK1A 抑制剂通过将抑制性 DREAM 复合物转化为其促增殖 MMB 构象来诱导人类 β 细胞复制。