Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.
Eur J Cell Biol. 2020 Jun;99(5):151094. doi: 10.1016/j.ejcb.2020.151094. Epub 2020 May 30.
Both type 1 and type 2 diabetes are associated with hyperglycemia and loss of functional beta cell mass. Inducing proliferation of preexisting beta cells is an approach to increase the numbers of beta cells. In this study, we examined a panel of selected small molecules for their proliferation-inducing effects on human pancreatic beta cells. Our results demonstrated that a small molecule inhibitor of the menin-MLL interaction (MI-2) and small molecule inhibitors of TGF-β signaling (SB431542, LY2157299, or LY364947) synergistically increased ex vivo replication of human beta cells. We showed that this increased proliferation did not affect insulin production, as a pivotal indication of beta cell function. We further provided evidence which suggested that menin-MLL and TGF-β inhibition cooperated through downregulation of cell cycle inhibitors CDKN1A, CDKN1B, and CDKN2C. Our findings might provide a new option for extending the pharmacological repertoire for induction of beta cell proliferation as a potential therapeutic approach for diabetes.
1 型和 2 型糖尿病均与高血糖和功能性β细胞数量减少有关。诱导现有β细胞增殖是增加β细胞数量的一种方法。在这项研究中，我们研究了一组选定的小分子，以评估它们对人胰腺β细胞的增殖诱导作用。结果表明，MENIN-MLL 相互作用的小分子抑制剂（MI-2）和 TGF-β 信号小分子抑制剂（SB431542、LY2157299 或 LY364947）协同增强了人β细胞的体外复制。我们表明，这种增殖增加不会影响胰岛素的产生，因为这是β细胞功能的关键指标。我们进一步提供的证据表明，menin-MLL 和 TGF-β 抑制通过下调细胞周期抑制剂 CDKN1A、CDKN1B 和 CDKN2C 而协同作用。我们的发现可能为扩大β细胞增殖的药理学作用提供新的选择，作为治疗糖尿病的潜在治疗方法。
