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型糖尿病都与高血糖症和功能性β细胞量减少有关。诱导先前存在的β细胞增殖是一种增加β细胞数量的方法。在这项研究中，我们检查了一组选定的小分子对人胰腺β细胞的增殖诱导作用。我们的结果表明，menin-MLL相互作用的小分子抑制剂（MI-2）和TGF-β信号转导的小分子抑制剂（SB431542，LY2157299或LY364947）在体外协同增效人β细胞的复制。我们表明，这种增加的增殖不会影响胰岛素的产生，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协同作用。我们的发现可能为扩展药理库以诱导β细胞增殖作为糖尿病的一种潜在治疗方法提供了新的选择。