DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis

The rising prevalence of diabetes is threatening global health. It is known not only for the occurrence of severe complications but also for the SARS-Cov-2 pandemic, which shows that it exacerbates susceptibility to infections. Current therapies focus on artificially maintaining insulin homeostasis, and a durable cure has not yet been achieved. We demonstrate that our set of small molecule inhibitors of DYRK1A kinase potently promotes beta-cell proliferation, enhances long-term insulin secretion, and balances glucagon level in the organoid model of the human islets. Comparable activity is seen in INS-1E and MIN6 cells, in isolated mice islets, and human iPSC-derived beta-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing beta-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human beta-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

Automated summary

This study demonstrates the efficacy of a set of small molecule inhibitors of DYRK1A kinase in promoting beta-cell proliferation, enhancing long-term insulin secretion, and balancing glucagon level in human islets. The compounds show significantly more pronounced effects compared to harmine and hold considerable promise for regenerative medicine in the treatment of T1DM and T2DM.