DYRK1A Kinase Inhibitors Promote β-Cell Survival and Insulin Homeostasis.

ABSTRACT: 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 β-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 β-cells. Our compounds exert a significantly more pronounced effect compared to harmine, the best-documented molecule enhancing β-cell proliferation. Using a body-like environment of the organoid, we provide a proof-of-concept that small-molecule-induced human β-cell proliferation via DYRK1A inhibition is achievable, which lends a considerable promise for regenerative medicine in T1DM and T2DM treatment.

SUBMITTER: Barzowska A 

PROVIDER: S-EPMC8467532 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature