| First Author | Dirice E | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 6 | Pages | 1660-71 |
| PubMed ID | 26953159 | Mgi Jnum | J:249662 |
| Mgi Id | MGI:5922915 | Doi | 10.2337/db15-1127 |
| Citation | Dirice E, et al. (2016) Inhibition of DYRK1A Stimulates Human beta-Cell Proliferation. Diabetes 65(6):1660-71 |
| abstractText | Restoring functional beta-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing beta-cells is the primary means of beta-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human beta-cells are remarkably resistant to stimulation of division (3,4). Here, we show that 5-iodotubercidin (5-IT), an annotated adenosine kinase inhibitor previously reported to increase proliferation in rodent and porcine islets (5), strongly and selectively increases human beta-cell proliferation in vitro and in vivo. Remarkably, 5-IT also increased glucose-dependent insulin secretion after prolonged treatment. Kinome profiling revealed 5-IT to be a potent and selective inhibitor of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) and cell division cycle-like kinase families. Induction of beta-cell proliferation by either 5-IT or harmine, another natural product DYRK1A inhibitor, was suppressed by coincubation with the calcineurin inhibitor FK506, suggesting involvement of DYRK1A and nuclear factor of activated T cells signaling. Gene expression profiling in whole islets treated with 5-IT revealed induction of proliferation- and cell cycle-related genes, suggesting that true proliferation is induced by 5-IT. Furthermore, 5-IT promotes beta-cell proliferation in human islets grafted under the kidney capsule of NOD-scid IL2Rg(null) mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human beta-cell proliferation. |
