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- Title
Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.
- Authors
Dirice, Ercument; Walpita, Deepika; Vetere, Amedeo; Meier, Bennett C.; Kahraman, Sevim; Jiang Hu; Dančík, Vlado; Burns, Sean M.; Gilbert, Tamara J.; Olson, David E.; Clemons, Paul A.; Kulkarni, Rohit N.; Wagner, Bridget K.; Hu, Jiang
- Abstract
Restoring functional β-cell mass is an important therapeutic goal for both type 1 and type 2 diabetes (1). While proliferation of existing β-cells is the primary means of β-cell replacement in rodents (2), it is unclear whether a similar principle applies to humans, as human β-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 β-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 β-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 β-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 β-cell proliferation.
- Subjects
CELL proliferation; ADENOSINE kinase; INSULIN; CALCINEURIN; NUCLEAR factor of activated T-cells; ANIMAL experimentation; CELL physiology; ENZYME inhibitors; ISLANDS of Langerhans; MICE; PHOSPHORYLATION; PROTEIN-tyrosine kinases; RESEARCH funding; TRANSFERASES; GENE expression profiling; CHEMICAL inhibitors; PHARMACODYNAMICS
- Publication
Diabetes, 2016, Vol 65, Issue 6, p1660
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db15-1127