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Diabetes. 2016 Jun;65(6):1660-71. doi: 10.2337/db15-1127. Epub 2016 Mar 7.

Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.

Author information

1
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA.
2
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
3
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
4
Chemical Biology Program, Harvard Medical School, Boston, MA Diabetes Unit, Departments of Medicine and Molecular Biology, Massachusetts General Hospital, Boston, MA.
5
Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
6
Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA bwagner@broadinstitute.org rohit.kulkarni@joslin.harvard.edu.
7
Center for the Science of Therapeutics, Broad Institute, Cambridge, MA bwagner@broadinstitute.org rohit.kulkarni@joslin.harvard.edu.

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.

PMID:
26953159
PMCID:
PMC4878416
DOI:
10.2337/db15-1127
[Indexed for MEDLINE]
Free PMC Article

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