title: Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.
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.
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA.
authors.forename: Ercument
authors.initials: E
authors.lastname: Dirice
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
authors.forename: Deepika
authors.initials: D
authors.lastname: Walpita
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Vetere
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA Program in Medical and Population Genetics, Broad Institute, Cambridge, MA.
authors.forename: Bennett C
authors.initials: BC
authors.lastname: Meier
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA.
authors.forename: Sevim
authors.initials: S
authors.lastname: Kahraman
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA.
authors.forename: Jiang
authors.initials: J
authors.lastname: Hu
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
authors.forename: Vlado
authors.initials: V
authors.lastname: Dančík
authors.affiliation: Chemical Biology Program, Harvard Medical School, Boston, MA Diabetes Unit, Departments of Medicine and Molecular Biology, Massachusetts General Hospital, Boston, MA.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Burns
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
authors.forename: Tamara J
authors.initials: TJ
authors.lastname: Gilbert
authors.affiliation: Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA.
authors.forename: David E
authors.initials: DE
authors.lastname: Olson
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Islet Cell and Regenerative Biology, Joslin Diabetes Center, Boston, MA bwagner@broadinstitute.org rohit.kulkarni@joslin.harvard.edu.
authors.forename: Rohit N
authors.initials: RN
authors.lastname: Kulkarni
authors.affiliation: Center for the Science of Therapeutics, Broad Institute, Cambridge, MA bwagner@broadinstitute.org rohit.kulkarni@joslin.harvard.edu.
authors.forename: Bridget K
authors.identifier: 0000-0002-2629-361X
authors.initials: BK
authors.lastname: Wagner
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D020869:Gene Expression Profiling; D006801:Humans; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D010766:Phosphorylation / Q000187:drug effects; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014372:Tubercidin / Q000031:analogs & derivatives* / Q000494:pharmacology; D000097603:Dyrk Kinases
chemical_list: D004791:Enzyme Inhibitors; D017346:Protein Serine-Threonine Kinases; D011505:Protein-Tyrosine Kinases; D014372:Tubercidin; D000097603:Dyrk Kinases; C034214:5-iodotubercidin