Inhibition of DYRK1A stimulates human β-cell proliferation

Ercument Dirice, Deepika Walpita, Amedeo Vetere, Bennett C. Meier, Sevim Kahraman, Jiang Hu, Vlado Dančík, Sean M. Burns, Tamara J. Gilbert, David Olson, Paul A. Clemons, Rohit N. Kulkarni, Bridget K. Wagner

Research output: Contribution to journalArticle

63 Scopus citations

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 IL2Rgnull mice. These results point to inhibition of DYRK1A as a therapeutic strategy to increase human β-cell proliferation.

Original languageEnglish (US)
Pages (from-to)1660-1671
Number of pages12
JournalDiabetes
Volume65
Issue number6
DOIs
StatePublished - Jun 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Dirice, E., Walpita, D., Vetere, A., Meier, B. C., Kahraman, S., Hu, J., Dančík, V., Burns, S. M., Gilbert, T. J., Olson, D., Clemons, P. A., Kulkarni, R. N., & Wagner, B. K. (2016). Inhibition of DYRK1A stimulates human β-cell proliferation. Diabetes, 65(6), 1660-1671. https://doi.org/10.2337/db15-1127