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Diabetes DOI:10.2337/db15-1127

Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.

Publication TypeJournal Article
Year of Publication2016
AuthorsDirice, E, Walpita, D, Vetere, A, Meier, BC, Kahraman, S, Hu, J, Dančík, V, Burns, SM, Gilbert, TJ, Olson, DE, Clemons, PA, Kulkarni, RN, Wagner, BK
JournalDiabetes
Volume65
Issue6
Pages1660-71
Date Published2016 Jun
ISSN1939-327X
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.

URLhttp://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26953159
DOI10.2337/db15-1127
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/26953159?dopt=Abstract

Alternate JournalDiabetes
PubMed ID26953159
PubMed Central IDPMC4878416
Grant ListP30 DK036836 / DK / NIDDK NIH HHS / United States
R01 DK067536 / DK / NIDDK NIH HHS / United States
R01 DK103215 / DK / NIDDK NIH HHS / United States