Publication Type | Journal Article |
Year of Publication | 2016 |
Authors | Dirice, 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 |
Journal | Diabetes |
Volume | 65 |
Issue | 6 |
Pages | 1660-71 |
Date Published | 2016 Jun |
ISSN | 1939-327X |
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. |
URL | http://diabetes.diabetesjournals.org/cgi/pmidlookup?view=long&pmid=26953159 |
DOI | 10.2337/db15-1127 |
Pubmed | |
Alternate Journal | Diabetes |
PubMed ID | 26953159 |
PubMed Central ID | PMC4878416 |
Grant List | P30 DK036836 / DK / NIDDK NIH HHS / United States R01 DK067536 / DK / NIDDK NIH HHS / United States R01 DK103215 / DK / NIDDK NIH HHS / United States |
Diabetes DOI:10.2337/db15-1127
Inhibition of DYRK1A Stimulates Human β-Cell Proliferation.
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