Details

Autor(en) / Beteiligte

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

Titel

Inhibition of DYRK1A Stimulates Human β-Cell Proliferation

Ist Teil von

• Diabetes (New York, N.Y.), 2016-06, Vol.65 (6), p.1660-1671

Ort / Verlag

United States: American Diabetes Association

Erscheinungsjahr

2016

Link zum Volltext

Quelle

EZB Free E-Journals

Beschreibungen/Notizen

• 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.