Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

Weijun Shen, Brandon Taylor, Qihui Jin, Nguyen-Tran Van, Shelly Meeusen, You-Qing Zhang, Anwesh Kamireddy, Austin Swafford, Andrew F. Powers, John Walker, John Lamb, Badry Bursalaya, Michael DiDonato, George Harb, Minhua Qiu, Christophe M. Filippi, Lisa Deaton, Carolina N. Turk, Wilma L. Suarez-Pinzon, Yahu Liu, Xueshi Hao, Tingting Mo, Shanshan Yan, Jing Li, Ann E. Herman, Bernhard J. Hering, Tom Wu, H. Martin Seidel, Peter McNamara, Richard Glynne and Bryan Laffitte ()
Additional contact information
Weijun Shen: Genomics Institute of the Novartis Research Foundation
Brandon Taylor: Genomics Institute of the Novartis Research Foundation
Qihui Jin: Genomics Institute of the Novartis Research Foundation
Nguyen-Tran Van: Genomics Institute of the Novartis Research Foundation
Shelly Meeusen: Genomics Institute of the Novartis Research Foundation
You-Qing Zhang: Genomics Institute of the Novartis Research Foundation
Anwesh Kamireddy: Genomics Institute of the Novartis Research Foundation
Austin Swafford: Genomics Institute of the Novartis Research Foundation
Andrew F. Powers: Genomics Institute of the Novartis Research Foundation
John Walker: Genomics Institute of the Novartis Research Foundation
John Lamb: Genomics Institute of the Novartis Research Foundation
Badry Bursalaya: Genomics Institute of the Novartis Research Foundation
Michael DiDonato: Genomics Institute of the Novartis Research Foundation
George Harb: Genomics Institute of the Novartis Research Foundation
Minhua Qiu: Genomics Institute of the Novartis Research Foundation
Christophe M. Filippi: Genomics Institute of the Novartis Research Foundation
Lisa Deaton: Genomics Institute of the Novartis Research Foundation
Carolina N. Turk: Genomics Institute of the Novartis Research Foundation
Wilma L. Suarez-Pinzon: University of Minnesota
Yahu Liu: Genomics Institute of the Novartis Research Foundation
Xueshi Hao: Genomics Institute of the Novartis Research Foundation
Tingting Mo: Genomics Institute of the Novartis Research Foundation
Shanshan Yan: Genomics Institute of the Novartis Research Foundation
Jing Li: Genomics Institute of the Novartis Research Foundation
Ann E. Herman: Genomics Institute of the Novartis Research Foundation
Bernhard J. Hering: University of Minnesota
Tom Wu: Genomics Institute of the Novartis Research Foundation
H. Martin Seidel: Genomics Institute of the Novartis Research Foundation
Peter McNamara: Genomics Institute of the Novartis Research Foundation
Richard Glynne: Genomics Institute of the Novartis Research Foundation
Bryan Laffitte: Genomics Institute of the Novartis Research Foundation

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: Abstract Insufficient pancreatic β-cell mass or function results in diabetes mellitus. While significant progress has been made in regulating insulin secretion from β-cells in diabetic patients, no pharmacological agents have been described that increase β-cell replication in humans. Here we report aminopyrazine compounds that stimulate robust β-cell proliferation in adult primary islets, most likely as a result of combined inhibition of DYRK1A and GSK3B. Aminopyrazine-treated human islets retain functionality in vitro and after transplantation into diabetic mice. Oral dosing of these compounds in diabetic mice induces β-cell proliferation, increases β-cell mass and insulin content, and improves glycaemic control. Biochemical, genetic and cell biology data point to Dyrk1a as the key molecular target. This study supports the feasibility of treating diabetes with an oral therapy to restore β-cell mass, and highlights a tractable pathway for future drug discovery efforts.

Date: 2015
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DOI: 10.1038/ncomms9372

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