Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

Weijun Shen; Brandon Taylor; Qihui Jin; Van Nguyen-Tran; 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; Bryan Laffitte

doi:10.1038/ncomms9372

Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

Weijun Shen, Brandon Taylor, Qihui Jin, Van Nguyen-Tran, 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 LiuXueshi Hao, Tingting Mo, Shanshan Yan, Jing Li, Ann E. Herman, Bernhard J Hering, Tom Wu, H. Martin Seidel, Peter McNamara, Richard Glynne, Bryan Laffitte

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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.

Original language	English (US)
Article number	8372
Journal	Nature communications
Volume	6
DOIs	https://doi.org/10.1038/ncomms9372
State	Published - Oct 26 2015

Bibliographical note

Funding Information:
This work was supported by the JDRF and the Novartis Research Foundation. We thank Seung Kim, Patricia Kilian, Richard Insel, Andrew Rakeman, Peter Lomedico, Julia Greenstein and Mark Keller for helpful discussions. We acknowledge Jennifer Athanacio and Robert Hill for excellent technical contributions to the project.

Publisher Copyright:
© 2015 Macmillan Publishers Limited. All rights reserved.

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Shen, W., Taylor, B., Jin, Q., Nguyen-Tran, V., Meeusen, S., Zhang, Y. Q., Kamireddy, A., Swafford, A., Powers, A. F., Walker, J., Lamb, J., Bursalaya, B., Didonato, M., Harb, G., Qiu, M., Filippi, C. M., Deaton, L., Turk, C. N., Suarez-Pinzon, W. L., ... Laffitte, B. (2015). Inhibition of DYRK1A and GSK3B induces human β-cell proliferation. Nature communications, 6, Article 8372. https://doi.org/10.1038/ncomms9372

Shen, W, Taylor, B, Jin, Q, Nguyen-Tran, V, Meeusen, S, Zhang, YQ, Kamireddy, A, Swafford, A, Powers, AF, Walker, J, Lamb, J, Bursalaya, B, Didonato, M, Harb, G, Qiu, M, Filippi, CM, Deaton, L, Turk, CN, Suarez-Pinzon, WL, Liu, Y, Hao, X, Mo, T, Yan, S, Li, J, Herman, AE, Hering, BJ, Wu, T, Martin Seidel, H, McNamara, P, Glynne, R & Laffitte, B 2015, 'Inhibition of DYRK1A and GSK3B induces human β-cell proliferation', Nature communications, vol. 6, 8372. https://doi.org/10.1038/ncomms9372

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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.",

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Inhibition of DYRK1A and GSK3B induces human β-cell proliferation

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