Inhibition of DYRK1A and GSK3B induces human β-cell proliferation View Full Text


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-10-26

AUTHORS

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

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. More... »

PAGES

8372

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms9372

    DOI

    http://dx.doi.org/10.1038/ncomms9372

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1030123628

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26496802


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