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Neratinib protects pancreatic beta cells in diabetes

Ardestani, Amin; Li, Sijia; Annamalai, Karthika; Lupse, Blaz; Geravandi, Shirin; Dobrowolski, Aleksandra; Yu, Shan; Zhu, Siying; Baguley, Tyler D.; Surakattula, Murali; Oetjen, Janina; Hauberg-Lotte, Lena; Herranz, Raquel; Awal, Sushil; Altenhofen, Delsi; Nguyen-Tran, Van; Joseph, Sean; Schultz, Peter G.; Chatterjee, Arnab K.; Rogers, Nikki; Tremblay, Matthew S.; Shen, Weijun; Maedler, Kathrin

Authors

Sijia Li

Karthika Annamalai

Blaz Lupse

Shirin Geravandi

Aleksandra Dobrowolski

Shan Yu

Siying Zhu

Tyler D. Baguley

Murali Surakattula

Janina Oetjen

Lena Hauberg-Lotte

Raquel Herranz

Sushil Awal

Delsi Altenhofen

Van Nguyen-Tran

Sean Joseph

Peter G. Schultz

Arnab K. Chatterjee

Nikki Rogers

Matthew S. Tremblay

Weijun Shen

Kathrin Maedler



Abstract

The loss of functional insulin-producing β-cells is a hallmark of diabetes. Mammalian sterile 20-like kinase 1 (MST1) is a key regulator of pancreatic β-cell death and dysfunction; its deficiency restores functional β-cells and normoglycemia. The identification of MST1 inhibitors represents a promising approach for a β-cell-protective diabetes therapy. Here, we identify neratinib, an FDA-approved drug targeting HER2/EGFR dual kinases, as a potent MST1 inhibitor, which improves β-cell survival under multiple diabetogenic conditions in human islets and INS-1E cells. In a pre-clinical study, neratinib attenuates hyperglycemia and improves β-cell function, survival and β-cell mass in type 1 (streptozotocin) and type 2 (obese Leprdb/db) diabetic mouse models. In summary, neratinib is a previously unrecognized inhibitor of MST1 and represents a potential β-cell-protective drug with proof-of-concept in vitro in human islets and in vivo in rodent models of both type 1 and type 2 diabetes.

Citation

Ardestani, A., Li, S., Annamalai, K., Lupse, B., Geravandi, S., Dobrowolski, A., …Maedler, K. (2019). Neratinib protects pancreatic beta cells in diabetes. Nature communications, 10(1), Article 5015. https://doi.org/10.1038/s41467-019-12880-5

Journal Article Type Article
Acceptance Date Oct 2, 2019
Online Publication Date Nov 1, 2019
Publication Date Dec 1, 2019
Deposit Date Jan 4, 2024
Publicly Available Date Jan 5, 2024
Journal Nature Communications
Electronic ISSN 2041-1723
Publisher Nature Publishing Group
Peer Reviewed Peer Reviewed
Volume 10
Issue 1
Article Number 5015
DOI https://doi.org/10.1038/s41467-019-12880-5
Keywords Mechanisms of disease; Type 2 diabetes
Public URL https://hull-repository.worktribe.com/output/4461600

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0

Copyright Statement
© The Author(s) 2019.
Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.




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