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Identification of small-molecule inducers of pancreatic beta-cell expansion.

Wang, Weidong and Walker, John and Wang, Xia and Tremblay, Matthew and Lee, Jae Wook and Wu, Xu and Schultz, Peter (2009) Identification of small-molecule inducers of pancreatic beta-cell expansion. Proceedings of the National Academy of Sciences of the United States of America, 106 (5). pp. 1427-1432. ISSN 1091-6490

Abstract

To identify small molecules that can induce beta-cell replication, a large chemical library was screened for proliferation of growth-arrested, reversibly immortalized mouse beta cells by using an automated high-throughput screening platform. A number of structurally diverse, active compounds were identified, including phorbol esters, which likely act through protein kinase C, and a group of thiophene-pyrimidines that stimulate beta-cell proliferation by activating the Wnt signaling pathway. A group of dihydropyridine (DHP) derivatives was also shown to reversibly induce beta-cell replication in vitro by activating L-type calcium channels (LTCCs). Our data suggest that the LTCC agonist 2a affects the expression of genes involved in cell cycle progression and cellular proliferation. Furthermore, treatment of beta cells with both LTCC agonist 2a and the Glp-1 receptor agonist Exendin-4 showed an additive effect on beta-cell replication. The identification of small molecules that induce beta-cell proliferation suggests that it may be possible to reversibly expand other quiescent cells to overcome deficits associated with degenerative and/or autoimmune diseases.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: beta-cell proliferation; diabetes mellitus; small molecules; Wnt agonist; L-type calcium channel agonist
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Date Deposited: 14 Dec 2009 13:49
Last Modified: 31 Jan 2013 00:57
URI: https://oak.novartis.com/id/eprint/1231

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