Identification of Small-molecule Inducers of Pancreatic Beta-cell Expansion

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2009 Jan 24

PMID 19164755

Citations 46

Authors

Weidong Wang

John R Walker

Xia Wang

Matthew S Tremblay

Jae Wook Lee

Xu Wu

Peter G Schultz

Affiliations

Soon will be listed here.

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.

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