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Biochem Pharmacol. 2017 Aug 15;138:140-149. doi: 10.1016/j.bcp.2017.05.007. Epub 2017 May 15.

High-throughput screening and bioinformatic analysis to ascertain compounds that prevent saturated fatty acid-induced β-cell apoptosis.

Author information

1
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
2
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium.
3
Department of Physics and Astronomy, Michigan State University, East Lansing, MI 48824, USA.
4
Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy.
5
ULB Center for Diabetes Research, Medical Faculty, Université Libre de Bruxelles (ULB), 808 Route de Lennik, B-1070 Brussels, Belgium; Division of Endocrinology, Erasmus Hospital, Université Libre de Bruxelles (ULB), B-1070 Brussels, Belgium.
6
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA. Electronic address: flevine@sbpdiscovery.org.

Abstract

Pancreatic β-cell lipotoxicity is a central feature of the pathogenesis of type 2 diabetes. To study the mechanism by which fatty acids cause β-cell death and develop novel approaches to prevent it, a high-throughput screen on the β-cell line INS1 was carried out. The cells were exposed to palmitate to induce cell death and compounds that reversed palmitate-induced cytotoxicity were ascertained. Hits from the screen were analyzed by an increasingly more stringent testing funnel, ending with studies on primary human islets treated with palmitate. MAP4K4 inhibitors, which were not part of the screening libraries but were ascertained by a bioinformatics analysis, and the endocannabinoid anandamide were effective at inhibiting palmitate-induced apoptosis in INS1 cells as well as primary rat and human islets. These targets could serve as the starting point for the development of therapeutics for type 2 diabetes.

KEYWORDS:

Beta-cell; Diabetes; Islet; Lipotoxicity

PMID:
28522407
DOI:
10.1016/j.bcp.2017.05.007
[Indexed for MEDLINE]

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