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

Biochemical Pharmacology
Seung-Hee LeeFred Levine

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.

Citations

Dec 12, 2017·Acta Physiologica·A D GreenP R Flatt
Dec 20, 2018·Journal of Cellular Physiology·Mohammad Javad Saeedi BorujeniAmid Yazdani
Sep 5, 2018·Therapeutic Innovation & Regulatory Science·Katsura TsukamotoNaoki Matsumaru
Nov 17, 2020·Frontiers in Microbiology·Yinhua WuXiaoyan Liu
Oct 20, 2019·Journal of Molecular Biology·Maria LytriviMiriam Cnop
Jan 27, 2021·Stem Cells·Phillip L Lewis, James M Wells
Aug 28, 2021·International Journal of Molecular Sciences·Maria Narożna, Błażej Rubiś

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