Identification of small molecules that protect pancreatic β cells against endoplasmic reticulum stress-induced cell death

Kim Tran, Yu Li, Hongliang Duan, Daleep Arora, Hui Ying Lim, Weidong Wang

Research output: Contribution to journalArticlepeer-review

17 Citations (Scopus)

Abstract

Endoplasmic reticulum (ER) stress plays an important role in the decline in pancreatic β cell function and mass observed in type 2 diabetes. Here, we developed a novel β cell-based high-throughput screening assay to identify small molecules that protect β cells against ER stress-induced cell death. Mouse βTC6 cells were treated with the ER stressor tunicamycin to induce ER stress, and cell death was measured as a reduction in cellular ATP. A collection of 17600 compounds was screened for molecules that promote β cell survival. Of the approximately 80 positive hits, two selected compounds were able to increase the survival of human primary β cells and rodent β cell lines subjected to ER stressors including palmitate, a free fatty acid of pathological relevance to diabetes. These compounds also restored ER stress-impaired glucose-stimulated insulin secretion responses. We show that the compounds promote β cell survival by reducing the expression of key genes of the unfolded protein response and apoptosis, thus alleviating ER stress. Identification of small molecules that prevent ER stress-induced β cell dysfunction and death may provide a new modality for the treatment of diabetes.

Original languageEnglish
Pages (from-to)2796-2806
Number of pages11
JournalACS Chemical Biology
Volume9
Issue number12
DOIs
Publication statusPublished - 19 Dec 2014
Externally publishedYes

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