title: Identification of small molecules that protect pancreatic β cells against endoplasmic reticulum stress-induced cell death.
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.
authors.affiliation: Immunobiology and Cancer Research Program and §Free Radical Biology and Aging Program, Oklahoma Medical Research Foundation , Oklahoma City, Oklahoma 73104, United States.
authors.forename: Kim
authors.initials: K
authors.lastname: Tran
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.forename: Hongliang
authors.initials: H
authors.lastname: Duan
authors.forename: Daleep
authors.initials: D
authors.lastname: Arora
authors.forename: Hui-Ying
authors.initials: HY
authors.lastname: Lim
authors.forename: Weidong
authors.initials: W
authors.lastname: Wang
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055808:Drug Discovery; D004721:Endoplasmic Reticulum / Q000187:drug effects; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000235:genetics; D015870:Gene Expression; D057166:High-Throughput Screening Assays; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D019308:Palmitic Acid / Q000037:antagonists & inhibitors / Q000494:pharmacology; D061251:Primary Cell Culture; D020011:Protective Agents / Q000737:chemistry / Q000494:pharmacology*; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013312:Stress, Physiological / Q000187:drug effects; D014415:Tunicamycin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D056811:Unfolded Protein Response / Q000187:drug effects* / Q000235:genetics
chemical_list: D007328:Insulin; D020011:Protective Agents; D054852:Small Molecule Libraries; D014415:Tunicamycin; D019308:Palmitic Acid; D000255:Adenosine Triphosphate; D053148:Caspase 3