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

ACS Chem Biol. 2014 Dec 19;9(12):2796-806. doi: 10.1021/cb500740d. Epub 2014 Oct 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Animals
  • Apoptosis / drug effects
  • Caspase 3 / genetics
  • Caspase 3 / metabolism
  • Cell Line
  • Cell Survival / drug effects
  • Drug Discovery
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Endoplasmic Reticulum Stress / genetics
  • Gene Expression
  • High-Throughput Screening Assays
  • Humans
  • Insulin / metabolism
  • Insulin Secretion
  • Insulin-Secreting Cells / cytology
  • Insulin-Secreting Cells / drug effects*
  • Insulin-Secreting Cells / metabolism
  • Mice
  • Palmitic Acid / antagonists & inhibitors
  • Palmitic Acid / pharmacology
  • Primary Cell Culture
  • Protective Agents / chemistry
  • Protective Agents / pharmacology*
  • Signal Transduction
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Stress, Physiological / drug effects
  • Tunicamycin / antagonists & inhibitors
  • Tunicamycin / pharmacology
  • Unfolded Protein Response / drug effects*
  • Unfolded Protein Response / genetics

Substances

  • Insulin
  • Protective Agents
  • Small Molecule Libraries
  • Tunicamycin
  • Palmitic Acid
  • Adenosine Triphosphate
  • Caspase 3