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

Area of Science:

• Endocrinology
• Molecular Biology
• Pharmacology

Background:

• Endoplasmic reticulum (ER) stress contributes to pancreatic beta cell dysfunction and loss in type 2 diabetes.
• Identifying therapeutic agents to protect beta cells from ER stress is crucial for diabetes management.

Purpose of the Study:

• To develop and utilize a high-throughput screening assay to discover small molecules that protect pancreatic beta cells from ER stress-induced cell death.
• To evaluate the efficacy of identified compounds in preserving beta cell function and mass.

Main Methods:

• A novel beta cell-based high-throughput screening assay was established using mouse betaTC6 cells and the ER stressor tunicamycin.
• Approximately 17,600 compounds were screened for their ability to prevent tunicamycin-induced cell death, measured by cellular ATP levels.
• Positive hits were further validated for their protective effects on human primary beta cells and rodent beta cell lines against various ER stressors, including palmitate.

Main Results:

• Two selected compounds demonstrated significant protection of beta cells against ER stress-induced cell death.
• These compounds enhanced the survival of both human and rodent beta cells exposed to ER stressors.
• The identified compounds restored glucose-stimulated insulin secretion impaired by ER stress and reduced the expression of key genes involved in the unfolded protein response and apoptosis.

Conclusions:

• The identified small molecules alleviate ER stress by downregulating the unfolded protein response and apoptosis pathways.
• These compounds represent promising therapeutic candidates for preventing ER stress-induced beta cell dysfunction and death, potentially offering a novel treatment strategy for type 2 diabetes.