Stimulation to secrete insulin induces pancreatic β-cell dysfunction through Tfe3 activation

Area of Science:

• Cell Biology
• Molecular Biology
• Endocrinology

Background:

• Diabetes progression is characterized by pancreatic beta-cell dysfunction and reduced insulin secretion.
• Downregulation of glucose-stimulated insulin secretion (GSIS)-related genes, including Mafa, is linked to beta-cell dysfunction.
• Mechanisms driving GSIS-related gene downregulation in diabetes remain unclear.

Purpose of the Study:

• To investigate the role of transcription factor Tfe3 in beta-cell dysfunction during diabetes progression.
• To elucidate the molecular mechanisms by which GSIS-related genes are downregulated.

Main Methods:

• Mice were administered glucose in drinking water to mimic diabetes progression.
• Beta-cells were analyzed for Tfe3 localization and expression of GSIS-related genes.
• In vitro insulin secretion assays were performed to assess Tfe3 activation and gene expression changes.
• Chromatin immunoprecipitation was used to determine Tfe3 binding to gene enhancers.

Main Results:

• Continuous glucose supplementation in mice induced nuclear accumulation of Tfe3 in beta-cells.
• Tfe3 accumulation correlated with Mafa downregulation and impaired glucose tolerance.
• Acute insulin stimulation in vitro activated Tfe3 and downregulated Mafa and other GSIS-related genes.
• Activated Tfe3 was found to bind and suppress enhancer activity of Mafa and other GSIS-related genes.

Conclusions:

• Tfe3 activation is a key mechanism linking insulin secretion stimulation to beta-cell dysfunction.
• Tfe3 acts as a transcriptional repressor of critical GSIS-related genes, including Mafa.
• Targeting Tfe3 activation may offer a therapeutic strategy for preserving beta-cell function in diabetes.