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

Yuki Aida1, Nozomu Kadota1, Mimi Takahashi1

  • 1Laboratory of Molecular Medical Bioscience, Graduate School of Medical Life Science, Yokohama City University, Yokohama 230-0045, Japan.

Iscience
|April 6, 2026
PubMed

Insights

High glucose and insulin secretion activate Tfe3 in pancreatic beta cells, leading to Mafa gene downregulation and impaired glucose tolerance in diabetes progression.

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.
Keywords:
Cell biologyEndocrinologyMolecular biology

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