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Tissue-specific deletion of Foxa2 in pancreatic beta cells results in hyperinsulinemic hypoglycemia

N J Sund1, M Z Vatamaniuk, M Casey

  • 1Department of Genetics, Penn Diabetes Center, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.

Genes & Development
|July 11, 2001
PubMed

Insights

The winged-helix transcription factor Foxa2 is crucial for pancreatic beta-cell function. Loss of Foxa2 in beta cells causes severe hypoglycemia and mimics familial hyperinsulinism, implicating FOXA2 in the disorder.

Area of Science:

  • Endocrinology
  • Molecular Biology
  • Genetics

Background:

  • The winged-helix transcription factor Foxa2 (formerly HNF-3 beta) plays a role in liver and pancreas development.
  • The ATP-sensitive potassium channel (K(ATP)) is critical for regulating insulin secretion from pancreatic beta cells.

Purpose of the Study:

  • To investigate the role of Foxa2 in pancreatic beta-cell differentiation and metabolism.
  • To explore the link between Foxa2 and familial hyperinsulinism.

Main Methods:

  • Conditional gene ablation in mice to specifically remove Foxa2 from beta cells (Foxa2(loxP/loxP); Ins.Cre mice).
  • Analysis of glucose and amino acid-stimulated insulin secretion.
  • Identification of Foxa2 target genes in pancreatic islets.

Main Results:

  • Mice lacking Foxa2 in beta cells exhibited severe hypoglycemia.
  • These mice showed dysregulated insulin secretion in response to glucose and amino acids, mimicking familial hyperinsulinism.
  • The two subunits of the beta-cell K(ATP) channel were identified as novel Foxa2 targets.

Conclusions:

  • Foxa2 plays a critical, unpredicted role in pancreatic beta-cell function and insulin secretion.
  • Foxa2 deficiency in beta cells leads to a phenotype resembling familial hyperinsulinism.
  • Human FOXA2 is a candidate gene for familial hyperinsulinism, and these mice provide a model for studying insulin secretion regulation.

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