Tissue-specific deletion of Foxa2 in pancreatic β cells results in hyperinsulinemic hypoglycemia
- Newman J. Sund1,2,
- Marko Z. Vatamaniuk2,3,
- Melissa Casey1,2,
- Siew-Lan Ang5,
- Mark A. Magnuson6,
- Doris A. Stoffers2,4,
- Franz M. Matschinsky2,3, and
- Klaus H. Kaestner1,2,7
- 1Department of Genetics, 2Penn Diabetes Center, 3Department of Biochemistry and Biophysics, and 4Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA; 5Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/Université Louis Pasteur, BP163, 67404 Illkirch cedex, CU de Strasbourg, France; 6Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
Abstract
We have used conditional gene ablation to uncover a dramatic and unpredicted role for the winged-helix transcription factor Foxa2 (formerly HNF-3β) in pancreatic β-cell differentiation and metabolism. Mice that lack Foxa2 specifically in β cells (Foxa2 loxP/loxP; Ins.Cre mice) are severely hypoglycemic and show dysregulated insulin secretion in response to both glucose and amino acids. This inappropriate hypersecretion of insulin in the face of profound hypoglycemia mimics pathophysiological and molecular aspects of familial hyperinsulinism. We have identified the two subunits of the β-cell ATP-sensitive K+ channel (KATP), the most frequently mutated genes linked to familial hyperinsulinism, as novel Foxa2 targets in islets. TheFoxa2 loxP/loxP; Ins.Cre mice will serve as a unique model to investigate the regulation of insulin secretion by the β cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism.
Keywords
Footnotes
-
↵7 Corresponding author.
-
E-MAIL kaestner{at}mail.med.upenn.edu; FAX (215) 573-5892.
-
Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.901601.
-
- Received April 5, 2001.
- Accepted May 16, 2001.
- Cold Spring Harbor Laboratory Press
