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

We have used conditional gene ablation to uncover a dramatic and unpredicte d role for the winged-helix transcription factor Foxa2 (formerly HNF-3 beta ) in pancreatic beta -cell differentiation and metabolism. Mice that lack F oxa2 specifically in beta cells (Foxa2(loxP/loxP); Ins.Cre mice) are severe ly hypoglycemic and show dysregulated insulin secretion in response to both glucose and amino acids. This inappropriate hypersecretion of insulin in t he face of profound hypoglycemia mimics pathophysiological and molecular as pects of familial hyperinsulinism. We have identified the two subunits of t he beta -cell ATP-sensitive K+ channel (K-ATP), the most frequently mutated genes linked to familial hyperinsulinism, as novel Foxa2 targets in islets . The Foxa2(loxP/loxP); Ins.Cre mice will serve as a unique model to invest igate the regulation of insulin secretion by the beta cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism.