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

被引:159
作者
Sund, NJ
Vatamaniuk, MZ
Casey, M
Ang, SL
Magnuson, MA
Stoffers, DA
Matschinsky, FM
Kaestner, KH [1 ]
机构
[1] Univ Penn, Sch Med, Dept Genet, Philadelphia, PA 19104 USA
[2] Univ Penn, Sch Med, Penn Diabet Ctr, Philadelphia, PA 19104 USA
[3] Univ Penn, Sch Med, Dept Biochem & Biophys, Philadelphia, PA 19104 USA
[4] Univ Penn, Sch Med, Div Endocrinol Diabet & Metab, Dept Med, Philadelphia, PA 19104 USA
[5] Univ Louis Pasteur Strasbourg 1, Inst Genet & Biol Mol & Cellulaire, CNRS, INSERM, F-67404 Illkirch, France
[6] CU Strasbourg, Strasbourg, France
[7] Vanderbilt Univ, Sch Med, Dept Physiol & Mol Biophys, Nashville, TN 37232 USA
基金
英国医学研究理事会;
关键词
hepatocyte nuclear factor; persistent hyperinsulinemic hypoglycemia of infancy; familial hyperinsulinism;
D O I
10.1101/gad.901601
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
We have used conditional gene ablation to uncover a dramatic and unpredicted role for the winged-helix transcription factor Foxa2 (formerly HNF-3 beta) in pancreatic beta -cell differentiation and metabolism. Mice that lack Foxa2 specifically in beta 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 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 investigate the regulation of insulin secretion by the beta cell and suggest the human FOXA2 as a candidate gene for familial hyperinsulinism.
引用
收藏
页码:1706 / 1715
页数:10
相关论文
共 39 条
[1]   Glucose action 'beyond ionic events' in the pancreatic β cell [J].
Aizawa, T ;
Komatsu, M ;
Asanuma, N ;
Sato, Y ;
Sharp, GWG .
TRENDS IN PHARMACOLOGICAL SCIENCES, 1998, 19 (12) :496-499
[2]   HYBRID INSULIN GENES REVEAL A DEVELOPMENTAL LINEAGE FOR PANCREATIC ENDOCRINE-CELLS AND IMPLY A RELATIONSHIP WITH NEURONS [J].
ALPERT, S ;
HANAHAN, D ;
TEITELMAN, G .
CELL, 1988, 53 (02) :295-308
[3]  
ANG SL, 1993, DEVELOPMENT, V119, P1301
[4]   HNF-3-BETA IS ESSENTIAL FOR NODE AND NOTOCHORD FORMATION IN MOUSE DEVELOPMENT [J].
ANG, SL ;
ROSSANT, J .
CELL, 1994, 78 (04) :561-574
[5]  
Dufort D, 1998, DEVELOPMENT, V125, P3015
[6]  
Duncan SA, 1997, DEVELOPMENT, V124, P279
[7]   Potassium channels, sulphonylurea receptors and control of insulin release [J].
Dunne, MJ ;
Cosgrove, KE ;
Shepherd, RM ;
Ämmälä, C .
TRENDS IN ENDOCRINOLOGY AND METABOLISM, 1999, 10 (04) :146-152
[8]   Familial persistent hyperinsulinemic hypoglycemia of infancy and mutations in the sulfonylurea receptor [J].
Dunne, MJ ;
Kane, C ;
Shepherd, RM ;
Sanchez, JA ;
James, RFL ;
Johnson, PRV ;
AynsleyGreen, A ;
Lu, S ;
Clement, JP ;
Lindley, KJ ;
Seino, S ;
AguilarBryan, L .
NEW ENGLAND JOURNAL OF MEDICINE, 1997, 336 (10) :703-706
[9]   POTASSIUM SELECTIVE ION CHANNELS IN INSULIN-SECRETING CELLS - PHYSIOLOGY, PHARMACOLOGY AND THEIR ROLE IN STIMULUS-SECRETION COUPLING [J].
DUNNE, MJ ;
PETERSEN, OH .
BIOCHIMICA ET BIOPHYSICA ACTA, 1991, 1071 (01) :67-82
[10]   Familial hyperinsulinism caused by an activating glucokinase mutation [J].
Glaser, B ;
Kesavan, P ;
Heyman, M ;
Davis, E ;
Cuesta, A ;
Buchs, A ;
Stanley, CA ;
Thornton, PS ;
Permutt, MA ;
Matschinsky, FM ;
Herold, KC .
NEW ENGLAND JOURNAL OF MEDICINE, 1998, 338 (04) :226-230