Conditional Hypovascularization and Hypoxia in Islets Do Not Overtly Influence Adult β-Cell Mass or Function
- Joke D'Hoker1,
- Nico De Leu1,
- Yves Heremans1,
- Luc Baeyens1,
- Kohtaro Minami2,
- Cai Ying1,
- Astrid Lavens1,
- Marie Chintinne1,
- Geert Stangé1,
- Judith Magenheim3,
- Avital Swisa3,
- Geert Martens1,
- Daniel Pipeleers1,
- Mark van de Casteele1,
- Susumo Seino2,
- Eli Keshet3,
- Yuval Dor3 and
- Harry Heimberg1⇑
- 1Diabetes Research Center, Vrije Universiteit Brussel, Brussels, Belgium
- 2Department of Physiology and Cellular Biology, Kobe University Graduate School of Medicine, Kobe, Japan
- 3Department of Cellular Biochemistry and Human Genetics, Institute of Medical Research, Hebrew University Hadassah Medical School, Jerusalem, Israel
- Corresponding author: Harry Heimberg, .
J.D. and N.D.L. contributed equally to this study.
It is generally accepted that vascularization and oxygenation of pancreatic islets are essential for the maintenance of an optimal β-cell mass and function and that signaling by vascular endothelial growth factor (VEGF) is crucial for pancreas development, insulin gene expression/secretion, and (compensatory) β-cell proliferation. A novel mouse model was designed to allow conditional production of human sFlt1 by β-cells in order to trap VEGF and study the effect of time-dependent inhibition of VEGF signaling on adult β-cell fate and metabolism. Secretion of sFlt1 by adult β-cells resulted in a rapid regression of blood vessels and hypoxia within the islets. Besides blunted insulin release, β-cells displayed a remarkable capacity for coping with these presumed unfavorable conditions: even after prolonged periods of blood vessel ablation, basal and stimulated blood glucose levels were only slightly increased, while β-cell proliferation and mass remained unaffected. Moreover, ablation of blood vessels did not prevent β-cell generation after severe pancreas injury by partial pancreatic duct ligation or partial pancreatectomy. Our data thus argue against a major role of blood vessels to preserve adult β-cell generation and function, restricting their importance to facilitating rapid and adequate insulin delivery.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-1827/-/DC1.
- Received December 26, 2012.
- Accepted August 14, 2013.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.