Impaired insulin secretion in vivo but enhanced insulin secretion from isolated islets in pancreatic beta cell-specific vascular endothelial growth factor-A knock-out mice.
OBJECTIVE
Endothelial cells are considered to be essential for normal pancreatic beta cell function. However, there have been no reports showing their importance for beta cell function.


METHODS
Using mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells, we investigated the relation between islet vascular structure and beta cell function.


RESULTS
Mice with disrupted vascular endothelial growth factor-A gene specifically in beta cells had reduced islet vascular density with impaired formation of endothelial fenestration. While their fasting glucose and body weight were comparable with control mice, their glucose- and tolbutamide-induced rapid insulin release were impaired, thus resulting in glucose intolerance. On the other hand, glucose and KCl enhanced the levels of insulin secreted from islets isolated from these mice. In addition, the production of soluble N-ethylmaleimide-sensitive factor attachment protein receptors in the islets was increased. Insulin content and expression of insulin I and pancreas duodenum homeobox 1 mRNA in the islets were also increased.


CONCLUSIONS
Our results indicate that an abnormal quality and quantity of blood vessels due to reduced expression of vascular endothelial growth factor-A in beta cells could be a cause of impaired insulin secretion without impairment of beta cell function.
Iwashita
N
N
Department of Medicine, Metabolism and Endocrinology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan.
Uchida
T
T
Choi
J B
JB
Azuma
K
K
Ogihara
T
T
Ferrara
N
N
Gerber
H
H
Kawamori
R
R
Inoue
M
M
Watada
H
H
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003433:Crosses, Genetic; D004730:Endothelium, Vascular / Q000502:physiology; D005260:Female; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism* / Q000502:physiology; D007515:Islets of Langerhans / Q000098:blood supply; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D012313:RNA / Q000235:genetics / Q000302:isolation & purification; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000172:deficiency* / Q000235:genetics
D001786:Blood Glucose; D007328:Insulin; D042461:Vascular Endothelial Growth Factor A; D012313:RNA