Islet microvasculature in islet hyperplasia and failure in a model of type 2 diabetes.
Gene expression profiling of islets from pre-diabetic male Zucker diabetic fatty (ZDF) rats showed increased expression of hypoxia-related genes, prompting investigation of the vascular integrity of the islets. The islet microvasculature was increased approximately twofold in young male ZDF rats by both morphometric analysis and quantifying mRNA levels of endothelial markers. ZDF rats at 12 weeks of age showed a significant reduction in the number of endothelial cells, which was prevented by pretreatment with pioglitazone. Light and electron microscopy of normoglycemic 7-week-old ZDF rats showed thickened endothelial cells with loss of endothelial fenestrations. By 12 weeks of age, there was disruption of the endothelium and intra-islet hemorrhage. Islets from 7- and 12-week-old ZDF rats showed an approximate three- and twofold increase in vascular endothelial growth factor (VEGF)-A mRNA and VEGF protein secretion, respectively, compared with lean controls. Thrombospondin-1 mRNA increased in 7- and 12-week-old rats by 2- and 10-fold, respectively, and was reduced by 50% in 12-week-old rats pretreated with pioglitazone. Islets from young male control rats induced migration of endothelial cells in a collagen matrix only after pretreatment with matrix metalloproteinase (MMP)-9. Islets from 7-week-old ZDF rats showed a fivefold increase in migration score compared with wild-type controls, even without MMP-9 treatment. Islets from 15-week-old ZDF rats did not induce migration; rather, they caused a significant rounding up of the duct-derived cells, suggesting a toxic effect. These data suggest that in the ZDF rat model of type 2 diabetes, an inability of the islet to maintain vascular integrity may contribute to beta-cell failure.
Li
Xianquan
X
University of Michigan Medical Center, Box 0678, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA.
Zhang
Lanjing
L
Meshinchi
Sasha
S
Dias-Leme
Claudia
C
Raffin
Diane
D
Johnson
Jeffery D
JD
Treutelaar
Mary K
MK
Burant
Charles F
CF
D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000503:physiopathology*; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D006965:Hyperplasia; D000860:Hypoxia / Q000235:genetics; D007333:Insulin Resistance; D007515:Islets of Langerhans / Q000098:blood supply* / Q000473:pathology*; D008297:Male; D008833:Microcirculation / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011924:Rats, Zucker; D020133:Reverse Transcriptase Polymerase Chain Reaction; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics
D012333:RNA, Messenger; D042461:Vascular Endothelial Growth Factor A