Li Xianquan, Zhang Lanjing, Meshinchi Sasha, Dias-Leme Claudia, Raffin Diane, Johnson Jeffery D, Treutelaar Mary K, Burant Charles F
University of Michigan Medical Center, Box 0678, 1500 E. Medical Center Dr., Ann Arbor, MI 48109, USA.
Diabetes. 2006 Nov;55(11):2965-73. doi: 10.2337/db06-0733.
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.
对糖尿病前期雄性Zucker糖尿病脂肪大鼠（ZDF）的胰岛进行基因表达谱分析，结果显示缺氧相关基因的表达增加，这促使人们对胰岛的血管完整性进行研究。通过形态计量分析和定量内皮标志物的mRNA水平发现，年轻雄性ZDF大鼠的胰岛微血管增加了约两倍。12周龄的ZDF大鼠内皮细胞数量显著减少，而吡格列酮预处理可预防这种情况。对血糖正常的7周龄ZDF大鼠进行光镜和电镜观察，发现内皮细胞增厚，内皮窗孔消失。到12周龄时，出现内皮破坏和胰岛内出血。与瘦型对照相比，7周龄和12周龄ZDF大鼠的胰岛中血管内皮生长因子（VEGF）-A mRNA和VEGF蛋白分泌分别增加了约三倍和两倍。血小板反应蛋白-1 mRNA在7周龄和12周龄大鼠中分别增加了2倍和10倍，而在吡格列酮预处理的12周龄大鼠中减少了50%。年轻雄性对照大鼠的胰岛仅在基质金属蛋白酶（MMP）-9预处理后才诱导内皮细胞在胶原基质中迁移。与野生型对照相比，7周龄ZDF大鼠的胰岛即使未经MMP-9处理，迁移评分也增加了五倍。15周龄ZDF大鼠的胰岛不诱导迁移；相反，它们导致导管来源的细胞显著变圆，提示有毒性作用。这些数据表明，在2型糖尿病的ZDF大鼠模型中，胰岛维持血管完整性的能力不足可能导致β细胞功能衰竭。
