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Beta cell specific probing with fluorescent exendin-4 is progressively reduced in type 2 diabetic mouse models

机译:在2型糖尿病小鼠模型中,用荧光exendin-4进行的beta细胞特异性探测逐渐减少

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Probes based on GLP-1R agonist exendin-4 have shown promise as in vivo beta cell tracers. However, questions remain regarding the beta cell specificity of exendin-4 probes, and it is unclear if the expression levels of the GLP-1R are affected in a type 2 diabetic state. Using in vivo probing followed by ex vivo imaging we found fluorescent exendin-4 probes to distinctly label the pancreatic islets in mice in a Glp-1r dependent manner. Furthermore, a co-localization study revealed a near 100 percent beta cell specificity with less than one percent probing in other analyzed cell types. We then tested if probing was affected in models of type 2 diabetes using the Lepr(db/db) (db/db) and the Diet-Induced Obese (DIO) mouse. Although nearly all beta cells continued to be probed, we observed a progressive decline in probing intensity in both models with the most dramatic reduction seen in db/db mice. This was paralleled by a progressive decrease in Glp-1r protein expression levels. These data confirm beta cell specificity for exendin-4 based probes in mice. Furthermore, they also suggest that GLP-1R targeting probes may provide a tool to monitor b cell function rather than mass in type 2 diabetic mouse models.
机译:基于GLP-1R激动剂exendin-4的探针已显示出作为体内β细胞示踪剂的希望。但是,关于exendin-4探针的β细胞特异性仍然存在疑问,目前尚不清楚在2型糖尿病状态下GLP-1R的表达水平是否受到影响。使用体内探测,然后进行离体成像,我们发现荧光exendin-4探针以Glp-1r依赖性方式明显标记小鼠的胰岛。此外,一项共同定位研究显示,在其他分析的细胞类型中,β细胞的特异性接近100%,探测不到1%。然后,我们使用Lepr(db / db)(db / db)和饮食诱发肥胖(DIO)小鼠测试了2型糖尿病模型中的探测是否受到影响。尽管几乎所有的β细胞都继续被探测,但我们观察到在两个模型中探测强度都逐渐下降,在db / db小鼠中观察到的下降最为明显。与此同时,Glp-1r蛋白表达水平逐渐下降。这些数据证实了小鼠中基于exendin-4的探针的β细胞特异性。此外,他们还暗示,GLP-1R靶向探针可能提供了监测b细胞功能而不是2型糖尿病小鼠模型中质量的工具。

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