Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1
Reversal of streptozotocin-induced diabetes in rats by gene therapy with betacellulin and pancreatic duodenal homeobox-1
复制标题
DOI：
10.1038/sj.gt.3302963
复制
发表时间：
2007-07-01
期刊：
影响因子：
5.1
通讯作者：
Grayburn, P. A.
中科院分区：
文献类型：
--
作者：
Chen, S.;Ding, J.;Grayburn, P. A.
超声靶向微泡破坏（UTMD）被用来指导β细胞素（BTC）和胰腺十二指肠同源框-1（PDX 1）大鼠胰腺后48小时，胰岛破坏链脲佐菌素（STZ）。通过注射STZ使Sprague-Dawley大鼠患糖尿病。对照组包括正常大鼠、仅STZ而不加UTMD和加DsRed报告基因的UTMD。STZ后48小时，所有大鼠的血糖均显着升高，并且在单独使用BTC的UTMD后继续升高。在使用PDX 1的UTMD后，血糖从第3天至第10天下降，但仍然升高（261 +/-78 mg/dl）。然而，在用BTC和PDX 1治疗的大鼠中，血糖在整个第10天保持低于200 mg/dl。这伴随着血液胰岛素和C肽的正常化。组织学显示在用BTC和PDX 1处理的大鼠中胰高血糖素染色细胞的胰岛样簇，但这些簇在UTMD处理后30天消失。虽然没有看到产生胰岛素的胰岛再生，但在单次UTMD治疗后，通过胰腺腺泡细胞异位产生胰岛素，糖尿病逆转长达15天。这些细胞共表达淀粉酶和胰岛素，并通过逆转录-PCR证明了几种β细胞标志物。通过UTMD的基因治疗可以通过恢复胰腺胰岛素的产生来逆转成年大鼠体内的糖尿病。
Ultrasound-targeted microbubble destruction (UTMD) was used to direct betacellulin (BTC) and pancreatic duodenal homeobox-1 (PDX1) to rat pancreas 48 h after islet destruction by streptozotocin (STZ). Sprague-Dawley rats were rendered diabetic by STZ injection. Controls included normal rats, STZ only without UTMD, and UTMD with DsRed reporter gene. Blood glucose increased dramatically in all rats 48 h after STZ, and continued to rise after UTMD with BTC alone. Blood glucose declined from day 3 to day 10 after UTMD with PDX1, but remained elevated (261 +/- 78mg/dl). However, in rats treated with both BTC and PDX1, blood glucose remained below 200 mg/dl throughout day 10. This was accompanied by normalization of blood insulin and C-peptide. Histology demonstrated islet-like clusters of glucagon-staining cells in the rats treated with BTC and PDX1, but these clusters disappeared by 30 days after UTMD treatment. Although regeneration of insulin-producing islets was not seen, diabetes was reversed for up to 15 days after a single UTMD treatment by ectopic insulin production by pancreatic acinar cells. These cells co-expressed amylase and insulin and demonstrated several beta-cell markers by reverse transcription-PCR. Gene therapy by UTMD can reverse diabetes in vivo in adult rats by restoring pancreatic insulin production.