Chen S, Ding J, Yu C, Yang B, Wood D R, Grayburn P A
Division of Cardiology, Department of Internal Medicine, Baylor University Medical Center, Baylor Heart and Vascular Institute, Dallas, TX 75226, USA.
Gene Ther. 2007 Jul;14(14):1102-10. doi: 10.1038/sj.gt.3302963. Epub 2007 Apr 26.
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+/-8 mg/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.
在链脲佐菌素（STZ）破坏大鼠胰岛48小时后，采用超声靶向微泡破坏技术（UTMD）将β细胞素（BTC）和胰腺十二指肠同源盒-1（PDX1）导入大鼠胰腺。通过注射STZ使Sprague-Dawley大鼠患糖尿病。对照组包括正常大鼠、仅注射STZ而不进行UTMD的大鼠以及携带DsRed报告基因的UTMD组。STZ处理48小时后，所有大鼠的血糖均显著升高，单独使用BTC进行UTMD后血糖继续上升。使用PDX1进行UTMD后，血糖从第3天到第10天下降，但仍维持在较高水平（261±8mg/dl）。然而，在同时接受BTC和PDX1治疗的大鼠中，整个第10天血糖均保持在200mg/dl以下。这伴随着血胰岛素和C肽的正常化。组织学检查显示，在接受BTC和PDX1治疗的大鼠中存在胰高血糖素染色细胞的胰岛样簇，但这些簇在UTMD治疗后第30天消失。虽然未观察到胰岛素产生胰岛的再生，但通过胰腺腺泡细胞异位产生胰岛素，单次UTMD治疗后糖尿病可逆转长达15天。这些细胞共表达淀粉酶和胰岛素，并通过逆转录聚合酶链反应显示出几种β细胞标志物。UTMD基因治疗可通过恢复胰腺胰岛素分泌在成年大鼠体内逆转糖尿病。
