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首页> 外文期刊>Life sciences >Engineered beta-cells secreting dipeptidyl peptidase IV-resistant glucagon-like peptide-1 show enhanced glucose-responsiveness.
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Engineered beta-cells secreting dipeptidyl peptidase IV-resistant glucagon-like peptide-1 show enhanced glucose-responsiveness.

机译：分泌二肽基肽酶IV抵抗胰高血糖素样肽-1的工程β细胞显示出增强的葡萄糖反应性。

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摘要

Type 2 diabetes is a polygenic disorder characterized by increased insulin resistance, and impaired insulin secretion leading to abnormalities of glucose and lipid metabolism. Reduced responsiveness of the beta-cells to glucose is a critical feature of this syndrome. Glucagon-like peptide 1, a product of the pro-glucagon gene makes beta-cells competent and has many other anti-diabetic properties. We speculated whether GLP-1-based gene therapy could be an approach for treatment of type 2 diabetes. We started with a clone of rat insulinoma cells (S4 cells), which showed reduced responsiveness to glucose in terms of insulin secretion. We transfected these cells with a plasmid encoding a mutated form of GLP-1 (GLP-1-Gly8), which is resistant to the degrading enzyme dipeptidyl-peptidase IV. Activity of secreted GLP-1-Gly8 was assayed using Chinese hamster lung fibroblasts (CHL) cells that expressed cloned GLP-1 receptor and that were transfected with CRE-Luc. Stable cell lines (Glipsulin cells) obtained by this means produced and stored immunoreactive GLP-1-Gly8. In addition to insulin, the Glipsulin cells secreted the GLP-1-Gly8. The secreted GLP-1-Gly8 was active as evidenced by the ability of the conditioned media to elevate cAMP levels in CHL cells expressing GLP-1 receptors. Glipsulin cells responded to glucose with a 6.8 fold increase in insulin secretion compared to a 2.2 fold increase in the control cells. Our results demonstrate that prolonged exposure to GLP-1-Gly8 secreted by increases glucose-responsiveness of these cells. We speculate that engineering GLP-1-Gly8 secretion by beta-cells is a potential gene therapeutic strategy to treat diabetes.
机译：2型糖尿病是一种多基因性疾病，其特征是胰岛素抵抗增强，胰岛素分泌受损，导致葡萄糖和脂质代谢异常。 β细胞对葡萄糖的反应性降低是该综合征的关键特征。胰高血糖素前体基因的产物胰高血糖素样肽1使β细胞具有功能，并具有许多其他抗糖尿病特性。我们推测基于GLP-1的基因疗法是否可以作为治疗2型糖尿病的方法。我们从大鼠胰岛素瘤细胞（S4细胞）的克隆开始，该克隆在胰岛素分泌方面显示出对葡萄糖的响应降低。我们用编码突变形式的GLP-1（GLP-1-Gly8）的质粒转染了这些细胞，该质粒对降解酶二肽基肽酶IV具有抗性。使用表达克隆的GLP-1受体并用CRE-Luc转染的中国仓鼠肺成纤维细胞（CHL）测定分泌的GLP-1-Gly8的活性。通过这种方法获得的稳定细胞系（脂蛋白细胞）产生并储存了免疫反应性GLP-1-Gly8。除胰岛素外，脂蛋白细胞还分泌GLP-1-Gly8。条件培养基可提高表达GLP-1受体的CHL细胞中cAMP水平，这证明了分泌的GLP-1-Gly8具有活性。脂蛋白细胞对葡萄糖的反应是胰岛素分泌增加了6.8倍，而对照细胞增加了2.2倍。我们的结果表明，长时间暴露于这些细胞分泌的葡萄糖反应性增加的分泌的GLP-1-Gly8中。我们推测，β-细胞工程改造GLP-1-Gly8分泌是治疗糖尿病的潜在基因治疗策略。

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