To be clinically efficient, beta cell replacement therapies such as pig islet xenotransplantation must ensure sufficient insulin secretion from grafted islets. While protection from host immune reaction is essential for islet engraftment and their subsequent functioning, intrinsic physiological properties of used cells are also a key factor. We have previously shown that islets with adenoviral-mediated expression of a dipeptidyl peptidase-resistant form of glucagon-like-peptide-1 (GLP-1) and a constitutively activated form of type 3 muscarinic receptor (M3R) in their beta cells have greatly improved insulin secretory response to glucose stimulation that is otherwise 4 to 10 times lower than human islets. Here, we describe in vitro characterization of the secretory function of pancreatic islets, derived from transgenic pigs expressing the GLP-1M3R cassette under the porcine insulin promoter (InsGLP-1M3R), and their usage to treat insulin-dependent diabetes in an immunodeficient mouse model. Our results show that InsGLP-1M3R islets isolated from neonatal and adult pigs secrete up to 15-fold more insulin in response to glucose stimulation compared to wild-type (WT) islets. They also proved to be more efficient in treating diabetes in a preclinical model as shown by a significantly higher percentage of normoglycemic recipients and higher porcine C-peptide levels up to 9 mo post implantation.

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双转基因新生猪胰岛作为 β 细胞替代治疗的替代来源


为了达到临床效率，猪胰岛异种移植等 β 细胞替代疗法必须确保移植胰岛分泌足够的胰岛素。虽然保护细胞免受宿主免疫反应对于胰岛植入及其后续功能至关重要，但所用细胞的内在生理特性也是一个关键因素。我们之前已经表明，腺病毒介导的胰高血糖素样肽-1 （GLP-1） 二肽酶抗性形式的胰岛和 3 型毒蕈碱受体 （M3R） 的组成型激活形式的胰岛在其 β 细胞中大大改善了胰岛素分泌对葡萄糖刺激的反应，否则比人胰岛低 4 到 10 倍。在这里，我们描述了胰岛分泌功能的体外表征，胰岛来源于在猪胰岛素启动子 （InsGLP-1M3R） 下表达 GLP-1M3R 盒的转基因猪，以及它们在免疫缺陷小鼠模型中用于治疗胰岛素依赖性糖尿病的用途。我们的结果表明，与野生型 （WT） 胰岛相比，从新生猪和成年猪中分离的 InsGLP-1M3R 胰岛在葡萄糖刺激下分泌的胰岛素多 15 倍。在临床前模型中，它们也被证明在治疗糖尿病方面更有效，如正常血糖受者的百分比显着升高和猪 C 肽水平升高（植入后长达 9 个月）所示。