Successful strategies for treating type 1 diabetes need to restore the function of pancreatic beta cells that are destroyed by the immune system and overcome further destruction of insulin-producing cells. Here, we infused adeno-associated virus carrying Pdx1 and MafA expression cassettes through the pancreatic duct to reprogram alpha cells into functional beta cells and normalized blood glucose in both beta cell-toxin-induced diabetic mice and in autoimmune non-obese diabetic (NOD) mice. The euglycemia in toxin-induced diabetic mice and new insulin⁺ cells persisted in the autoimmune NOD mice for 4 months prior to reestablishment of autoimmune diabetes. This gene therapy strategy also induced alpha to beta cell conversion in toxin-treated human islets, which restored blood glucose levels in NOD/SCID mice upon transplantation. Hence, this strategy could represent a new therapeutic approach, perhaps complemented by immunosuppression, to bolster endogenous insulin production. Our study thus provides a potential basis for further investigation in human type 1 diabetes.

中文翻译：

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由病毒基因治疗诱导的将Alpha细胞内源性重编程为Beta细胞可逆转自身免疫性糖尿病。

治疗1型糖尿病的成功策略需要恢复被免疫系统破坏的胰岛β细胞的功能，并克服胰岛素产生细胞的进一步破坏。在这里，我们通过胰管注入携带Pdx1和MafA表达盒的腺相关病毒，以将β细胞重编程为功能性β细胞，并使β细胞毒素诱导的糖尿病小鼠和自身免疫性非肥胖糖尿病（NOD）的血糖正常化老鼠。毒素诱导的糖尿病小鼠的正常血糖和新的胰岛素⁺在自身免疫性糖尿病重建之前，这些细胞在自身免疫性NOD小鼠中持续存在4个月。这种基因治疗策略还诱导了毒素治疗的人类胰岛中的α至β细胞转化，该胰岛在移植后恢复了NOD / SCID小鼠的血糖水平。因此，该策略可能代表一种新的治疗方法，也许通过免疫抑制来补充，以增强内源性胰岛素的产生。因此，我们的研究为进一步研究人类1型糖尿病提供了潜在的基础。