Loss of pancreatic beta cells is the central feature of all forms of diabetes. Current therapies fail to halt the declined beta cell mass. Thus, strategies to preserve beta cells are imperatively needed. In this study, we identified paired box 6 (PAX6) as a critical regulator of beta cell survival. Under diabetic conditions, the human beta cell line EndoC-βH1, db/db mouse and human islets displayed dampened insulin and incretin signalings and reduced beta cell survival, which were alleviated by PAX6 overexpression. Adeno-associated virus (AAV)-mediated PAX6 overexpression in beta cells of streptozotocin-induced diabetic mice and db/db mice led to a sustained maintenance of glucose homeostasis. AAV-PAX6 transduction in human islets reduced islet graft loss and improved glycemic control after transplantation into immunodeficient diabetic mice. Our study highlights a previously unappreciated role for PAX6 in beta cell survival and raises the possibility that ex vivo PAX6 gene transfer into islets prior to transplantation might enhance islet graft function and transplantation outcome.

中文翻译：

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配对盒 6 基因递送可保留 β 细胞并提高胰岛移植功效

胰腺β细胞的丧失是所有形式糖尿病的核心特征。目前的疗法无法阻止β细胞质量的下降。因此，迫切需要保护β细胞的策略。在这项研究中，我们确定配对框 6 (PAX6) 是 β 细胞存活的关键调节因子。在糖尿病条件下，人 β 细胞系 EndoC-βH1、db/db小鼠和人胰岛表现出胰岛素和肠促胰岛素信​​号减弱，β 细胞存活率降低，PAX6 过表达可缓解这种情况。腺相关病毒（AAV）介导的链脲佐菌素诱导的糖尿病小鼠和db/db小鼠的β细胞中PAX6过度表达导致葡萄糖稳态的持续维持。人胰岛中的 AAV-PAX6 转导减少了胰岛移植物的损失，并改善了移植到免疫缺陷糖尿病小鼠后的血糖控制。我们的研究强调了 PAX6 在 β 细胞存活中以前未被认识到的作用，并提出了在移植前将PAX6基因离体转移到胰岛中可能增强胰岛移植物功能和移植结果的可能性。