Immunology Programme, The Babraham Institute, Cambridge CB22 3AT, UK.
Department of Medical Cell Biology, Uppsala University, 751 05 Uppsala, Sweden.
Biomolecules. 2022 Oct 16;12(10):1493. doi: 10.3390/biom12101493.
In type 1 diabetes, dysfunctional glucose regulation occurs due to the death of insulin-producing beta-cells in the pancreatic islets. Initiation of this process is caused by the inheritance of an adaptive immune system that is predisposed to responding to beta-cell antigens, most notably to insulin itself, coupled with unknown environmental insults priming the autoimmune reaction. While autoimmunity is a primary driver in beta-cell death, there is growing evidence that cellular stress participates in the loss of beta-cells. In the beta-cell fragility model, partial loss of islet mass requires compensatory upregulation of insulin production in the remaining islets, driving a cellular stress capable of triggering apoptosis in the remaining cells. The Glis3-Manf axis has been identified as being pivotal to the relative fragility or robustness of stressed islets, potentially operating in both type 1 and type 2 diabetes. Here, we have used an AAV-based gene delivery system to enhance the expression of the anti-apoptotic protein Manf in the beta-cells of NOD mice. Gene delivery substantially lowered the rate of diabetes development in treated mice. Manf-treated mice demonstrated minimal insulitis and superior preservation of insulin production. Our results demonstrating the therapeutic potential of Manf delivery to enhance beta-cell robustness and avert clinical diabetes.
在 1 型糖尿病中，由于胰腺胰岛中产生胰岛素的β细胞死亡，导致葡萄糖调节功能障碍。这个过程的启动是由适应性免疫系统的遗传引起的，该免疫系统易对β细胞抗原产生反应，最显著的是对胰岛素本身，再加上未知的环境刺激引发自身免疫反应。虽然自身免疫是β细胞死亡的主要驱动因素，但越来越多的证据表明细胞应激参与了β细胞的丧失。在β细胞脆弱性模型中，胰岛质量的部分丧失需要剩余胰岛中胰岛素产生的代偿性上调，从而引发剩余细胞凋亡的细胞应激。Glis3-Manf 轴被确定为应激胰岛相对脆弱性或稳健性的关键，可能在 1 型和 2 型糖尿病中都起作用。在这里，我们使用基于 AAV 的基因传递系统来增强 NOD 小鼠β细胞中抗凋亡蛋白 Manf 的表达。基因传递显著降低了治疗小鼠糖尿病的发展速度。Manf 治疗的小鼠表现出最小的胰岛炎和胰岛素产生的更好保留。我们的结果表明，Manf 传递具有增强β细胞稳健性和避免临床糖尿病的治疗潜力。
