Agricultural Biotechnology Research Center, Academia Sinica, Taipei, Taiwan.
Graduate Institute of Life Science, National Defense Medical Center, Taipei, Taiwan.
EMBO Mol Med. 2021 Oct 7;13(10):e11668. doi: 10.15252/emmm.201911668. Epub 2021 Sep 20.
Loss of β-cell number and function is a hallmark of diabetes. β-cell preservation is emerging as a promising strategy to treat and reverse diabetes. Here, we first found that Pdia4 was primarily expressed in β-cells. This expression was up-regulated in β-cells and blood of mice in response to excess nutrients. Ablation of Pdia4 alleviated diabetes as shown by reduced islet destruction, blood glucose and HbA1c, reactive oxygen species (ROS), and increased insulin secretion in diabetic mice. Strikingly, this ablation alone or in combination with food reduction could fully reverse diabetes. Conversely, overexpression of Pdia4 had the opposite pathophysiological outcomes in the mice. In addition, Pdia4 positively regulated β-cell death, dysfunction, and ROS production. Mechanistic studies demonstrated that Pdia4 increased ROS content in β-cells via its action on the pathway of Ndufs3 and p22 . Finally, we found that 2-β-D-glucopyranosyloxy1-hydroxytrideca 5,7,9,11-tetrayne (GHTT), a Pdia4 inhibitor, suppressed diabetic development in diabetic mice. These findings characterize Pdia4 as a crucial regulator of β-cell pathogenesis and diabetes, suggesting Pdia4 is a novel therapeutic and diagnostic target of diabetes.
β 细胞数量和功能的丧失是糖尿病的一个标志。β 细胞的保护正成为治疗和逆转糖尿病的一种有前途的策略。在这里，我们首先发现 Pdia4 主要在 β 细胞中表达。这种表达在响应过量营养时在 β 细胞和小鼠的血液中上调。Pdia4 的缺失减轻了糖尿病，表现为胰岛破坏减少、血糖和 HbA1c 降低、活性氧（ROS）减少和胰岛素分泌增加。令人惊讶的是，这种缺失单独或与减少食物摄入相结合可以完全逆转糖尿病。相反，Pdia4 的过表达在小鼠中产生了相反的病理生理结果。此外，Pdia4 还可促进 β 细胞死亡、功能障碍和 ROS 产生。机制研究表明，Pdia4 通过其对 Ndufs3 和 p22 途径的作用增加了 β 细胞中的 ROS 含量。最后，我们发现 2-β-D-吡喃葡萄糖氧基-1-羟基十三烷 5,7,9,11-四炔（GHTT），一种 Pdia4 抑制剂，可抑制糖尿病小鼠的糖尿病发展。这些发现表明 Pdia4 是 β 细胞发病机制和糖尿病的关键调节因子，提示 Pdia4 是糖尿病的一种新的治疗和诊断靶点。
