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^phox. 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.

中文翻译：

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Pdia4调节糖尿病β细胞发病机制：分子机制和靶向治疗

β细胞数量和功能的丧失是糖尿病的标志。β细胞保存正在成为治疗和逆转糖尿病的有前景的策略。在这里，我们首先发现 Pdia4 主要在 β 细胞中表达。响应于过量的营养，这种表达在小鼠的 β 细胞和血液中上调。Pdia4 的消融可减轻糖尿病，表现为糖尿病小鼠的胰岛破坏、血糖和 HbA1c、活性氧 (ROS) 和胰岛素分泌增加。引人注目的是，这种消融单独或与减少食物相结合可以完全逆转糖尿病。相反，Pdia4 的过表达在小鼠中具有相反的病理生理结果。此外，Pdia4 正向调节 β 细胞死亡、功能障碍和 ROS 产生。^火狐。最后，我们发现 Pdia4 抑制剂 2-β-D-吡喃葡萄糖基氧基1-羟基十三烷 (GHTT) 可抑制糖尿病小鼠的糖尿病发展。这些发现将 Pdia4 描述为 β 细胞发病机制和糖尿病的关键调节因子，表明 Pdia4 是糖尿病的新治疗和诊断靶点。