The translocon-associated protein-δ (TRAPδ) plays a role in insulin biosynthesis within pancreatic β cells. However, its pathophysiological significance in maintaining islet β cell function and glucose homeostasis remains unclear. In this study, we generated a mouse model featuring pancreatic β cell-specific deletion of TRAPδ (TRAPδ βKO). Our findings revealed that TRAPδ βKO resulted in decreased circulating insulin levels in mice fed either a normal chow diet or a high-fat diet. Multiple independent experiments established that, while TRAPδ deletion reduced insulin content in the islets, it had no discernible effect on insulin gene expression, the insulin/proinsulin ratio, or the expression and glycosylation of the prohormone enzymes involved in proinsulin processing. These data suggest that TRAPδ does not play a pivotal role in the transcription of the insulin gene or proinsulin processing. However, untranslocated preproinsulin levels were significantly increased when islets were treated with a proteasomal inhibitor, suggesting that TRAPδ deficiency may hinder preproinsulin translocation, resulting in a rapid degradation of untranslocated preproinsulin that accounts for the decreased insulin production. Remarkably, despite the moderate decrease in circulating insulin levels in TRAPδ βKO mice, their glucose levels remained unaffected, indicating the presence of compensatory mechanisms that help maintain glucose homeostasis. Insulin tolerance tests further revealed improved insulin sensitivity, accompanied by upregulation of phosphorylated AKT in the peripheral tissues of TRAPδ βKO mice. Collectively, these data highlight the important role of TRAPδ in insulin biosynthesis and β cell function. The moderate reduction in circulating insulin appears to promote insulin sensitivity in insulin target tissues.

中文翻译：

---

胰腺β细胞 TRAPδ 缺乏症会减少胰岛素的产生，但会提高胰岛素敏感性


转位菌相关蛋白δ （TRAPδ） 在胰腺β细胞内的胰岛素生物合成中发挥作用。然而，其在维持胰岛β细胞功能和葡萄糖稳态方面的病理生理意义仍不清楚。在这项研究中，我们生成了一个小鼠模型，其特征是胰腺β细胞特异性 TRAPδ 缺失 （TRAPδ βKO）。我们的研究结果显示，TRAPδ βKO 导致喂食正常食物或高脂肪饮食的小鼠的循环胰岛素水平降低。多项独立实验确定，虽然 TRAPδ 缺失降低了胰岛中的胰岛素含量，但它对胰岛素基因表达、胰岛素/胰岛素原比率或参与胰岛素原加工的激素原酶的表达和糖基化没有明显影响。这些数据表明，TRAPδ 在胰岛素基因转录或胰岛素原加工中不起关键作用。然而，当胰岛用蛋白酶体抑制剂处理时，未易位的胰岛素原水平显着增加，这表明 TRAPδ 缺乏可能阻碍胰岛素原易位，导致未易位的胰岛素原快速降解，这是胰岛素产生减少的原因。值得注意的是，尽管 TRAPδ βKO 小鼠的循环胰岛素水平适度降低，但它们的葡萄糖水平仍然不受影响，表明存在有助于维持葡萄糖稳态的代偿机制。胰岛素耐量试验进一步显示胰岛素敏感性改善，伴随着 TRAPδ βKO 小鼠外周组织中磷酸化 AKT 的上调。总的来说，这些数据强调了 TRAPδ 在胰岛素生物合成和β细胞功能中的重要作用。 循环胰岛素的适度减少似乎促进了胰岛素靶组织中的胰岛素敏感性。