高甘油三酯血症性急性胰腺炎（HAP）是严重的急危重性疾病，胰岛素可通过增加脂蛋白脂肪酶活性快速降酯而被推荐用于HAP治疗，但确切机制并未阐明。内质网自噬是自噬研究的新领域，与细胞中其他类型的选择性自噬和细胞凋亡之间关系密切，在多种疾病发生发展中具有重要作用。我们前期研究建立了HAP动物模型，发现胰岛素除可以快速降低甘油三酯外，还可改善胰腺损伤，减轻胰腺局部炎症及相关脏器损伤，而且此过程中腺泡细胞内质网自噬发生了变化。因此我们提出假设：胰岛素促进HAP恢复可能存在更复杂的机制，即通过调节内质网自噬，起到腺泡细胞保护作用，抑制炎症介质释放，改善脏器损伤。本研究拟通过体内外模型，深入研究胰岛素对腺泡细胞的保护作用及其对内质网自噬调控的分子机制。本项目的实施将为HAP的发病机制及防治提供新的证据，有助于深入阐明胰岛素治疗HAP的分子机制，对于提高临床HAP的预防和治疗具有重大意义。

Hypertriglyceridemic acute pancreatitis (HAP) is a serious acute and sometimes fatal disease. Earlier studies showed that insulin could decrease triglycerides by stimulating lipoprotein lipase activity, but the exact mechanism of insulin treatment is still unclear. Endoplasmic reticulophagy (ER-phagy), a new branch of macroautophagy, is closely related to other types of selective autophagy and apoptosis, and plays an important role in the development of various diseases. Based on the established HAP model, we found that insulin treatment not only could quickly reduce triglycerides, but also could protect acinar cells, reduce pancreatic inflammation and related organ damage. ER-phagy also changed in this process. Therefore, we hypothesize that there is a more complex mechanism in insulin treatment, possibly by triggering ER-phagy and resolution of cellular stress, allowing cells to process threats and survive. To further reveal the roles of insulin, we plan to investigate its protection functions on acinar cell in vitro and in vivo models, and identify its target genes and possible molecular mechanism of regulating ER-phagy. The studies of this project may provide new evidences for understanding the pathogenesis of HAP and help to elucidate the molecular mechanism of insulin treatment for HAP, also be helpful to improve the diagnosis and treatment of HAP.