Aim: To investigate the effect and mechanism of glucagon-like peptide-1 receptor agonist (GLP-1 RA) on the function of islet β cells. Methods: Type 2 diabetes C57BL/6J mice were successfully induced by high fat diet (HFD) feeding for 12 weeks then were randomly divided into HFD+NaCl group (n=5) , HFD+Exenatide group (n=5, 24 nmol•kg-1­•d‑1) and NC group (n=5) . Tolerance tests and insulin measurement were performed after 8 weeks of drug therapy. Weight was measured weekly and fasting blood glucose was measured every 4 weeks. The pancreas were stained with LC3B Immunofluorescence at the end of the experiment. The PA induced primary islet β cells were treated with exendin-4 and PA induced Min6 cells were treated with exendin-4, GW501516 for 24h, which BSA as the control group, then detected the protein levels of PPARδ, LC3B-II and P62. At the same time, PA induced MIN6 cells were treated with GSIS. What's more, we silenced PPARδ transfected with siRNA to verify the role of PPARδ in GLP-1 receptor agonist activation of β-cell autophagy. Results: Compared with the normal control group, the body weight and fasting blood glucose increase and significant peripheral insulin resistance in the high fat group, while the above indexes are significantly improved in the high-fat fed mice after GLP-1 RA treatment. Immunofluorescence biopsies of pancreatic tissue show that LC3B expression decrease after high fat diet, while GLP-1 RA intervention significantly increase. In addition, GLP-1 RA not only can promote the expression of PPARδ and LC3B-II protein and inhibit the expression of P62 protein in primary islet β cells and MIN6 cells, but also significantly increase glucose stimulation insulin secretion in MIN6 cells. More importantly, GW501516 is found to be consistent with GLP-1 RA in MIN6 cells, while GLP-1 RA promote autophagy disappeare after PPARδ expression is silenced. Conclusion: GLP-1 RA can improve the function of islet β cells by activating the autophagy pathway through PPARδ. Disclosure Y.Su: None. B.Lin: None. Y.Chen: None. Z.Liu: None. L.Gan: None. W.Xu: None. Funding Science & Technology Project of Guangzhou（202102010175）

中文翻译：

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1518-PUB：PPARd 在使用 GLP-1 受体激动剂改善胰岛 ß 细胞功能中调节自噬途径中的作用

目的：探讨胰高血糖素样肽-1受体激动剂（GLP-1 RA）对胰岛β细胞功能的影响及机制。方法：成功诱导2型糖尿病C57BL/6J小鼠高脂饮食（HFD）喂养12周后随机分为HFD+NaCl组（n=5）、HFD+艾塞那肽组（n=5, 24 nmol• kg-1•d-1) 和 NC 组 (n=5) 。药物治疗 8 周后进行耐受性试验和胰岛素测量。每周测量体重，每 4 周测量空腹血糖。在实验结束时用 LC3B 免疫荧光对胰腺进行染色。用exendin-4处理PA诱导的原代胰岛β细胞，用exendin-4、GW501516处理PA诱导的Min6细胞24h，以BSA为对照组，检测PPARδ、LC3B-II和P62蛋白水平。同时，用 GSIS 处理 PA 诱导的 MIN6 细胞。更重要的是，我们沉默了转染siRNA的PPARδ，以验证PPARδ在GLP-1受体激动剂激活β细胞自噬中的作用。结果：与正常对照组相比，高脂组体重和空腹血糖升高，外周胰岛素抵抗明显，而高脂组小鼠经GLP-1 RA治疗后上述指标均有明显改善。胰腺组织的免疫荧光活检显示，高脂饮食后 LC3B 表达降低，而 GLP-1 RA 干预显着增加。此外，GLP-1 RA不仅能促进原代胰岛β细胞和MIN6细胞中PPARδ和LC3B-II蛋白的表达，抑制P62蛋白的表达，还能显着增加葡萄糖刺激 MIN6 细胞中的胰岛素分泌。更重要的是，发现GW501516与MIN6细胞中的GLP-1 RA一致，而GLP-1 RA在PPARδ表达沉默后促进自噬消失。结论：GLP-1 RA可通过PPARδ激活自噬通路，改善胰岛β细胞功能。披露 Y.Su：没有。B.Lin：没有。Y.Chen：没有。Z.Liu：没有。L.Gan：没有。W.Xu：没有。广州市科技资助项目（202102010175）Y.Chen：没有。Z.Liu：没有。L.Gan：没有。W.Xu：没有。广州市科技资助项目（202102010175）Y.Chen：没有。Z.Liu：没有。L.Gan：没有。W.Xu：没有。广州市科技资助项目（202102010175）