Huang Chenghu, Yuan Li, Cao Shuyi
Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, P.R. China.
Int J Mol Med. 2015 Jul;36(1):173-85. doi: 10.3892/ijmm.2015.2207. Epub 2015 May 12.
The number of pro-α cells is known to increase in response to β cell injury and these cells then generate glucagon-like peptide-1 (GLP-1), thus attenuating the development of diabetes. The aim of the present study was to further examine the role and the mechanisms responsible for intra-islet GLP-1 production as a self-protective response against lipotoxicity. The levels of the key enzyme, prohormone convertase 1/3 (PC1/3), as well as the synthesis and release of GLP-1 in models of lipotoxicity were measured. Furthermore, islet viability, apoptosis, oxidative stress and inflammation, as well as islet structure were assessed after altering GLP-1 receptor signaling. Both prolonged exposure to palmitate and a high-fat diet facilitated PC1/3 expression, as well as the synthesis and release of GLP-1 induced by β cell injury and the generation of pro-α cells. Prolonged exposure to palmitate increased reactive oxygen species (ROS) production, and the antioxidant, N-acetylcysteine (NAC), partially prevented the detrimental effects induced by palmitate on β cells, resulting in decreased GLP-1 levels. Furthermore, the inhibition of GLP-1 receptor (GLP-1R) signaling by treatment with exendin‑(9-39) further decreased cell viability, increased cell apoptosis and caused a stronger inhibition of the β cell-specific transcription factor, pancreatic duodenal homeobox 1 (PDX1). Moreover, treatment with the GLP-1R agonist, liraglutide, normalized islet structure and function, resulting in a decrease in cell death and in the amelioration of β cell marker expression. Importantly, liraglutide maintained the oxidative balance and decreased inflammatory factor and p65 expression. Overall, our data demonstrate that an increase in the number of pro-α cells and the activation of the intra-islet GLP-1 system comprise a self-defense mechanism for enhancing β cell survival to combat lipid overload, which is in part mediated by oxidative stress and inflammation.
已知前α细胞的数量会因β细胞损伤而增加，这些细胞随后会生成胰高血糖素样肽-1（GLP-1），从而减轻糖尿病的发展。本研究的目的是进一步研究胰岛内GLP-1产生作为针对脂毒性的自我保护反应的作用及其机制。我们测量了脂毒性模型中关键酶激素原转化酶1/3（PC1/3）的水平以及GLP-1的合成和释放。此外，在改变GLP-1受体信号后，评估了胰岛活力、凋亡、氧化应激和炎症以及胰岛结构。长时间暴露于棕榈酸酯和高脂饮食均促进了PC1/3的表达，以及β细胞损伤诱导的GLP-1的合成和释放以及前α细胞的生成。长时间暴露于棕榈酸酯会增加活性氧（ROS）的产生，抗氧化剂N-乙酰半胱氨酸（NAC）部分预防了棕榈酸酯对β细胞的有害影响，导致GLP-1水平降低。此外，用艾塞那肽-（9-39）处理抑制GLP-1受体（GLP-1R）信号会进一步降低细胞活力，增加细胞凋亡，并对β细胞特异性转录因子胰腺十二指肠同源盒1（PDX1）产生更强的抑制作用。此外，用GLP-1R激动剂利拉鲁肽处理可使胰岛结构和功能正常化，导致细胞死亡减少和β细胞标志物表达改善。重要的是，利拉鲁肽维持了氧化平衡并降低了炎症因子和p65的表达。总体而言，我们的数据表明，前α细胞数量的增加和胰岛内GLP-1系统的激活构成了一种自我防御机制，可增强β细胞存活以对抗脂质过载，这部分是由氧化应激和炎症介导的。
