Chen Ke, Zhao Liling, He Honghui, Wan Xinxing, Wang Fang, Mo Zhaohui
Department of Endocrinology, Third Xiangya Hospital of Central South University, Changsha, Hunan 410013, P.R. China.
Int J Mol Med. 2014 Oct;34(4):1073-80. doi: 10.3892/ijmm.2014.1883. Epub 2014 Aug 8.
Exposure to high glucose may cause glucotoxicity, leading to pancreatic β cell dysfunction including cell apoptosis, impaired glucose‑stimulated insulin secretion (GSIS) and intracellular lipid accumulation. Sterol regulatory element binding protein-1c (SREBP-1c), a key nuclear transcription factor that regulates lipid metabolism, has been proven to play a role in insulin secretion. Insulin induced gene-1 (Insig-1) is an upstream regulatory factor of SREBP-1c. The overexpression of Insig-1 significantly inhibits SREBP-1c expression and thereby blocks the expression of downstream genes. It has been proven that silibinin, a natural flavanone, is involved in a variety of biological functions. In the present study, we examined whether silibinin protects high glucose-induced β cell dysfunction through the Insig-1/SREBP-1c pathway. Our data demonstrated that 30.0 µM of silibinin significantly improved cell viability (P<0.05) after rat insulinoma INS-1 cells were exposed to high glucose for 72 h. Silibinin partially attenuated GSIS following exposure to high glucose for either 24 or 72 h (both P<0.05). As shown by reverse transcription quantitative PCR, silibinin upregulated the mRNA expression of insulin secretion‑related genes [insulin receptor substrate 2 (IRS-2), pancreatic and duodenal homeobox 1 (PDX-1) and insulin], but downregulated uncoupling protein‑2 (UCP-2) expression. Silibinin inhibited intracellular lipid accumulation and free fatty acid (FFA) synthesis. Further experiments revealed that silibinin improved β cell function through the regulation of the Insig-1/SREBP-1c pathway. In conclusion, these results clearly suggest that the protection of β cells from glucotoxicity can be significantly enhanced through the regulation of the Insig-1/SREBP-1c pathway. Thus, silibinin may be a novel therapeutic agent for β cell dysfunction.
暴露于高糖环境可能会导致糖毒性，进而引发胰腺β细胞功能障碍，包括细胞凋亡、葡萄糖刺激的胰岛素分泌（GSIS）受损以及细胞内脂质蓄积。固醇调节元件结合蛋白-1c（SREBP-1c）是一种调节脂质代谢的关键核转录因子，已被证实参与胰岛素分泌过程。胰岛素诱导基因-1（Insig-1）是SREBP-1c的上游调节因子。Insig-1的过表达显著抑制SREBP-1c的表达，从而阻断下游基因的表达。已证实水飞蓟宾这种天然黄酮类化合物具有多种生物学功能。在本研究中，我们探究了水飞蓟宾是否通过Insig-1/SREBP-1c途径保护高糖诱导的β细胞功能障碍。我们的数据表明，大鼠胰岛素瘤INS-1细胞在高糖环境中暴露72小时后，30.0 μM的水飞蓟宾显著提高了细胞活力（P<0.05）。在高糖环境中暴露24小时或72小时后，水飞蓟宾均部分减轻了GSIS（P均<0.05）。逆转录定量PCR结果显示，水飞蓟宾上调了胰岛素分泌相关基因[胰岛素受体底物2（IRS-2）、胰腺十二指肠同源盒1（PDX-1）和胰岛素]的mRNA表达，但下调了解偶联蛋白-2（UCP-2）的表达。水飞蓟宾抑制细胞内脂质蓄积和游离脂肪酸（FFA）合成。进一步实验表明，水飞蓟宾通过调节Insig-1/SREBP-1c途径改善β细胞功能。总之，这些结果清楚地表明，通过调节Insig-1/SREBP-1c途径可显著增强对β细胞免受糖毒性的保护作用。因此，水飞蓟宾可能是一种治疗β细胞功能障碍的新型药物。
