Li Zeting, Pei Ling, Xiao Huangmeng, Chen Nan, Lai Fenghua, Yue Shufang, Xu Changliu, Li Yanbing, Xiao Haipeng, Cao Xiaopei
Department of Endocrinology, Sun Yat-sen University First Affiliated Hospital, Guangzhou, China.
Endocr Connect. 2024 Oct 4;13(11). doi: 10.1530/EC-23-0548. Print 2024 Oct 1.
Glucose-like peptide-1 (GLP-1) is a vital hormone in the intestines that regulates glucose metabolism. Although pancreatic-derived factor (PANDER) overexpression is known to suppress GLP-1, the underlying mechanisms are unclear. Our study aims to uncover how PANDER influences GLP-1 synthesis and secretion. We established a PANDER overexpression model in STC-1 intestinal cells, confirming its inhibitory effect on GLP-1 secretion. This effect was reversed in PANDER-knockout cells. Additionally, a negative correlation between PANDER and GLP-1 was observed in patients with a history of gestational diabetes. Subsequently, through whole transcriptome gene sequencing in PANDER-overexpressed STC-1 cells, we discovered that the activation of IL-6 and its related STAT3 signaling pathway was significantly inhibited, and this finding was validated by Western blotting and quantitative reverse transcription PCR. Finally, rescue experiments confirmed that the IL-6-related STAT3/Akt/GSK3β/β-catenin signaling pathway mediates the negative regulatory effect of PANDER on GLP-1. Taken together, our data identify IL-6 as a bridge connecting PANDER and GLP-1 in the STC-1 cells, demonstrating potential therapeutic targets for diabetes treatment by targeting the PANDER-IL-6-GLP-1 axis.
胰高血糖素样肽-1（GLP-1）是肠道中调节葡萄糖代谢的一种重要激素。尽管已知胰腺衍生因子（PANDER）的过表达会抑制GLP-1，但潜在机制尚不清楚。我们的研究旨在揭示PANDER如何影响GLP-1的合成与分泌。我们在STC-1肠道细胞中建立了PANDER过表达模型，证实了其对GLP-1分泌的抑制作用。在PANDER基因敲除细胞中，这种作用得到了逆转。此外，在有妊娠期糖尿病病史的患者中观察到PANDER与GLP-1之间呈负相关。随后，通过对过表达PANDER的STC-1细胞进行全转录组基因测序，我们发现IL-6及其相关的STAT3信号通路的激活受到显著抑制，这一发现通过蛋白质免疫印迹法和定量逆转录PCR得到了验证。最后，挽救实验证实IL-6相关的STAT3/Akt/GSK3β/β-连环蛋白信号通路介导了PANDER对GLP-1的负调控作用。综上所述，我们的数据确定IL-6是STC-1细胞中连接PANDER和GLP-1的桥梁，表明通过靶向PANDER-IL-6-GLP-1轴为糖尿病治疗提供了潜在的治疗靶点。
