Wang Xing, Long Dongmei, Hu Xianghong, Guo Nan
Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China.
Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry, Nanchong Vocational and Technical College, Nanchong, China.
Front Pharmacol. 2023 Aug 4;14:1172360. doi: 10.3389/fphar.2023.1172360. eCollection 2023.
Gluconeogenesis is closely related to the occurrence and development of type 2 diabetes mellitus (T2DM). Gentiopicroside (GPS) is the main active secoiridoid glycoside in Gentiana manshurica Kitagawa, which can improve chronic complications associated with diabetes and regulate glucose metabolism. However, the effects and potential mechanisms by which GPS affects T2DM understudied and poorly understood. In this study, we systematically explored the pharmacological effects of GPS on T2DM induced by a high-fat diet (HFD) and streptozotocin (STZ) as well as explored its related mechanisms. The results showed that GPS supplementation discernibly decreased blood glucose levels, food intake and water consumption, ameliorated glucose intolerance, abnormal pyruvate tolerance, insulin resistance and dyslipidemia. Furthermore, GPS discernibly ameliorated pathological morphological abnormalities of the liver and pancreas, reduced hepatic steatosis and maintain the balance between α-cells and β-cells in pancreas. Moreover, GPS significantly inhibited gluconeogenesis, as evidenced by the suppressed protein expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase) in the liver. Additionally, the results of Western blot analysis revealed that GPS increased p-PI3K, p-AKT, and p-FOXO1 expression levels, and decreased FOXO1 expression at protein level in the liver. Furthermore, the results of the immunostaining and Western blot analysis demonstrated that GPS supplementation increased the expression of zonula occludens-1 (ZO-1) and occludin in the ileum. Collectively, these results indicate that GPS may inhibit hepatic gluconeogenesis by regulating the PI3K/AKT/FOXO1 signaling pathway and maintain intestinal barrier integrity, and ultimately improve T2DM. Together, these findings indicate that GPS is a potential candidate drug for the prevention and treatment of T2DM, and the results of our study will provide experimental basis for further exploration of the possibility of GPS as a therapeutic agent for T2DM.
糖异生作用与2型糖尿病（T2DM）的发生发展密切相关。龙胆苦苷（GPS）是北龙胆中主要的活性裂环环烯醚萜苷，可改善糖尿病相关的慢性并发症并调节糖代谢。然而，GPS对T2DM的影响及潜在机制尚不清楚且研究较少。在本研究中，我们系统地探究了GPS对高脂饮食（HFD）和链脲佐菌素（STZ）诱导的T2DM的药理作用及其相关机制。结果表明，补充GPS可显著降低血糖水平、食物摄入量和饮水量，改善葡萄糖不耐受、丙酮酸耐量异常、胰岛素抵抗和血脂异常。此外，GPS可明显改善肝脏和胰腺的病理形态异常，减轻肝脏脂肪变性，并维持胰腺中α细胞和β细胞之间的平衡。此外，GPS显著抑制糖异生作用，肝脏中磷酸烯醇式丙酮酸羧激酶（PEPCK）和葡萄糖6磷酸酶（G6Pase）的蛋白表达受到抑制证明了这一点。另外，蛋白质印迹分析结果显示，GPS可增加肝脏中p-PI3K、p-AKT和p-FOXO1的表达水平，并降低FOXO1的蛋白表达水平。此外，免疫染色和蛋白质印迹分析结果表明，补充GPS可增加回肠中紧密连接蛋白1（ZO-1）和闭合蛋白的表达。总体而言，这些结果表明，GPS可能通过调节PI3K/AKT/FOXO1信号通路抑制肝脏糖异生作用并维持肠道屏障完整性，最终改善T2DM。综上所述，这些发现表明GPS是预防和治疗T2DM的潜在候选药物，我们的研究结果将为进一步探索GPS作为T2DM治疗药物的可能性提供实验依据。
