Gentiopicroside modulates glucose homeostasis in high-fat-diet and streptozotocin-induced type 2 diabetic mice

Xing Wang; Dongmei Long; Xianghong Hu; Nan Guo

doi:10.3389/fphar.2023.1172360

Gentiopicroside modulates glucose homeostasis in high-fat-diet and streptozotocin-induced type 2 diabetic mice

Front Pharmacol. 2023 Aug 4:14:1172360. doi: 10.3389/fphar.2023.1172360. eCollection 2023.

Authors

Xing Wang¹, Dongmei Long², Xianghong Hu¹, Nan Guo³

Affiliations

¹ Department of Pharmacology, School of Pharmacy, North Sichuan Medical College, Nanchong, China.
² Nanchong Key Laboratory of Disease Prevention, Control and Detection in Livestock and Poultry, Nanchong Vocational and Technical College, Nanchong, China.
³ Department of Pharmacy, Minhang Hospital, Fudan University, Shanghai, China.

Abstract

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.

Keywords: FOxO1; PI3K/akt pathway; gentiopicroside; hepatic gluconeogenesis; type 2 diabetes mellitus.

Grants and funding

The present study was supported by Youth Science Fund of Sichuan Natural Science Foundation (No. 2023NSFSC1676), the Municipal-school Cooperative Scientific Research Project (No. 22SXZRKX0012), the Innovation and Entrepreneurship Training Program for College Students in Sichuan Province (No. 202210634012), the North Sichuan Medical College PhD Research Fund (CBY21-QD16), and the Shanghai Sailing Program (No. 22YF1439800).