Geniposide and Gentiopicroside Suppress Hepatic Gluconeogenesis via Regulation of AKT-FOXO1 Pathway

Background. Hepatic gluconeogenesis plays an important role in regulating fasting plasma glucose levels and is a target of anti-diabetic drugs. Several kinds of iridoid glucosides exhibit hypoglycemic effect, whereas the mechanism was not clear. Aim of the study. In this study, the effects of geniposide and gentiopicroside, two natural iridoid glucosides, on hepatic gluconeogenesis were investigated. Methods. Glucose uptake assay, MTT assay, q-PCR, luciferase assay and western blot assay were performed to investigate the pharmacological effect of geniposide and gentiopicroside on human liver cell line L02. Thereby the fast blood glucose and intraperitoneal glucose tolerance were measured in high fat diet induced hyperglycemic mice after geniposide or gentiopicroside administration. Results. The results showed that geniposide and gentiopicroside inhibited the transcription of G6PC and PEPCK in L02 cells and in mice. Additional experimental data indicated that these two compounds were able to inhibit the transcriptional activity of FOXO1 by inducing phosphorylation of AKT at Ser473. Furthermore, we found that these two compounds alleviated high fat diet induced hyperglycemia in mice. Conclusions. Geniposide and gentiopicroside might reduce blood glucose and suppress hepatic gluconeogenesis by regulating the AKT-FOXO1 pathway, and the potential use of these two iridoid glucosides as anti-diabetic agents merits further in-depth exploration. (C) 2018 IMSS. Published by Elsevier Inc.