Hypoglycemic and Hypolipidemic Effects of Triterpenoid Standardized Extract of Agave durangensis Gentry

Diabetes mellitus is a chronic, degenerative, and multifactorial disease characterized by hyperglycemia, and at least 537 million people suffered from diabetes in 2021. <i>Agave durangensis</i> Gentry, a species of agave native to the state of Durango, reports phenolic compounds, flavonols, flavonoids, and saponins and could be an alternative for the treatment of diabetes. The aim of this work was to identify the compounds in the leaves of <i>Agave durangensis</i> Gentry and their potential activity in diabetes. The leaf extract of <i>Agave durangensis</i> Gentry (EAD) was characterized by ultra-performance liquid chromatography-mass spectrometry (UPLC-MS), and different families of bioactive compounds were quantified by analytical methods. Probable pharmacological targets were identified in silico, and the inhibition of dipeptidyl peptidase-4 (DPP4) was validated in vitro. A model of hyperglycemia was established with streptozotocin in male Wistar rats, and we administered EAD intragastrically at a dose of 300 mg/kg, as well as combinations of the extract with metformin and sitagliptin over 30 days. Biochemical and histological parameters were analyzed. We identified thirty-six major compounds, where triterpenes represented 30% of the extract. Molecular docking showed that the extract could interact with α-glucosidases and DPP4 since a large number of compounds in the extract have a Δ G lower than that reported for the controls, and DPP4 inhibition was confirmed by in vitro assays. In vivo assays demonstrated that the administration of the extract was able to significantly decrease glucose levels by 56.75% and glycosylated hemoglobin by 52.28%, which is higher than that reported for sitagliptin with a decrease of 35.22%. In addition, the extract decreased triglycerides by 59.28% and very-low-density lipoprotein (VLDL) cholesterol by 60.27%, and when administered in combination with metformin, it decreased them more than when metformin was administered alone. For all the above reasons, <i>Agave durangensis</i> Gentry extract could be used for the development of phytomedicine for the treatment of diabetes.