<i>Echeveria subrigida</i> Leaf Extracts Standardized for Isorhamnetin-3-O-Glucoside Show Antidiabetic Effects via the PI3K/Akt Pathway in Rats
Authors: Escobar-Zu&ntilde;iga Yudith , Delgado-Vargas Francisco , L&oacute;pez-Valenzuela Jos&eacute; Angel , Parra-Unda Jes&uacute;s Ricardo , Romero-Quintana Jos&eacute; Geovanni , Loarca-Pi&ntilde;a Guadalupe , D&aacute;vila-Paredes Margarita del Socorro , Pineda-Hidalto Karen Virginia , López-Angulo Gabriela 
Published: February 2025

Background: Treatments for type 2 diabetes mellitus (DM2) are not universally effective, underscoring the need for new therapeutic alternatives. Extracts of Echeveria subrigida have demonstrated potent in vitro activities, such as antioxidant and α-glucosidase inhibitory effects, as well as in vivo activities, including hypoglycemic, antihyperglycemic, immunomodulatory, and adaptogenic effects. Objectives: The present study aimed to investigate the antidiabetic mechanisms of ethanolic (EEEs) and methanolic (MEEs) extracts of E. subrigida, standardized for isorhamnetin-3-O-glucoside (I3G), in streptozotocin (STZ)-induced diabetic rats. Methods: The E. subrigida extracts, EEEs and MEEs, were obtained by maceration and standardized for the content of I3G. The antidiabetic effect was evaluated using STZ-induced diabetic rats, which were randomly allocated to experimental groups (n = 6). Isorhamnetin (ISO) and metformin (MET) treatments served as positive controls. Parameters were measured at least in triplicate, and means were compared using the Fisher test (P < 0.05). The following evaluations were conducted: Levels of monocyte chemoattractant protein-1 (MCP-1), leptin, and inflammatory-related cytokines in serum; expression of proteins in the phosphatidylinositol 3-kinase (PI3K) and adenosine monophosphate-activated protein kinase (AMPK) pathways; transcriptional expression of peroxisome proliferator-activated receptor alpha (PPARα) and sterol regulatory element-binding protein 1c (SREBP-1c) in liver tissue; and histology of the liver and pancreas. Results: All treatments, except ISO, demonstrated antidiabetic effects, with glucose levels in MET (183.75 ± 61.89 mg/dL) and MEEs (168.00 ± 48.10 mg/dL) rats comparable to healthy control (HC) rats (109.25 ± 6.11 mg/dL). Leptin levels decreased in diabetic control (DC) rats (0.17 ± 0.07 ng/mL), while levels in the EEEs (0.65 ± 0.06 ng/mL) and MEEs (0.77 ± 0.09 ng/mL) groups were similar to those of the HC group (0.71 ± 0.19 ng/mL). The levels (pg/mL) of cytokines (IL-10, IL-6, IFN-γ, and IL-4) were elevated in DC rats (72.26 ± 12.91, 36.72 ± 2.91, 4.56 ± 0.63, and 16.34 ± 2.06, respectively), but were effectively reduced in rats treated with EEEs (29.64 ± 2.86, 9.85 ± 2.92, 1.11 ± 0.24, and 6.71 ± 1.15, respectively) and MEEs (26.65 ± 5.31, 7.30 ± 1.89, 1.25 ± 0.28, and 5.55 ± 0.43, respectively). Liver histology showed nearly normal structures, although pancreatic histology revealed hypertrophied Langerhans islets across all DM2 groups. The Akt activation and inactivation of AS160 by phosphorylation were detected in the livers of EEEs and MEEs rats without AMPK activation. Additionally, these groups expressed the SREBP-1c mRNA. Conclusions: The EEEs and MEEs exhibited antidiabetic activity via the PI3K/Akt pathway, suggesting E. subrigida as a potential preventive or therapeutic agent for type 2 diabetes.