Unlocking the Role of Chia (Salvia hispanica L.) Seed Phenolic Metabolites in Postprandial Glucose Modulation: in vitro, in vivo, and Antioxidant Evidence Supported by Molecular Docking.

Salvia hispanica L. (chia) seeds are recognized as a functional food rich in phenolic compounds, yet the mechanistic basis linking their chemical profile with antidiabetic activity remains insufficiently defined. To evaluate the antioxidant properties, α-glucosidase inhibition, antihyperglycemic and hypoglycemic responses of chia seed extracts of increasing polarity, and to characterize their major phenolics using UPLC-DAD-ESI-MS and molecular docking. n-hexane, dichloromethane, and methanolic extracts were assessed in normoglycemic Wistar rats using an oral sucrose tolerance test and an acute hypoglycemia model. In vitro inhibition of maltase, sucrase, and starch-degrading enzymes was quantified. Total phenolic content and antioxidant activity were determined by Folin-Ciocalteu, 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid (ABTS) assays. UPLC-DAD-ESI-MS tentatively identified phenolic constituents, and molecular docking was performed against α-glucosidase catalytic domains. The methanolic extract (MESh) exhibited the highest phenolic content and antioxidant activity, a phenolic profile dominated by rosmarinic acid, caffeic acid, and their hexosides, and the strongest antihyperglycemic effect, producing a glycemic curve comparable to acarbose. MESh moderately inhibited sucrase (61.5%), while the dichloromethane extracts moderately inhibited maltase (62.9%). Docking analyses revealed that rosmarinic acid and its hexoside displayed high binding affinities (-7.7 to - 8.1 kcal/mol) toward α-glucosidase targets, closely approaching those of acarbose (-7.9 to - 9.1 kcal/mol) and exceeding those of caffeic-acid derivatives, supporting their potential contribution to the in vitro and in vivo responses. Chia seed extracts exhibit complementary antidiabetic-related activities involving antioxidant effects, modulation of intestinal α-glucosidases, and attenuation of postprandial glycemic excursions. Rosmarinic-acid derivatives emerge as key contributors to these effects. These findings reinforce S. hispanica as a promising functional food for glycemic regulation.