Early-stage antidiabetic potential of hemp seed hull-derived Cannabisins A, B, and F: Integrated computational and experimental evidence for intestinal α-glucosidase inhibition and incretin modulation

Diabetes mellitus is characterized by chronic hyperglycemia and postprandial glucose excursions, highlighting the need for gut-targeted interventions. Here, we identify three hemp-derived phenylpropionamides-Cannabisin A (CA), Cannabisin B (CB), and Cannabisin F (CF)-as novel modulators of intestinal glucose handling. Computational modeling and enzyme kinetics established CA and CF as potent non-competitive α-glucosidase inhibitors, whereas CB displayed weaker uncompetitive inhibition but a unique incretin-enhancing profile. In differentiated Caco-2 monolayers, CA and CF markedly reduced sucrose-derived glucose flux, comparable to acarbose, while CB exerted moderate suppression but selectively augmented active GLP-1 secretion. In vivo oral sucrose tolerance tests (single-dose and 5-day repeated-dosing under sucrose-loading dietary conditions) confirmed that CA and CF lowered postprandial glycemic excursions with acarbose-like efficacy, whereas CB induced delayed yet sustained incretin and insulin responses. Brush-border membrane assays and transporter analyses supported enzyme- and GLUT2/SGLT1-level modulation, with CB additionally downregulating GLUT5. Multivariate clustering (PCA, PLS-DA, MANOVA) separated CA/CF with classical α-GIs from CB as a distinct incretin-dominant subgroup. Integrated ADME and microbial metabolism predictions indicated poor systemic absorption and gut-restricted action. Importantly, fecal SCFA profiling suggested lower gastrointestinal side-effect potential for CB compared with acarbose and CA/CF. Collectively, these findings define CA and CF as potent intestinal α-glucosidase inhibitors and CB as a mechanistically distinct, incretin-enhancing modulator. Hemp phenylpropionamides thus represent promising next-generation agents for safe, intestine-targeted management of postprandial hyperglycemia.