Antidiabetic Effects of Ecklonia cava and Dieckol via DPP-IV Inhibition and Glucose Transport Regulation

Brown seaweeds are recognized for their rich content of phlorotannins with promising antidiabetic properties through multi-targeted modulation of glucose metabolism. This study investigated the antidiabetic potential of the ethyl acetate fraction of Ecklonia cava (EC-ETAC) and its major phlorotannin, dieckol, focusing on inhibition of carbohydrate-digesting enzymes, intestinal glucose absorption, dipeptidyl peptidase-IV (DPP-IV) activity, and hepatic glucose metabolism. EC-ETAC potently inhibited α-glucosidase (IC50 = 2.2 ± 0.2 µg/mL) and α-amylase (IC50 = 41.0 ± 1.2 µg/mL), outperforming acarbose by 26-fold and 6-fold, respectively. Pure dieckol showed strong activity with IC50 values of 2.213 ± 0.04 µM (α-glucosidase) and 156.87 ± 0.124 µM (α-amylase). In differentiated Caco-2 cells, both EC-ETAC and dieckol downregulated SGLT1 and GLUT2 protein expression to ~0.5-fold of control and suppressed 2-NBDG glucose uptake by 46–53% over 120 min, effects not seen with acarbose. Dieckol inhibited DPP-IV activity (IC50 = 12.12 ± 0.021 µM), reducing in situ activity to 53.89% at 25 µM without changing DPP-IV protein levels. Molecular docking revealed high-affinity binding of dieckol to DPP-IV (−10.396 kcal/mol), directly occluding the catalytic triad (Ser630, His740). In insulin-resistant HepG2 cells, dieckol restored glucose uptake to 108.97% of control via AMPK activation (1.21-fold), GLUT2 normalization (0.84-fold), and PGC-1α recalibration (0.96-fold), matching or surpassing 1 mM metformin. These results demonstrate dual-inhibition mechanism combined with hepatic AMPK restoration, establishing dieckol as a promising marine-derived multi-targeted agent for T2DM management.