Multi‐Targeted Anti‐Diabetic Effects of Trifuhalol A From Edible Seaweed via Glycation Inhibition, Glucose Uptake Enhancement and Pancreatic Islet Protection

Trifuhalol A (TFA), a phlorotannin derived from the edible brown seaweed Agarum cribrosum, has been reported to exert diverse physiological activities, yet its anti-diabetic mechanism remains unclear. This study systematically investigates the multi-targeted anti-diabetic effects of TFA, with a particular focus on enhancing glucose uptake and protecting pancreatic islets. In vitro enzyme inhibition assays demonstrated that TFA significantly inhibited the activities of α-glucosidase and α-amylase, indicating its potential to attenuate postprandial glycemic excursions by modulating carbohydrate hydrolysis. Additionally, TFA effectively suppressed the formation of advanced glycation end-products (AGEs), potentially reducing the risk of diabetes-associated complications. Mechanistically, TFA enhanced glucose uptake in C2C12 myotubes by activating the PI3K/Akt and AMPK signaling pathways, which in turn promoted the translocation of glucose transporter type 4 (GLUT4) to the plasma membrane, thereby facilitating cellular glucose utilization and insulin sensitivity. Furthermore, in vivo investigations using an alloxan-induced type 1 diabetic zebrafish further confirmed the bioefficacy of TFA, as evidenced by its capacity to reduce hyperglycemia, alleviate oxidative stress, and protect pancreatic islets, without eliciting observable systemic toxicity. Taken together, these findings provide both mechanistic and functional evidence supporting TFA as a safe and potent multi-target bioactive compound with promising applications in the development of functional foods and therapeutic strategies for diabetes management.