Bioactive peptides PIISVYWK and FSVVPSPK improve glucose homeostasis by targeting DPP-IV and glucose transport in type 2 diabetic mice.

Type 2 Diabetes Mellitus (T2DM) is a metabolic disorder characterized by chronic hyperglycemia, insulin resistance, and progressive β-cell dysfunction, often exacerbated by inflammation and oxidative stress. Effective management requires multi-targeted approaches, including modulation of glucose metabolism, suppression of inflammatory pathways, and pancreatic protection. This study investigates the antidiabetic and immunomodulatory potential of PIISVYWK (P1) and FSVVPSPK (P2), bioactive peptides from blue mussel, Mytilus edulis, in regulating these pathways. In vitro, P1 and P2 were assessed for their ability to inhibit α-glucosidase and DPP-IV activity in Caco-2 cells, alongside glucose uptake and transporter protein expression (SGLT-1 and GLUT2). In vivo, HFD/STZ-induced diabetic mice were administered P1 or P2 (1 mg/kg or 10 mg/kg) or metformin (200 mg/kg) for four weeks. Peptide treatment significantly improved glycemic control by inhibiting α-glucosidase and DPP-IV, increasing GLP-1 levels, and reducing intestinal glucose uptake. Additionally, P1 and P2 exhibited strong anti-inflammatory effects by suppressing NF-κB activation and reducing circulating IL-6, TNF-α, and IL-1β levels. Enhanced antioxidant enzyme activity (SOD, GPx, CAT) further mitigated oxidative stress, preventing pancreatic damage. Peptides also preserved β-cell function by enhancing insulin secretion and regulating glucagon levels. These findings suggest that P1 and P2 peptides exert antidiabetic effects through multi-targeted mechanisms, including immunomodulation, making them promising therapeutic candidates for T2DM management.