Two Novel Insulin-Sensitizing Peptides MGPR and AGPAGPR from Miichthys miiuy Fish Maw Alleviate Insulin Resistance Via Regulating the PPARγ-Driven IRS1/PI3K/AKT Signaling Pathway

Insulin resistance (IR) is a core feature of type 2 diabetes mellitus (T2DM). As a traditional dietary supplement for T2DM management, fish maw has a long history in traditional Chinese medicine (TCM). Recent studies support the antidiabetic potential of bioactive peptides derived from fish maw, yet their effects and mechanisms against IR remain elusive. This study combined network pharmacology, molecular docking, molecular dynamics simulations, and experimental validation to explore the anti-IR effects of peptides from Miichthys miiuy fish maw. Results showed that MGPR and AGPAGPR may intact with PPARγ, thereby regulating the IRS-1/PI3K/AKT signaling pathway. They elevated PPARγ transcriptional activity, upregulated PI3K, p-AKT, GLUT4, and p-GSK3β, and downregulated p-IRS-1. In IR-HepG2 cells and diabetic zebrafish, these peptides improved glucose consumption and promoted lipid droplet formation. Thus, MGPR and AGPAGPR may serve as promising natural insulin sensitizers for IR-related glycemic control.