Inhibiting the fibrotic aggregation of the human islet amyloid polypeptide (hIAPP) and accelerating aggregate clearance are crucial factors in type II diabetes regulation. Autophagy plays a central role in hIAPP fibrotic degradation. We investigated how the coix seed prolamin-derived active peptide (LPFYPN, LP6) and its modifying peptides affect hIAPP aggregation and autophagic processes in induced rat insulinoma (INS-1) cells. Both LP6 and its modified peptides inhibited the fibrotic aggregation of hIAPP, an effect related to the binding site within the core region of hIAPP. Additionally, LP6 and the modified peptides reduced hIAPP-induced cytotoxicity, enhanced LC3-II/LC3-I, decreased p62 protein levels, and promoted autophagy by inhibiting the PI3K-Akt-mTOR signaling pathway, thereby upregulating ULK-1 and Beclin-1 expression. Finally, LP6 modified with selenium showed superior inhibition of hIAPP aggregation and cytotoxicity as well as regulation of autophagic flow. These findings emphasize the potential of LP6 and its modified peptides in regulating type II diabetes and other amyloid-related diseases and indicate that they could be further developed as novel functional food ingredients against type 2 diabetes mellitus (T2DM).
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