Dietary Polyphenols as Multitargeted Modulators of Islet Amyloid Polypeptide Aggregation/Fibrillation and β-Cell Proteotoxicity in Type 2 Diabetes Management

Abstract

Islet amyloid polypeptide (IAPP) is a β-cell peptide hormone, cosecreted with insulin, that critically regulates postprandial glucose metabolism. Under β-cell stress, IAPP self-assembles into toxic amyloid fibrils, resulting in dysfunction, cytotoxicity, and loss of β-cell mass, which typically occurs in the onset of type 2 diabetes. Polyphenols are dietary bioactives with antifibrillation activities across the IAPP aggregation cascade by intercepting nucleation, arresting elongation, stabilizing off-pathway oligomers, and remodelling preformed amyloid fibrils. Polyphenols also modulate downstream toxicity axes including membrane disruption, endoplasmic reticulum stress, and unfolded protein response, thus alleviating mTORC1-driven autophagy/mitophagy impairment and oxidative stress via Nrf2/ARE upregulation. This review evaluates the mechanistic and translational evidence for polyphenols as IAPP-modulating cytoprotective food bioactives. Furthermore, challenges with bioavailability and biostability, the disaggregation paradox, the pharmacokinetic gap between assay and plasma concentration, and species-specific limitations in vivo are discussed as major translational barriers requiring future investigations.